Non-small cell lung cancer, nonsquamous

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 Eric K. Singhi, MD
MD Anderson Cancer Center
Houston, TX, USA
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 Amit Kulkarni, MBBS
University of Minnesota
Minneapolis, MN, USA
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Note: these are regimens tested in histology-specific populations, please see the main NSCLC page for other regimens.

57 regimens on this page
83 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ESMO

NCCN

Perioperative therapy

Carboplatin, Pemetrexed, Durvalumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior EFS (co-primary endpoint)
EFS12: 73.4% vs 64.5%
(sHR 0.68, 95% CI 0.53-0.88)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

28-day cycle for up to 12 cycles

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin, Pemetrexed, Durvalumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior EFS (co-primary endpoint)
EFS12: 73.4% vs 64.5%
(sHR 0.68, 95% CI 0.53-0.88)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

28-day cycle for up to 12 cycles

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin, Pemetrexed, Pembrolizumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wakelee et al. 2023 (KEYNOTE-671) 2018-04 to 2021-12 Phase 3 (E-esc) Cisplatin & Pemetrexed Superior EFS (co-primary endpoint)
EFS24: 62.4% vs 40.6%
(HR 0.58, 95% CI 0.46-0.72)

Note: these dosing instructions are for perioperative therapy.

Neoadjuvant

Chemotherapy

Immunotherapy

21-day cycle for 4 cycles


Definitive

Local therapy


Adjuvant

Immunotherapy

21-day cycle for up to 13 cycles

References

  1. KEYNOTE-671: Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Gao S, Chen KN, Dooms C, Majem M, Eigendorff E, Martinengo GL, Bylicki O, Rodríguez-Abreu D, Chaft JE, Novello S, Yang J, Keller SM, Samkari A, Spicer JD; KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):491-503. Epub 2023 Jun 3. link to original article contains dosing details in supplement PubMed NCT03425643

Neoadjuvant therapy

Carboplatin & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Durvalumab
1b. Cisplatin, Pemetrexed, Durvalumab 		Inferior EFS (co-primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin & Pemetrexed

Regimen variant #1, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Forde et al. 2022 (CheckMate 816) 2017-2019 Phase 3 (C) 1a. CP & Nivolumab
1b. CVb & Nivolumab
1c. DC & Nivolumab
1d. Cisplatin, Pemetrexed, Nivolumab 		Inferior EFS

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

  • CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wakelee et al. 2023 (KEYNOTE-671) 2018-04 to 2021-12 Phase 3 (C) Cisplatin, Pemetrexed, Pembrolizumab Inferior EFS
Heymach et al. 2023 (AEGEAN) 2019-01-02 to 2022-04-19 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Durvalumab
1b. Cisplatin, Pemetrexed, Durvalumab 		Inferior EFS (co-primary endpoint)

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528
  2. KEYNOTE-671: Wakelee H, Liberman M, Kato T, Tsuboi M, Lee SH, Gao S, Chen KN, Dooms C, Majem M, Eigendorff E, Martinengo GL, Bylicki O, Rodríguez-Abreu D, Chaft JE, Novello S, Yang J, Keller SM, Samkari A, Spicer JD; KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Aug 10;389(6):491-503. Epub 2023 Jun 3. link to original article contains dosing details in supplement PubMed NCT03425643
  3. AEGEAN: Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, Ostoros G, Tran TV, You J, Lee KY, Antonuzzo L, Papai-Szekely Z, Akamatsu H, Biswas B, Spira A, Crawford J, Le HT, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M; AEGEAN Investigators. Perioperative Durvalumab for Resectable Non-Small-Cell Lung Cancer. N Engl J Med. 2023 Nov 2;389(18):1672-1684. Epub 2023 Oct 23. link to original article contains dosing details in supplement PubMed NCT03800134

Cisplatin, Pemetrexed, Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Forde et al. 2022 (CheckMate 816) 2017-2019 Phase 3 (E-RT-esc) 1a. CP
1b. CVb
1c. DC
1d. Cisplatin & Pemetrexed 		Superior EFS (co-primary endpoint)
Median EFS: 31.6 vs 20.8 mo
(HR 0.63, 97.38% CI 0.43-0.91)

Superior pCR rate (co-primary endpoint)
pCR rate: 24% vs 2.2%
(OR 13.94, 99% CI 3.49-55.75)

Note: there were additional comparator options depending on histology; see the respective histology-specific pages for more details.

Biomarker eligibility criteria

  • CheckMate 816: No sensitizing EGFR or ALK mutations

Chemotherapy

Immunotherapy

21-day cycle for 3 cycles

Subsequent treatment

References

  1. CheckMate 816: Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Epub 2022 Apr 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02998528

Adjuvant therapy

Cisplatin & Pemetrexed

PemP: Pememetrexed & Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kenmotsu et al. 2020 (JIPANG) 2012-2016 Phase 3 (E-switch-ic) CVb Did not meet primary endpoint of RFS
Median RFS: 38.9 vs 37.3 mo
(HR 0.98, 95% CI 0.81-1.20) 		Fewer grade 3-4 toxicities

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article contains dosing details in manuscript PubMed UMIN000006737
    1. Update: Kenmotsu H, Yamamoto N, Misumi T, Yoh K, Saito H, Sugawara S, Yamazaki K, Nakagawa K, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Takahashi T, Tsuboi M. Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 1;41(34):5242-5246. Epub 2023 Sep 1. link to original article PubMed

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine
NP: Navelbine (Vinorelbine) & Platinol (Cisplatin)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Kenmotsu et al. 2020 (JIPANG) 2012-2016 Phase 3 (C) Cisplatin & Pemetrexed Did not meet primary endpoint of RFS More grade 3-4 toxicities

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. JIPANG: Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T, Goto K, Daga H, Ikeda N, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Tsuboi M. Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Jul 1;38(19):2187-2196. Epub 2020 May 14. link to original article contains dosing details in manuscript PubMed UMIN000006737
    1. Update: Kenmotsu H, Yamamoto N, Misumi T, Yoh K, Saito H, Sugawara S, Yamazaki K, Nakagawa K, Sugio K, Seto T, Toyooka S, Date H, Mitsudomi T, Okamoto I, Yokoi K, Saka H, Okamoto H, Takiguchi Y, Takahashi T, Tsuboi M. Five-Year Overall Survival Analysis of the JIPANG Study: Pemetrexed or Vinorelbine Plus Cisplatin for Resected Stage II-IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 1;41(34):5242-5246. Epub 2023 Sep 1. link to original article PubMed

UFT monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kato et al. 2004 1994-1997 Phase 3 (E-esc) Observation Seems to have superior OS (primary endpoint)
OS60: 88% vs 85%
(HR 0.71, 95% CI 0.52-0.98)

Preceding treatment

Chemotherapy

2-year course

References

  1. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M; Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med. 2004 Apr 22;350(17):1713-21. link to original article contains dosing details in abstract PubMed

Definitive therapy for locally advanced disease

Cisplatin, Etoposide, RT

EP & RT: Etoposide, Platinol (Cisplatin), Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Senan et al. 2016 (PROCLAIM) 2008-2012 Phase 3 (C) Cisplatin, Pemetrexed, RT, then Pemetrexed consolidation Did not meet primary endpoint of OS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 1.8 to 200 cGy fractions x 30 to 33 fractions (total dose: 60 to 6600 cGy)

6- to 6.5-week course

Subsequent treatment

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00686959
    1. Dataset: Project Data Sphere

Consolidation after definitive therapy for inoperable disease

Carboplatin & Paclitaxel (CP)

Regimen

Study Dates of enrollment Evidence
Senan et al. 2016 (PROCLAIM) 2008-2012 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00686959
    1. Dataset: Project Data Sphere

Cisplatin & Etoposide (EP)

Regimen

Study Dates of enrollment Evidence
Senan et al. 2016 (PROCLAIM) 2008-2012 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

28-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00686959
    1. Dataset: Project Data Sphere

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen

Study Dates of enrollment Evidence
Senan et al. 2016 (PROCLAIM) 2008-2012 Non-randomized part of phase 3 RCT

Note: the dose of cisplatin is not specified for this regimen in Senan et al. 2016; 75 mg/m2 is a common dosing for this regimen in other settings.

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. PROCLAIM: Senan S, Brade A, Wang LH, Vansteenkiste J, Dakhil S, Biesma B, Martinez Aguillo M, Aerts J, Govindan R, Rubio-Viqueira B, Lewanski C, Gandara D, Choy H, Mok T, Hossain A, Iscoe N, Treat J, Koustenis A, San Antonio B, Chouaki N, Vokes E. PROCLAIM: randomized phase III trial of pemetrexed-cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016 Mar 20;34(9):953-62. Epub 2016 Jan 25. link to original article contains dosing details in manuscript PubMed NCT00686959
    1. Dataset: Project Data Sphere

Advanced or metastatic disease, first-line

ABCP

ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel

Regimen variant #1, 1200/15/6/175 x 4

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS1 (co-primary endpoint)
Median OS: 19 vs 14.7 mo
(HR 0.84, 95% CI 0.71-1.00)

Superior PFS (co-primary endpoint)
Median PFS: 8.3 vs 6.8 mo
(HR 0.62, 95% CI 0.52-0.74)

1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

21-day cycles


Regimen variant #2, 1200/15/6/175 x 6

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS1 (co-primary endpoint)
Median OS: 19 vs 14.7 mo
(HR 0.84, 95% CI 0.71-1.00)

Superior PFS (co-primary endpoint)
Median PFS: 8.3 vs 6.8 mo
(HR 0.62, 95% CI 0.52-0.74)

1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #3, 1200/15/6/200 x 4

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS1 (co-primary endpoint)
Median OS: 19 vs 14.7 mo
(HR 0.84, 95% CI 0.71-1.00)

Superior PFS (co-primary endpoint)
Median PFS: 8.3 vs 6.8 mo
(HR 0.62, 95% CI 0.52-0.74)

1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

21-day cycles


Regimen variant #4, 1200/15/6/200 x 6

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (E-RT-esc) 1. ACP Not reported
2. BCP Seems to have superior OS1 (co-primary endpoint)
Median OS: 19 vs 14.7 mo
(HR 0.84, 95% CI 0.71-1.00)

Superior PFS (co-primary endpoint)
Median PFS: 8.3 vs 6.8 mo
(HR 0.62, 95% CI 0.52-0.74)

1Reported efficacy is based on the 2021 update.
Note: the total number of cycles given in IMpower150 was determined prior to randomization. This is the FDA-recommended dose for atezolizumab.

Immunotherapy

Targeted therapy

Chemotherapy

21-day cycles

References

  1. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains dosing details in manuscript PubMed NCT02366143
    1. PRO analysis: Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA. Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Aug 1;38(22):2530-2542. Epub 2020 May 27. link to original article link to PMC article PubMed
    2. Update: Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. Epub 2021 Jul 24. link to original article PubMed

Atezolizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (primary endpoint)
Median OS: 20.2 vs 13.1 mo
(HR 0.59, 95% CI 0.40-0.89)

1Reported efficacy is for TC3/IC3 only i.e., PD-L1 TC>50%.

Immunotherapy

21-day cycles

References

  1. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed

Carboplatin & Docetaxel

DCb: Docetaxel & Carboplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) 2007-2009 Phase 3 (C) Carboplatin & Pemetrexed Did not meet primary endpoint of OS Inferior survival without treatment-emergent grade 3/4 toxicity

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains dosing details in abstract PubMed NCT00520676

Carboplatin & Gemcitabine (GCb)

GCb: Gemcitabine & Carboplatin
CG: Carboplatin & Gemcitabine

Regimen

Study Dates of enrollment Evidence
Jian et al. 2017 2011-2014 Non-randomized part of phase 3 RCT

Note: the manuscript does not specify whether gemcitabine is given more than once per cycle.

Chemotherapy

28-day cycle for 2 cycles

Subsequent treatment

References

  1. Jian H, Li W, Ma Z, Huang J, Feng J, Song Y, Gao B, Zhu H, Tao M, Bai C, Ma S, Pan H, Qin S, Hua D, Yu Y, Lu S. Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. Sci Rep. 2017 Aug 16;7(1):8483. link to original article link to PMC article contains dosing details in manuscript PubMed

Carboplatin & nab-Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
West et al. 2019 (IMpower130) 2015-2017 Phase 3 (C) Carboplatin, nab-Paclitaxel, Atezolizumab Seems to have inferior OS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 4 to 6 cycles

References

  1. IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article contains dosing details in abstract PubMed NCT02367781

Carboplatin, nab-Paclitaxel, Atezolizumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
West et al. 2019 (IMpower130) 2015-2017 Phase 3 (E-RT-esc) Carboplatin & nab-Paclitaxel Seems to have superior OS (co-primary endpoint)
Median OS: 18.6 vs 13.9 mo
(HR 0.79, 95% CI 0.64-0.98)

Note: the FDA-recommended dose is specific to the atezolizumab dosing.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMpower130: West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter HJ, Kopp HG, Daniel D, McCune S, Mekhail T, Zer A, Reinmuth N, Sadiq A, Sandler A, Lin W, Ochi Lohmann T, Archer V, Wang L, Kowanetz M, Cappuzzo F. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jul;20(7):924-937. Epub 2019 May 20. link to original article contains dosing details in abstract PubMed NCT02367781

Carboplatin & Paclitaxel (CP)

TC: Taxol (Paclitaxel) & Carboplatin
CP: Carboplatin & Paclitaxel

Regimen variant #1, 5/80

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yadav et al. 2021 NR in abstract Phase 3 (C) Carboplatin & Pemetrexed Did not meet primary endpoint of PFS6

Chemotherapy

28-day cycle for 4 cycles


Regimen variant #2, 6/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2015 (BEYOND) 2011-05-23 to 2012-05-03 Phase 3 (C) CP & Bevacizumab Inferior PFS/OS

Chemotherapy

Supportive therapy

21-day cycle for up to 6 cycles


Regimen variant #3, 6/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sandler et al. 2006 (ECOG E4599) 2001-2004 Phase 3 (C) PacCBev Inferior OS
Mok et al. 2009 (IPASS) 2006-03 to 2007-10 Phase 3 (C) Gefitinib Inferior PFS
Scagliotti et al. 2012 (MONET1) 2007-2010 Phase 3 (C) TC & Motesanib Did not meet primary endpoint of OS
Kubota et al. 2017 (MONET-A) 2012-2015 Phase 3 (C) TC & Motesanib Might have inferior PFS

Chemotherapy

21-day cycle for 3 or more cycles

References

  1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains dosing details in manuscript PubMed NCT00021060
    1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains dosing details in manuscript PubMed
  2. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains dosing details in manuscript PubMed NCT00322452
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
    2. Dataset: Project Data Sphere
  3. MONET1: Scagliotti GV, Vynnychenko I, Park K, Ichinose Y, Kubota K, Blackhall F, Pirker R, Galiulin R, Ciuleanu TE, Sydorenko O, Dediu M, Papai-Szekely Z, Banaclocha NM, McCoy S, Yao B, Hei YJ, Galimi F, Spigel DR. International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1. J Clin Oncol. 2012 Aug 10;30(23):2829-36. Epub 2012 Jul 2. link to original article contains dosing details in abstract PubMed NCT00460317
  4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains dosing details in abstract PubMed NCT01364012
  5. MONET-A: Kubota K, Yoshioka H, Oshita F, Hida T, Yoh K, Hayashi H, Kato T, Kaneda H, Yamada K, Tanaka H, Ichinose Y, Park K, Cho EK, Lee KH, Lin CB, Yang JC, Hara K, Asato T, Nakagawa K. Phase III, randomized, placebo-controlled, double-blind trial of motesanib (AMG-706) in combination with paclitaxel and carboplatin in East Asian patients with advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2017 Nov 10;35(32):3662-3670. Epub 2017 Sep 13. link to original article contains dosing details in manuscript PubMed JapicCTI-121887
  6. Yadav A, Malik PS, Khurana S, Jain D, Vishnubhatla S, Yadav M, Pathy S, Mohan A, Kumar L. An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Oncology. 2021;99(6):389-396. Epub 2021 Mar 18. link to original article contains dosing details in abstract PubMed
  7. M14-359: NCT02264990

Carboplatin & Paclitaxel (CP) & Bevacizumab

PacCBev: Paclitaxel, Carboplatin, Bevacizumab
B+CP: Bevacizumab, Carboplatin, Paclitaxel
BCP: Bevacizumab, Carboplatin, Paclitaxel
CbTB: Carboplatin, Taxol (Paclitaxel), Bevacizumab

Regimen variant #1, 6/175/15 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

Targeted therapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 6/175/15 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

Note: the total number of cycles given was determined prior to randomization; this dose was used for Asian patients.

Chemotherapy

Targeted therapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #3, 6/200/15 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al. 2013 (PointBreak) 2008-2012 Phase 3 (C) PemCBev, then PemBev maint. Did not meet primary endpoint of OS
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase 3 (C) See link See link
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS

Note: the total number of cycles given in IMpower150 was determined prior to randomization.

Chemotherapy

Targeted therapy

Supportive therapy

  • Premedications per paclitaxel label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #4, 6/200/15 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sandler et al. 2006 (ECOG E4599) 2001-2004 Phase 3 (E-RT-esc) CP Superior OS (primary endpoint)
Median OS: 12.3 vs 10.3 mo
(HR 0.79, 95% CI 0.67-0.92)
Zhou et al. 2015 (BEYOND) 2011-05-23 to 2012-05-03 Phase 3 (E-esc) Carboplatin & Paclitaxel Superior PFS (primary endpoint)
Median PFS: 9.2 vs 6.5 mo
(HR 0.40, 95% CI 0.29-0.54)

Superior OS (secondary endpoint)
Median OS: 24.3 vs 17.7 mo
(HR 0.68, 95% CI 0.50-0.93)
Socinski et al. 2018 (IMpower150) 2015-03 to 2016-12 Phase 3 (C) 1. ACP Not reported
2. ABCP Seems to have inferior OS
Sugawara et al. 2021 (TASUKI-52) 2017-2019 Phase 3 (C) CP, Bevacizumab, Nivolumab Inferior PFS

Note: the total number of cycles given in IMpower150 was determined prior to randomization.

Chemotherapy

  • Carboplatin (Paraplatin) as follows:
    • Cycles 1 to 6: AUC 6 IV over 15 to 30 minutes once on day 1, given second, starting 60 minutes after the completion of paclitaxel
  • Paclitaxel (Taxol) as follows:
    • Cycles 1 to 6: 200 mg/m2 IV over 3 hours once on day 1, given first

Targeted therapy

  • Bevacizumab (Avastin) as follows:
    • Cycles 1 to 6: 15 mg/kg IV once on day 1, given third, starting 60 minutes after the completion of carboplatin
      • Infusion time per Johnson, et al. 2004 was over 90 minutes for cycle 1; if tolerated, given over 30 to 60 minutes for cycles 2 and later
    • Cycle 7 onwards: 15 mg/kg IV once on day 1

21-day cycles

References

  1. ECOG E4599: Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article contains dosing details in manuscript PubMed NCT00021060
    1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article contains dosing details in manuscript PubMed
  2. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  3. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00948675
  4. BEYOND: Zhou C, Wu YL, Chen G, Liu X, Zhu Y, Lu S, Feng J, He J, Han B, Wang J, Jiang G, Hu C, Zhang H, Cheng G, Song X, Lu Y, Pan H, Zheng W, Yin AY. BEYOND: a randomized, double-blind, placebo-controlled, multicenter, phase III study of first-line carboplatin/paclitaxel plus bevacizumab or placebo in Chinese patients with advanced or recurrent nonsquamous non-small-cell lung cancer. J Clin Oncol. 2015 Jul 1;33(19):2197-204. Epub 2015 May 26. link to original article contains dosing details in abstract PubMed NCT01364012
  5. IMpower150: Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. Epub 2018 Jun 4. link to original article contains dosing details in manuscript PubMed NCT02366143
    1. PRO analysis: Reck M, Wehler T, Orlandi F, Nogami N, Barone C, Moro-Sibilot D, Shtivelband M, González Larriba JL, Rothenstein J, Früh M, Yu W, Deng Y, Coleman S, Shankar G, Patel H, Kelsch C, Lee A, Piault E, Socinski MA. Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 Aug 1;38(22):2530-2542. Epub 2020 May 27. link to original article link to PMC article PubMed
    2. Update: Socinski MA, Nishio M, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodríguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kong S, Lee A, Coleman S, Zou W, McCleland M, Shankar G, Reck M. IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC. J Thorac Oncol. 2021 Nov;16(11):1909-1924. Epub 2021 Jul 24. link to original article PubMed
  6. TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article contains dosing details in manuscript PubMed NCT03117049

Carboplatin & Paclitaxel (CP), Bevacizumab, Nivolumab


Regimen variant #4, 6/200/15 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sugawara et al. 2021 (TASUKI-52) 2017-2019 Phase 3 (E-esc) CP & Bevacizumab Superior PFS (primary endpoint)
Median PFS: 12.1 vs 8.1 mo
(HR 0.56, 96.4% CI 0.43-0.71)

Chemotherapy

Targeted therapy

Immunotherapy

21-day cycles

References

  1. TASUKI-52: Sugawara S, Lee JS, Kang JH, Kim HR, Inui N, Hida T, Lee KH, Yoshida T, Tanaka H, Yang CT, Nishio M, Ohe Y, Tamura T, Yamamoto N, Yu CJ, Akamatsu H, Namba Y, Sumiyoshi N, Nakagawa K. Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer. Ann Oncol. 2021 Sep;32(9):1137-1147. Epub 2021 Jun 15. link to original article contains dosing details in manuscript PubMed NCT03117049

Carboplatin & Pemetrexed

CP: Carboplatin & Pemetrexed
Carbo-Pem: Carboplatin & Pemetrexed

Example orders

Regimen variant #1, 5/500 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Langer et al. 2016 (KEYNOTE-021) 2014-2016 Randomized Phase 2 (C) See link See link
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab 		Inferior OS
Yadav et al. 2021 NR in abstract Phase 3 (E-switch-ic) CP Did not meet primary endpoint of PFS6

Chemotherapy

Supportive therapy

  • (Ardizzoni et al. 2012 contained more details):
  • Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
  • Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Subsequent treatment


Regimen variant #2, 5/500 x 4, then maintenance pem x 2y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 2018-08-23 to 2019-07-30 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Sintilimab
1b. Cisplatin, Pemetrexed, Sintilimab 		Inferior PFS
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (C) Investigator's choice of:
1a. CP & Cemiplimab
1b. Cisplatin, Paclitaxel, Cemiplimab
1c. Carboplatin, Pemetrexed, Cemiplimab
1d. Cisplatin, Pemetrexed, Cemiplimab 		Inferior OS

Chemotherapy

21-day cycle for up to 36 cycles (2 years)


Regimen variant #3, 5/500 x 4, then indefinite maintenance pem

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189) 2016-02-26 to 2017-03-06 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Pembrolizumab
1b. Cisplatin, Pemetrexed, Pembrolizumab 		Inferior OS
Zhou et al. 2022 (GEMSTONE-302) 2018-2020 Phase 3 (C) Carboplatin, Pemetrexed, Sugemalimab Inferior PFS

Chemotherapy

Supportive therapy

  • (Ardizzoni et al. 2012 contained more details):
  • Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
  • Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycles


Regimen variant #4, 5/500 x 4-6, then indefinite maintenance pem

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2020 (CameL) 2017-05-12 to 2018-06-06 Phase 3 (C) Carboplatin, Pemetrexed, Camrelizumab Inferior PFS
Lu et al. 2021 (RATIONALE 304) 2018-07-23 to 2019-07-31 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Tislelizumab
1b. Cisplatin, Pemetrexed, Tislelizumab 		Inferior PFS
Wang et al. 2023 (CHOICE-01) 2019-04-02 to 2020-08-05 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Toripalimab
1b. Cisplatin, Pemetrexed, Toripalimab 		Inferior OS

Chemotherapy

21-day cycles


Regimen variant #5, 5/500 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rodrigues-Pereira et al. 2011 (H3E-CR-S380) 2007-2009 Phase 3 (E-switch-ic) Carboplatin & Docetaxel Did not meet primary endpoint of OS Superior survival without treatment-emergent grade 3/4 toxicity
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase 3 (C) Pembrolizumab Inferior OS

Note: Patients in KEYNOTE-042 receiving this treatment had nonsquamous NSCLC.

Chemotherapy

Supportive therapy

  • (Ardizzoni et al. 2012 contained more details):
  • Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
  • Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy.
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for up to 6 cycles

Subsequent treatment


Regimen variant #6, 6/500 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase 3 (E-switch-ooc) See link See link
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab 		Inferior OS

Chemotherapy

Supportive therapy

  • (Ardizzoni et al. 2012 contained more details):
  • Dexamethasone (Decadron) 4 mg or equivalent corticosteroid PO twice per day on the day before, the day of, and day after each dose of pemetrexed
  • Folic acid (Folate) 350 to 600 mcg PO once per day, starting 1 to 2 weeks before the first dose of pemetrexed, to be taken throughout pemetrexed therapy
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM once every 9 weeks, first dose 1 to 2 weeks before the first dose of pemetrexed, to be given throughout pemetrexed therapy

21-day cycle for up to 4 cycles

Subsequent treatment

  • Pemetrexed maintenance (optional in CheckMate 9LA)


Regimen variant #7, 6/500 x 4, then maintenance pem x 2y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (C) Investigator's choice of:
1a. CP & Cemiplimab
1b. Cisplatin, Paclitaxel, Cemiplimab
1c. Carboplatin, Pemetrexed, Cemiplimab
1d. Cisplatin, Pemetrexed, Cemiplimab 		Inferior OS

Chemotherapy

21-day cycle for up to 36 cycles (2 years)


Regimen variant #8, 6/500 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2019 (KEYNOTE-042) 2014-2017 Phase 3 (C) Pembrolizumab Inferior OS
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (C) Atezolizumab Inferior OS1

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.

Chemotherapy

Supportive therapy

21-day cycle for up to 6 cycles

Subsequent treatment


Regimen variant #9, 6/500 indefinitely

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Edelman et al. 2017 (CALGB 30801) 2010-2013 Phase 3 (C) CP & Celecoxib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. H3E-CR-S380: Rodrigues-Pereira J, Kim JH, Magallanes M, Lee DH, Wang J, Ganju V, Martínez-Barrera L, Barraclough H, van Kooten M, Orlando M. A randomized phase 3 trial comparing pemetrexed/carboplatin and docetaxel/carboplatin as first-line treatment for advanced, nonsquamous non-small cell lung cancer. J Thorac Oncol. 2011 Nov;6(11):1907-14. link to original article contains dosing details in abstract PubMed NCT00520676
  2. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00948675
  3. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02039674
  4. CALGB 30801: Edelman MJ, Wang X, Hodgson L, Cheney RT, Baggstrom MQ, Thomas SP, Gajra A, Bertino E, Reckamp KL, Molina J, Schiller JH, Mitchell-Richards K, Friedman PN, Ritter J, Milne G, Hahn OM, Stinchcombe TE, Vokes EE; Alliance for Clinical Trials in Oncology. Phase III randomized, placebo-controlled, double-blind trial of celecoxib in addition to standard chemotherapy for advanced non-small-cell lung cancer with cyclooxygenase-2 overexpression: CALGB 30801 (Alliance). J Clin Oncol. 2017 Jul 1;35(19):2184-2192. Epub 2017 May 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01041781
  5. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains dosing details in manuscript PubMed NCT02578680
    1. PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article PubMed
    2. Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
    3. Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
    4. Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article PubMed
  6. KEYNOTE-042: Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019 May 4;393(10183):1819-1830. Epub 2019 Apr 4. link to original article PubMed NCT02220894
    1. Update: de Castro G Jr, Kudaba I, Wu YL, Lopes G, Kowalski DM, Turna HZ, Caglevic C, Zhang L, Karaszewska B, Laktionov KK, Srimuninnimit V, Bondarenko I, Kubota K, Mukherjee R, Lin J, Souza F, Mok TSK, Cho BC. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy as First-Line Therapy in Patients With Non-Small-Cell Lung Cancer and Programmed Death Ligand-1 Tumor Proportion Score ≥ 1% in the KEYNOTE-042 Study. J Clin Oncol. 2023 Apr 10;41(11):1986-1991. Epub 2022 Oct 28. link to original article link to PMC article PubMed
  7. MYSTIC: Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. link to original article contains dosing details in supplement link to PMC article PubMed NCT02453282
  8. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed
  9. ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article contains dosing details in manuscript PubMed NCT03607539
  10. IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article PubMed NCT02657434
  11. CameL: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Zhang T, Shi W, Zou J; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021 Mar;9(3):305-314. Epub 2020 Dec 18. link to original article contains dosing details in abstract PubMed NCT03134872
    1. Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Tai Y, Ma X, Shi W; CameL Study Group. Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial. J Thorac Oncol. 2023 May;18(5):628-639. Epub 2023 Jan 13. link to original article PubMed
  12. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed
  13. Yadav A, Malik PS, Khurana S, Jain D, Vishnubhatla S, Yadav M, Pathy S, Mohan A, Kumar L. An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. Oncology. 2021;99(6):389-396. Epub 2021 Mar 18. link to original article contains dosing details in abstract PubMed
  14. RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article contains dosing details in manuscript PubMed NCT03663205
    1. HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article PubMed
  15. GEMSTONE-302: Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R, Yu Y, Yao W, Chang J, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Wang J, Li P, Qin M, Lu D, Yang J. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022 Feb;23(2):220-233. Epub 2022 Jan 14. link to original article contains dosing details in abstract PubMed NCT03789604
    1. Update: Zhou C, Wang Z, Sun M, Cao L, Ma Z, Wu R, Yu Y, Yao W, Sun S, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Hu C, Liu J, Liu Y, Wang M, Li X, Sun P, Shu Y, Zhou J, Li J, Gu K, Wang C, Zhao H, Zhang Y, Liu C, Wang J, Chen R, Qin M, Wang H, Yang J. Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC. Nat Cancer. 2023 Jun;4(6):860-871. Epub 2023 Jun 15. link to original article PubMed
  16. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
    1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed
  17. CHOICE-01: Wang Z, Wu L, Li B, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Tang X, Yu J, Maher E, Feng H, Yao S, Keegan P, Wang J. Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01). J Clin Oncol. 2023 Jan 20;41(3):651-663. Epub 2022 Oct 7. link to original article link to PMC article PubMed NCT03856411
  18. B-FAST: NCT03178552
  19. M14-359: NCT02264990

Carboplatin, Pemetrexed, Atezolizumab

APP: Atezolizumab, Platinum (Carboplatin), Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nishio et al. 2020 (IMpower132) 2016-04-07 to 2017-05-31 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS1 (co-primary endpoint)
Median PFS: 8 vs 5 mo
(HR 0.60, 95% CI 0.49-0.72)

1IMpower132 did not meet the co-primary endpoint of OS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article contains dosing details in manuscript PubMed NCT02657434
  2. APPLE: JapicCTI-194565

Carboplatin, Pemetrexed, Bevacizumab

PemCBev: Pemetrexed, Carboplatin, Bevacizumab
BevCPem: Bevacizumab, Carboplatin, Pemetrexed

Regimen variant #1, 5/500/7.5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schuette et al. 2017 (65Plus) 2009-NR Phase 3 (C) Pemetrexed & Bevacizumab Inconclusive whether non-inferior PFS

Chemotherapy

Targeted therapy

21-day cycle for 4 to 6 cycles

Subsequent treatment


Regimen variant #2, 6/500/15

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al. 2013 (PointBreak) 2008-2012 Phase 3 (E-switch-ic) PacCBev, then Bev maintenance Did not meet primary endpoint of OS
Seto et al. 2019 (COMPASS) 2010-2015 Non-randomized part of phase 3 RCT

Chemotherapy

Targeted therapy

Supportive therapy

  • Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycle for 4 cycles

Subsequent treatment

References

  1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  2. 65Plus: Schuette W, Schneider CP, Engel-Riedel W, Schumann C, Kohlhaeufl M, Serke MHU, Hoeffken G, Kortsik C, Reck M. 65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer. Lung Cancer (Auckl). 2017 Nov 6;8:217-229. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00976456
  3. COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains dosing details in abstract PubMed UMIN000004194

Carboplatin, Pemetrexed, Camrelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2020 (CameL) 2017-05-12 to 2018-06-06 Phase 3 (E-esc) Carboplatin & Pemetrexed Superior PFS (co-primary endpoint)
Median PFS: 11.3 vs 8.3 mo
(HR 0.60, 95% CI 0.45-0.79)

Superior OS1 (secondary endpoint)
Median OS: 27.1 vs 19.8 mo
(HR 0.72, 95% CI 0.57-0.92)

1Reported efficacy is based on the 2023 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CameL: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Zhang T, Shi W, Zou J; CameL Study Group. Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial. Lancet Respir Med. 2021 Mar;9(3):305-314. Epub 2020 Dec 18. link to original article contains dosing details in abstract PubMed NCT03134872
    1. Update: Zhou C, Chen G, Huang Y, Zhou J, Lin L, Feng J, Wang Z, Shu Y, Shi J, Hu Y, Wang Q, Cheng Y, Wu F, Chen J, Lin X, Wang Y, Huang J, Cui J, Cao L, Liu Y, Zhang Y, Pan Y, Zhao J, Wang L, Chang J, Chen Q, Ren X, Zhang W, Fan Y, He Z, Fang J, Gu K, Dong X, Jin F, Gao H, An G, Ding C, Jiang X, Xiong J, Zhou X, Hu S, Lu P, Liu A, Guo S, Huang J, Zhu C, Zhao J, Gao B, Chen Y, Hu C, Zhang J, Zhang H, Zhao H, Tai Y, Ma X, Shi W; CameL Study Group. Camrelizumab Plus Carboplatin and Pemetrexed as First-Line Treatment for Advanced Nonsquamous NSCLC: Extended Follow-Up of CameL Phase 3 Trial. J Thorac Oncol. 2023 May;18(5):628-639. Epub 2023 Jan 13. link to original article PubMed

Carboplatin, Pemetrexed, Cemiplimab

Regimen variant #1, 5/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (E-RT-esc) Investigator's choice of:
1a. CP
1b. Cisplatin & Paclitaxel
1c. Carboplatin & Pemetrexed
1d. Cisplatin & Pemetrexed 		Superior OS (primary endpoint)
Median OS: 21.9 vs 13 mo
(HR 0.71, 95% CI 0.53-0.93)

Chemotherapy

Immunotherapy

21-day cycle for up to 36 cycles (2 years)


Regimen variant #2, 6/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (E-RT-esc) Investigator's choice of:
1a. CP
1b. Cisplatin & Paclitaxel
1c. Carboplatin & Pemetrexed
1d. Cisplatin & Pemetrexed 		Superior OS (primary endpoint)
Median OS: 21.9 vs 13 mo
(HR 0.71, 95% CI 0.53-0.93)

Chemotherapy

Immunotherapy

21-day cycle for up to 36 cycles (2 years)

References

  1. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
    1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed

Carboplatin, Pemetrexed, Ipilimumab, Nivolumab

Regimen variant #1, AUC 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (primary endpoint)
Median OS: 15.8 vs 11 mo
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

21-day cycles


Regimen variant #2, AUC 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (primary endpoint)
Median OS: 15.8 vs 11 mo
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed

Carboplatin, Pemetrexed, Pembrolizumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Langer et al. 2016 (KEYNOTE-021) 2014-2016 Randomized Phase 2 (E-esc) Carboplatin & Pemetrexed Superior ORR (primary endpoint)
Gandhi et al. 2018 (KEYNOTE-189) 2016-02-26 to 2017-03-06 Phase 3 (E-RT-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (co-primary endpoint)
Median OS: 22 vs 10.6 mo
(HR 0.56, 95% CI 0.46-0.69)

Superior PFS (co-primary endpoint)
Median PFS: 8.8 vs 4.9 mo
(HR 0.52, 95% CI 0.43-0.64)
Tan et al. 2023 (CANOPY-1) 2019-06-25 to 2020-01-17 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Canakinumab, Pembrolizumab
1b. Cisplatin, Pemetrexed, Canakinumab, Pembrolizumab 		Did not meet co-primary endpoints of PFS/OS
Awaiting publication (TROPION-Lung07) 2023-ongoing Phase 3 (C) 1. Datopotamab-DXd & Pembrolizumab
2a. Carboplatin, Pemeterexed, Datopotamab-DXd, Pembrolizumab
2b. Cisplatin, Pemeterexed, Datopotamab-DXd, Pembrolizumab 		TBD if different co-primary endpoints of PFS/OS

1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

Immunotherapy

  • Pembrolizumab (Keytruda) as follows:
    • Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy

Supportive therapy

21-day cycles

References

  1. KEYNOTE-021: Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article contains dosing details in manuscript supplementary appendix link to PMC article PubMed NCT02039674
  2. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains dosing details in manuscript PubMed NCT02578680
    1. PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article PubMed
    2. Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
    3. Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
    4. Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article PubMed
  3. CANOPY-1: Tan DSW, Felip E, de Castro G, Solomon BJ, Greystoke A, Cho BC, Cobo M, Kim TM, Ganguly S, Carcereny E, Paz-Ares L, Bennouna J, Garassino MC, Schenker M, Kim SW, Brase JC, Bury-Maynard D, Passos VQ, Deudon S, Dharan B, Song Y, Caparica R, Johnson BE. Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial. J Clin Oncol. 2024 Jan 10;42(2):192-204. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03631199
  4. KEYLYNK-006: NCT03976323
  5. KEYVIBE-007: NCT05226598
  6. TROPION-Lung07: NCT05555732

Carboplatin, Pemetrexed, Sintilimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 2018-08-23 to 2019-07-30 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS (primary endpoint)
Median PFS: 8.9 vs 5 mo
(HR 0.48, 95% CI 0.36-0.64)

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article contains dosing details in manuscript PubMed NCT03607539

Carboplatin, Pemetrexed, Sugemalimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhou et al. 2022 (GEMSTONE-302) 2018-2020 Phase 3 (E-esc) Carboplatin & Pemetrexed Superior OS1 (secondary endpoint)
Median OS: 25.4 vs 16.9 mo
(HR 0.65, 95% CI 0.50-0.84)

Superior PFS (primary endpoint)
Median PFS: 9 vs 4.9 mo
(HR 0.48, 95% CI 0.39-0.60)

1Reported efficacy is based on 2023 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. GEMSTONE-302: Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R, Yu Y, Yao W, Chang J, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Wang J, Li P, Qin M, Lu D, Yang J. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022 Feb;23(2):220-233. Epub 2022 Jan 14. link to original article contains dosing details in abstract PubMed NCT03789604
    1. Update: Zhou C, Wang Z, Sun M, Cao L, Ma Z, Wu R, Yu Y, Yao W, Sun S, Chen J, Zhuang W, Cui J, Chen X, Lu Y, Shen H, Hu C, Liu J, Liu Y, Wang M, Li X, Sun P, Shu Y, Zhou J, Li J, Gu K, Wang C, Zhao H, Zhang Y, Liu C, Wang J, Chen R, Qin M, Wang H, Yang J. Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC. Nat Cancer. 2023 Jun;4(6):860-871. Epub 2023 Jun 15. link to original article PubMed

Carboplatin, Pemetrexed, Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2021 (RATIONALE 304) 2018-07-23 to 2019-07-31 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS (primary endpoint)
Median PFS: 9.7 vs 7.6 mo
(HR 0.645, 95% CI 0.46-0.90)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article contains dosing details in manuscript PubMed NCT03663205
    1. HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article PubMed

Cisplatin & Docetaxel (DC)

DC: Docetaxel & Cisplatin
DP: Docetaxel & Platinol (Cisplatin)
Doc-Cis: Docetaxel & Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Park et al. 2017 (TRAIL) 2011-2013 Phase 3 (C) Cisplatin & Pemetrexed Inconclusive whether non-inferior PFS

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains dosing details in abstract PubMed NCT01282151

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

Regimen variant #1, 75/1250

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2012 (NExUS) 2007-2009 Phase 3 (C) GC & Sorafenib Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, 80/1250 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-02 to 2006-08 Phase 3 (C) 1. GC & Bevacizumab; low-dose Inferior PFS
2. GC & Bevacizumab; standard-dose Seems to have inferior PFS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #3, 80/1250 x 9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Han et al. 2012 (First-SIGNAL) 2005-2007 Phase 3 (C) Gefitinib Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 9 cycles

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains dosing details in abstract PubMed NCT00806923
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed
  2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains dosing details in abstract PubMed NCT00455936
  3. NExUS: Paz-Ares LG, Biesma B, Heigener D, von Pawel J, Eisen T, Bennouna J, Zhang L, Liao M, Sun Y, Gans S, Syrigos K, Lemarie E, Gottfried M, Vansteenkiste J, Alberola V, Strauss UP, Montegriffo E, Ong TJ, Santoro A; NSCLC [non–small-cell lung cancer] Research Experience Utilizing Sorafenib (NExUS) Investigators Study Group. Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol. 2012 Sep 1;30(25):3084-92. Epub 2012 Jul 30. link to original article contains dosing details in abstract PubMed NCT00449033
    1. Dataset: Project Data Sphere

Cisplatin & Gemcitabine (GC) & Bevacizumab

Regimen variant #1, low-dose bev

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-02 to 2006-08 Phase 3 (E-RT-esc) 1. Cisplatin & Gemcitabine Superior PFS1 (primary endpoint)
(HR 0.75, 95% CI 0.64-0.87)
2. GC & Bevacizumab; standard-dose Not reported

1Reported efficacy is based on the 2010 update.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, standard-dose bev

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Reck et al. 2009 (AVAil) 2005-02 to 2006-08 Phase 3 (E-RT-esc) 1. Cisplatin & Gemcitabine Seems to have superior PFS1 (primary endpoint)
(HR 0.85, 95% CI 0.73-1.00)
2. GC & Bevacizumab; low-dose Not reported

1Reported efficacy is based on the 2010 update.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. AVAil: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Epub 2009 Feb 2. Erratum in: J Clin Oncol. 2009 May 10;27(14):2415. link to original article contains dosing details in manuscript PubMed NCT00806923
    1. Update: Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C; BO17704 Study Group. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010 Sep;21(9):1804-9. Epub 2010 Feb 11. link to original article link to PMC article PubMed

Cisplatin & Pemetrexed

Pem-Cis: Pemetrexed & Cisplatin
Cis-Pem: Cisplatin & Pemetrexed

Regimen variant #1, 70/500 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Park et al. 2017 (TRAIL) 2011-2013 Phase 3 (E-switch-ic) Cisplatin & Docetaxel Inconclusive whether non-inferior PFS (primary endpoint)

Chemotherapy

21-day cycle for up to 4 cycles


Regimen variant #2, 75/500 x 4-6

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Paz-Ares et al. 2012 (PARAMOUNT) 2008-2010 Non-randomized part of phase 3 RCT
Wu et al. 2014 (JMIL) 2009-11 to 2010-10 Phase 3 (C) GC Did not meet primary endpoint of OS
Paz-Ares et al. 2015 (INSPIRE) 2009-2011 Phase 3 (C) Pem-Cis & Necitumumab Did not meet primary endpoint of OS
Reck et al. 2016 (KEYNOTE-024) 2014-09-19 to 2015-10-29 Phase 3 (C) Pembrolizumab Inferior OS Inferior HRQoL
Rizvi et al. 2020 (MYSTIC) 2015-07-21 to 2016-06-08 Phase 3 (C) 1. Durvalumab Might have inferior OS
2. Durvalumab & Tremelimumab Did not meet co-primary endpoints of PFS/OS
Herbst et al. 2020 (IMpower110) 2015-2018 Phase 3 (C) Atezolizumab Inferior OS1
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Ipilimumab, Nivolumab
1b. Cisplatin, Pemetrexed, Ipilimumab, Nivolumab 		Inferior OS
Lu et al. 2021 (RATIONALE 304) 2018-07-23 to 2019-07-31 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Tislelizumab
1b. Cisplatin, Pemetrexed, Tislelizumab 		Inferior PFS Inferior HRQoL

1Reported efficacy for IMpower110 is for TC3/IC3 only i.e., PD-L1 TC>50%.
Note: Selection of platinum agent in IMpower110, KEYNOTE-189, and MYSTIC was per investigator choice.

Chemotherapy

Supportive therapy

21-day cycle for 4 to 6 cycles

Subsequent treatment


Regimen variant #3, 75/500 x 4, then maintenance pem x 2y

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 2018-08-23 to 2019-07-30 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Sintilimab
1b. Cisplatin, Pemetrexed, Sintilimab 		Inferior PFS
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (C) Investigator's choice of:
1a. CP & Cemiplimab
1b. Cisplatin, Paclitaxel, Cemiplimab
1c. Carboplatin, Pemetrexed, Cemiplimab
1d. Cisplatin, Pemetrexed, Cemiplimab 		Inferior OS

Chemotherapy

21-day cycle for up to 35 cycles (2 years)


Regimen variant #4, 75/500 x 4, then indefinite maintenance pem

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189) 2016-02-26 to 2017-03-06 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Pembrolizumab
1b. Cisplatin, Pemetrexed, Pembrolizumab 		Inferior OS
Wang et al. 2023 (CHOICE-01) 2019-04-02 to 2020-08-05 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Toripalimab
1b. Cisplatin, Pemetrexed, Toripalimab 		Inferior OS

Note: Selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

Supportive therapy

21-day cycles

References

  1. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00789373
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
  2. JMIL: Wu YL, Lu S, Cheng Y, Zhou C, Wang M, Qin S, Lu Y, Zhang Y, Zhu Y, Song X, Wang X, Barraclough H, Zhang X, Chi H, Orlando M. Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer. Lung Cancer. 2014 Sep;85(3):401-7. Epub 2014 Jul 17. link to original article PubMed NCT01005680
  3. INSPIRE: Paz-Ares L, Mezger J, Ciuleanu TE, Fischer JR, von Pawel J, Provencio M, Kazarnowicz A, Losonczy G, de Castro G Jr, Szczesna A, Crino L, Reck M, Ramlau R, Ulsperger E, Schumann C, Miziara JE, Lessa ÁE, Dediu M, Bálint B, Depenbrock H, Soldatenkova V, Kurek R, Hirsch FR, Thatcher N, Socinski MA; INSPIRE investigators. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncol. 2015 Mar;16(3):328-37. Epub 2015 Feb 18. link to original article PubMed NCT00982111
  4. KEYNOTE-024: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Epub 2016 Oct 8. link to original article link to supplementary appendix contains dosing details in manuscript PubMed NCT02142738
    1. HRQoL analysis: Brahmer JR, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Zhang J, Lubiniecki GM, Deitz AC, Rangwala R, Reck M. Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1600-1609. Epub 2017 Nov 9. link to original article PubMed
    2. Update: Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol. 2019 Mar 1;37(7):537-546. Epub 2019 Jan 8. link to original article PubMed
  5. TRAIL: Park CK, Oh IJ, Kim KS, Choi YD, Jang TW, Kim YS, Lee KH, Shin KC, Jung CY, Yang SH, Ryu JS, Jang SH, Yoo SS, Yong SJ, Lee KY, In KH, Lee MK, Kim YC. Randomized phase III study of docetaxel plus cisplatin versus pemetrexed plus cisplatin as first-line treatment of nonsquamous non-small-cell lung cancer: a TRAIL trial. Clin Lung Cancer. 2017 Jul;18(4):e289-e296. Epub 2017 Jan 11. link to original article contains dosing details in abstract PubMed NCT01282151
  6. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains dosing details in manuscript PubMed NCT02578680
    1. PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article PubMed
    2. Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
    3. Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
    4. Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article PubMed
  7. MYSTIC: Rizvi NA, Cho BC, Reinmuth N, Lee KH, Luft A, Ahn MJ, van den Heuvel MM, Cobo M, Vicente D, Smolin A, Moiseyenko V, Antonia SJ, Le Moulec S, Robinet G, Natale R, Schneider J, Shepherd FA, Geater SL, Garon EB, Kim ES, Goldberg SB, Nakagawa K, Raja R, Higgs BW, Boothman AM, Zhao L, Scheuring U, Stockman PK, Chand VK, Peters S; MYSTIC Investigators. Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non-Small Cell Lung Cancer: The MYSTIC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):661-674. link to original article contains dosing details in supplement link to PMC article PubMed NCT02453282
  8. IMpower110: Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020 Oct 1;383(14):1328-1339. link to original article contains dosing details in manuscript PubMed NCT02409342
    1. Update: Jassem J, de Marinis F, Giaccone G, Vergnenegre A, Barrios CH, Morise M, Felip E, Oprean C, Kim YC, Andric Z, Mocci S, Enquist I, Komatsubara K, McCleland M, Kuriki H, Villalobos M, Phan S, Spigel DR, Herbst RS. Updated Overall Survival Analysis From IMpower110: Atezolizumab Versus Platinum-Based Chemotherapy in Treatment-Naive Programmed Death-Ligand 1-Selected NSCLC. J Thorac Oncol. 2021 Nov;16(11):1872-1882. Epub 2021 Jul 12. link to original article PubMed
  9. ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article PubMed NCT03607539
  10. IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article PubMed NCT02657434
  11. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed
  12. RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article contains dosing details in manuscript PubMed NCT03663205
    1. HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article PubMed
  13. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
    1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed
  14. CHOICE-01: Wang Z, Wu L, Li B, Cheng Y, Li X, Wang X, Han L, Wu X, Fan Y, Yu Y, Lv D, Shi J, Huang J, Zhou S, Han B, Sun G, Guo Q, Ji Y, Zhu X, Hu S, Zhang W, Wang Q, Jia Y, Wang Z, Song Y, Wu J, Shi M, Li X, Han Z, Liu Y, Yu Z, Liu AW, Wang X, Zhou C, Zhong D, Miao L, Zhang Z, Zhao H, Yang J, Wang D, Wang Y, Li Q, Zhang X, Ji M, Yang Z, Cui J, Gao B, Wang B, Liu H, Nie L, He M, Jin S, Gu W, Shu Y, Zhou T, Feng J, Yang X, Huang C, Zhu B, Yao Y, Tang X, Yu J, Maher E, Feng H, Yao S, Keegan P, Wang J. Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01). J Clin Oncol. 2023 Jan 20;41(3):651-663. Epub 2022 Oct 7. link to original article link to PMC article PubMed NCT03856411
  15. B-FAST: NCT03178552
  16. M14-359: NCT02264990

Cisplatin, Pemetrexed, Atezolizumab

APP: Atezolizumab, Platinum (Cisplatin), Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nishio et al. 2020 (IMpower132) 2016-04-07 to 2017-05-31 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS1 (co-primary endpoint)
Median PFS: 8 vs 5 mo
(HR 0.60, 95% CI 0.49-0.72)

1IMpower132 did not meet the co-primary endpoint of OS

Chemotherapy

Immunotherapy

21-day cycles

References

  1. IMpower132: Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M, Longeras PD, Goldschmidt J Jr, Novello S, Orlandi F, Sanborn RE, Szalai Z, Ursol G, Mendus D, Wang L, Wen X, McCleland M, Hoang T, Phan S, Socinski MA. Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2021 Apr;16(4):653-664. Epub 2020 Dec 14. link to original article contains dosing details in manuscript PubMed NCT02657434

Cisplatin, Pemetrexed, Bevacizumab

Regimen variant #1, maintenance bevacizumab only

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Barlesi et al. 2013 (AVAPERL) 2009-08 to 2010-07 Phase 3 (C) Cisplatin, Pemetrexed, Bevacizumab; with pem/bev maintenance Inferior PFS

Chemotherapy

Targeted therapy

  • Bevacizumab (Avastin) 7.5 mg/kg IV over 90 minutes once on day 1
    • If well tolerated, subsequent infusions were given over 60 minutes, then 30 minutes

Supportive therapy

21-day cycles


Regimen variant #2, maintenance pemetrexed & bevacizumab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Barlesi et al. 2013 (AVAPERL) 2009-08 to 2010-07 Phase 3 (E-esc) Cisplatin, Pemetrexed, Bevacizumab; with bev maintenance Superior PFS (primary endpoint)
Median PFS: 7.4 vs 3.7 mo
(HR 0.48, 95% CI 0.35-0.66)

Chemotherapy

Targeted therapy

Supportive therapy

21-day cycles

References

  1. AVAPERL: Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, Ahn MJ, Aerts JG, Gorbunova V, Vikström A, Wong EK, Perez-Moreno P, Mitchell L, Groen HJ. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013 Aug 20;31(24):3004-11. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed NCT00961415
    1. Update: Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, Chella A, Kim JH, Ahn MJ, Reck M, Pazzola A, Kim HT, Aerts JG, Morando C, Loundou A, Groen HJ, Rittmeyer A. Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol. 2014 May;25(5):1044-52. Epub 2014 Feb 27. link to original article PubMed

Cisplatin, Pemetrexed, Cemiplimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gogishvili et al. 2022 (EMPOWER-Lung 3 part 2) 2019-06-17 to 2020-09-30 Phase 3 (E-RT-esc) Investigator's choice of:
1a. CP
1b. Cisplatin & Paclitaxel
1c. Carboplatin & Pemetrexed
1d. Cisplatin & Pemetrexed 		Superior OS (primary endpoint)
Median OS: 21.9 vs 13 mo
(HR 0.71, 95% CI 0.53-0.93)

Chemotherapy

Immunotherapy

21-day cycle for up to 36 cycles (2 years)

References

  1. EMPOWER-Lung 3 part 2: Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Gullo G, Rietschel P. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022 Nov;28(11):2374-2380. Epub 2022 Aug 25. link to original article contains dosing details in supplement link to PMC article PubMed NCT03409614
    1. PRO analysis: Makharadze T, Quek RGW, Melkadze T, Gogishvili M, Ivanescu C, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, Konidaris G, Rietschel P, Gullo G. Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3. Cancer. 2023 Jul 15;129(14):2256-2265. Epub 2023 May 8. link to original article PubMed

Cisplatin, Pemetrexed, Ipilimumab, Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2021 (CheckMate 9LA) 2017-2019 Phase 3 (E-RT-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (primary endpoint)
Median OS: 15.8 vs 11 mo
(HR 0.72, 95% CI 0.61-0.86)

1Reported efficacy is based on the 2021 update.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. CheckMate 9LA: Paz-Ares L, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Salman P, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, John T, Carbone DP, Meadows-Shropshire S, Agrawal S, Oukessou A, Yan J, Reck M. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):198-211. Epub 2021 Jan 18. link to original article contains dosing details in manuscript PubMed NCT03215706
    1. Update: Reck M, Ciuleanu TE, Cobo M, Schenker M, Zurawski B, Menezes J, Richardet E, Bennouna J, Felip E, Juan-Vidal O, Alexandru A, Sakai H, Lingua A, Reyes F, Souquet PJ, De Marchi P, Martin C, Pérol M, Scherpereel A, Lu S, Paz-Ares L, Carbone DP, Memaj A, Marimuthu S, Zhang X, Tran P, John T. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021 Oct;6(5):100273. Epub 2021 Oct 1. Erratum in: ESMO Open. 2021 Dec;6(6):100345. link to original article link to PMC article PubMed

Cisplatin, Pemetrexed, Pembrolizumab

Regimen variant #1, limited pemetrexed

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (LEAP-006) 2019-ongoing Phase 3 (C) 1a. Carboplatin, Lenvatinib, Pemetrexed, Pembrolizumab
1b. Cisplatin, Lenvatinib, Pemetrexed, Pembrolizumab 		TBD if different co-primary endpoints of PFS/OS

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles


Regimen variant #2, indefinite pemetrexed

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gandhi et al. 2018 (KEYNOTE-189) 2016-02-26 to 2017-03-06 Phase 3 (E-RT-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior OS1 (co-primary endpoint)
Median OS: 22 vs 10.6 mo
(HR 0.56, 95% CI 0.46-0.69)

Superior PFS (co-primary endpoint)
Median PFS: 8.8 vs 4.9 mo
(HR 0.52, 95% CI 0.43-0.64)
Tan et al. 2023 (CANOPY-1) 2019-06-25 to 2020-01-17 Phase 3 (C) 1a. Carboplatin, Pemetrexed, Canakinumab, Pembrolizumab
1b. Cisplatin, Pemetrexed, Canakinumab, Pembrolizumab 		Did not meet co-primary endpoints of PFS/OS

1Reported efficacy for KEYNOTE-189 is based on the 2021 update.
Note: selection of platinum agent in KEYNOTE-189 was per investigator choice.

Chemotherapy

Immunotherapy

  • Pembrolizumab (Keytruda) as follows:
    • Cycles 1 to 35: 200 mg IV over 30 minutes once on day 1, given first, at least 30 minutes prior to chemotherapy

Supportive therapy

21-day cycles

References

  1. KEYNOTE-189: Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol contains dosing details in manuscript PubMed NCT02578680
    1. PRO analysis: Garassino MC, Gadgeel S, Esteban E, Felip E, Speranza G, Domine M, Hochmair MJ, Powell S, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Wei Z, Burke T, Pietanza MC, Rodríguez-Abreu D. Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):387-397. Epub 2020 Feb 6. link to original article PubMed
    2. Update: Gadgeel S, Rodríguez-Abreu D, Speranza G, Esteban E, Felip E, Dómine M, Hui R, Hochmair MJ, Clingan P, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Garon EB, Novello S, Rubio-Viqueira B, Boyer M, Kurata T, Gray JE, Yang J, Bas T, Pietanza MC, Garassino MC. Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol. 2020 May 10;38(14):1505-1517. Epub 2020 Mar 9. link to original article PubMed
    3. Update: Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, Speranza G, De Angelis F, Dómine M, Cheng SY, Bischoff HG, Peled N, Reck M, Hui R, Garon EB, Boyer M, Kurata T, Yang J, Pietanza MC, Souza F, Garassino MC. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021 Jul;32(7):881-895. Epub 2021 Apr 22. link to original article PubMed
    4. Update: Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023 Apr 10;41(11):1992-1998. Epub 2023 Feb 21. link to original article link to PMC article PubMed
  2. CANOPY-1: Tan DSW, Felip E, de Castro G, Solomon BJ, Greystoke A, Cho BC, Cobo M, Kim TM, Ganguly S, Carcereny E, Paz-Ares L, Bennouna J, Garassino MC, Schenker M, Kim SW, Brase JC, Bury-Maynard D, Passos VQ, Deudon S, Dharan B, Song Y, Caparica R, Johnson BE. Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial. J Clin Oncol. 2024 Jan 10;42(2):192-204. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03631199
  3. KEYLYNK-006: NCT03976323
  4. KEYVIBE-007: NCT05226598
  5. LEAP-006: NCT03829319
  6. TROPION-Lung07: NCT05555732

Cisplatin, Pemetrexed, Sintilimab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2020 (ORIENT-11) 2018-08-23 to 2019-07-30 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS (primary endpoint)
Median PFS: 8.9 vs 5 mo
(HR 0.48, 95% CI 0.36-0.64)

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. ORIENT-11: Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, Chen G, Mei X, Yang Z, Ma R, Bi M, Ren X, Zhou J, Li B, Song Y, Feng J, Li J, He Z, Zhou R, Li W, Lu Y, Wang Y, Wang L, Yang N, Zhang Y, Yu Z, Zhao Y, Xie C, Cheng Y, Zhou H, Wang S, Zhu D, Zhang W, Zhang L. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol. 2020 Oct;15(10):1636-1646. Epub 2020 Aug 8. link to original article contains dosing details in manuscript PubMed NCT03607539

Cisplatin, Pemetrexed, Tislelizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lu et al. 2021 (RATIONALE 304) 2018-07-23 to 2019-07-31 Phase 3 (E-esc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Superior PFS (primary endpoint)
Median PFS: 9.7 vs 7.6 mo
(HR 0.645, 95% CI 0.46-0.90)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. RATIONALE 304: Lu S, Wang J, Yu Y, Yu X, Hu Y, Ai X, Ma Z, Li X, Zhuang W, Liu Y, Li W, Cui J, Wang D, Liao W, Zhou J, Wang Z, Sun Y, Qiu X, Gao J, Bao Y, Liang L, Wang M. Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. Epub 2021 May 23. link to original article contains dosing details in manuscript PubMed NCT03663205
    1. HRQoL analysis: Lu S, Yu Y, Barnes G, Qiu X, Bao Y, Tang B. Examining the Impact of Tislelizumab Added to Chemotherapy on Health-Related Quality-of-Life Outcomes in Previously Untreated Patients With Nonsquamous Non-Small Cell Lung Cancer. Cancer J. 2022 Mar-Apr 01;28(2):96-104. link to original article link to PMC article PubMed

Gefitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Han et al. 2012 (First-SIGNAL) 2005-2007 Phase 3 (E-switch-ooc) Cisplatin & Gemcitabine Did not meet primary endpoint of OS
Mok et al. 2009 (IPASS) 2006-03 to 2007-10 Phase 3 (E-RT-switch-ooc) Carboplatin & Paclitaxel Might have superior OS1 (secondary endpoint)
Median OS: 18.8 vs 17.4 mo
(HR 0.90, 95% CI 0.79-1.02)

Superior PFS (primary endpoint)
PFS12: 24.9% vs 6.7%
(HR 0.74, 95% CI 0.68-0.85)
Yang et al. 2014 (H3E-CR-S131) 2009-2012 Phase 3 (C) Cisplatin & Pemetrexed, then Gefitinib maint. Did not meet primary endpoint of PFS

1Reported efficacy for IPASS is based on the 2011 update.

Targeted therapy

Continued indefinitely

References

  1. IPASS: Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. Epub 2009 Aug 19. link to original article contains dosing details in manuscript PubMed NCT00322452
    1. Update: Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011 Jul 20;29(21):2866-74. Epub 2011 Jun 13. link to original article PubMed
    2. Dataset: Project Data Sphere
  2. First-SIGNAL: Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, Ahn MJ, Yun T, Ahn JS, Suh C, Lee JS, Yoon SJ, Han JH, Lee JW, Jo SJ, Lee JS. First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol. 2012 Apr 1;30(10):1122-8. Epub 2012 Feb 27. link to original article contains dosing details in abstract PubMed NCT00455936
  3. H3E-CR-S131: Yang JC, Kang JH, Mok T, Ahn MJ, Srimuninnimit V, Lin CC, Kim DW, Tsai CM, Barraclough H, Altug S, Orlando M, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian patients with locally advanced or metastatic non-squamous non-small cell lung cancer: a randomised, phase 3 trial. Eur J Cancer. 2014 Sep;50(13):2219-30. Epub 2014 Jun 18. link to original article PubMed NCT01017874
    1. Update: Yang JC, Srimuninnimit V, Ahn MJ, Lin CC, Kim SW, Tsai CM, Mok T, Orlando M, Puri T, Wang X, Park K. First-line pemetrexed plus cisplatin followed by gefitinib maintenance therapy versus gefitinib monotherapy in East Asian never-smoker patients with locally advanced or metastatic nonsquamous non-small cell lung cancer: final overall survival results from a randomized phase 3 study. J Thorac Oncol. 2016 Mar;11(3):370-9. Epub 2015 Dec 25. link to original article PubMed

Ipilimumab & Nivolumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hellmann et al. 2018 (CheckMate 227) 2015-08 to 2016-11 Phase 3 (E-RT-switch-ooc) 1. Nivolumab Not reported
2a. Cisplatin & Pemetrexed
2b. Carboplatin & Pemetrexed 		Superior OS (co-primary endpoint)1
OS60: 24% vs 14%

1Reported efficacy is based on the 2022 update. Note that the proportional hazards assumption was not met; HR is therefore not reported here.

Biomarker eligibility criteria

  • PD-L1 expression of 1% or more

Immunotherapy

42-day cycles

References

  1. CheckMate 227: Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018 May 31;378(22):2093-2104. Epub 2018 Apr 16. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02477826
    1. PRO analysis: Reck M, Schenker M, Lee KH, Provencio M, Nishio M, Lesniewski-Kmak K, Sangha R, Ahmed S, Raimbourg J, Feeney K, Corre R, Franke FA, Richardet E, Penrod JR, Yuan Y, Nathan FE, Bhagavatheeswaran P, DeRosa M, Taylor F, Lawrance R, Brahmer J. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur J Cancer. 2019 Jul;116:137-147. Epub 2019 Jun 11. link to original article PubMed
    2. Update: Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim SW, Carcereny Costa E, Park K, Alexandru A, Lupinacci L, de la Mora Jimenez E, Sakai H, Albert I, Vergnenegre A, Peters S, Syrigos K, Barlesi F, Reck M, Borghaei H, Brahmer JR, O'Byrne KJ, Geese WJ, Bhagavatheeswaran P, Rabindran SK, Kasinathan RS, Nathan FE, Ramalingam SS. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019 Nov 21;381(21):2020-2031. Epub 2019 Sep 28. link to original article PubMed
    3. Update: Paz-Ares LG, Ramalingam SS, Ciuleanu TE, Lee JS, Urban L, Caro RB, Park K, Sakai H, Ohe Y, Nishio M, Audigier-Valette C, Burgers JA, Pluzanski A, Sangha R, Gallardo C, Takeda M, Linardou H, Lupinacci L, Lee KH, Caserta C, Provencio M, Carcereny E, Otterson GA, Schenker M, Zurawski B, Alexandru A, Vergnenegre A, Raimbourg J, Feeney K, Kim SW, Borghaei H, O'Byrne KJ, Hellmann MD, Memaj A, Nathan FE, Bushong J, Tran P, Brahmer JR, Reck M. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial. J Thorac Oncol. 2022 Feb;17(2):289-308. Epub 2021 Oct 12. link to original article PubMed
    4. Update: Brahmer JR, Lee JS, Ciuleanu TE, Bernabe Caro R, Nishio M, Urban L, Audigier-Valette C, Lupinacci L, Sangha R, Pluzanski A, Burgers J, Mahave M, Ahmed S, Schoenfeld AJ, Paz-Ares LG, Reck M, Borghaei H, O'Byrne KJ, Gupta RG, Bushong J, Li L, Blum SI, Eccles LJ, Ramalingam SS. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023 Feb 20;41(6):1200-1212. Epub 2022 Oct 12. link to original article link to PMC article PubMed

Advanced or metastatic disease, first-line, elderly or poor performance status

Gemcitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gridelli et al. 2018 (MILES-4) 2011-2016 Phase 3 (C) 1. Cisplatin & Gemcitabine
2. Cisplatin & Pemetrexed 		Did not meet primary endpoint of OS
3. Pemetrexed Not reported

Note: MILES-4 involved only patients at least 70 years old.

Chemotherapy

Supportive therapy

  • "Antiemetic agents and other supportive treatments were provided at the discretion of the treating physician."

21-day cycle for 4 to 6 cycles

References

  1. MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains dosing details in manuscript PubMed NCT01656551

Pemetrexed monotherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gridelli et al. 2018 (MILES-4) 2011-2016 Phase 3 (E-switch-ic) 1. Cisplatin & Gemcitabine
2. Cisplatin & Pemetrexed 		Did not meet primary endpoint of OS
3. Gemcitabine Not reported

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. MILES-4: Gridelli C, Morabito A, Cavanna L, Luciani A, Maione P, Bonanno L, Filipazzi V, Leo S, Cinieri S, Ciardiello F, Burgio MA, Bilancia D, Cortinovis D, Rosetti F, Bianco R, Gebbia V, Artioli F, Bordonaro R, Fregoni V, Mencoboni M, Nelli F, Riccardi F, di Isernia G, Costanzo R, Rocco G, Daniele G, Signoriello S, Piccirillo MC, Gallo C, Perrone F. Cisplatin-based first-line treatment of elderly patients with advanced non-small-cell lung cancer: joint analysis of MILES-3 and MILES-4 phase III trials. J Clin Oncol. 2018 Sep 1;36(25):2585-2592. Epub 2018 Jul 20. link to original article contains dosing details in manuscript PubMed NCT01656551

Maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al. 2013 (PointBreak) 2008-2012 Non-randomized part of phase 3 RCT
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase 3 (C) See link See link
Ramalingam et al. 2019 (ECOG-ACRIN E5508) 2010-2015 Phase 3 (C) 1. Pemetrexed
2. Pemetrexed & Bevacizumab 		Did not meet primary endpoint of OS
Seto et al. 2019 (COMPASS) 2010-2015 Phase 3 (C) Pemetrexed & Bevacizumab Might have inferior OS

Preceding treatment

Targeted therapy

21-day cycles

References

  1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  2. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00948675
  3. ECOG-ACRIN E5508: Ramalingam SS, Dahlberg SE, Belani CP, Saltzman JN, Pennell NA, Nambudiri GS, McCann JC, Winegarden JD, Kassem MA, Mohamed MK, Rothman JM, Lyss AP, Horn L, Stinchcombe TE, Schiller JH. Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508. J Clin Oncol. 2019 Sep 10;37(26):2360-2367. Epub 2019 Jul 30. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01107626
  4. COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains dosing details in abstract PubMed UMIN000004194

Pemetrexed monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2012 (PARAMOUNT) 2008-2010 Phase 3 (E-RT-esc) Placebo Superior PFS (primary endpoint)
Median PFS: 4.1 vs 2.8 mo
(HR 0.62, 95% CI 0.49-0.79)
Zinner et al. 2015 (PRONOUNCE) 2009-2013 Phase 3 (E-switch-ooc) See link See link
Souquet et al. 2021 (IFCT-GFPC-1101) 2012-2016 Phase 3 (C) Response-adapted maintenance Did not meet primary endpoint of OS

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycles

References

  1. PARAMOUNT: Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. Epub 2012 Feb 16. link to original article contains dosing details in manuscript PubMed NCT00789373
    1. HRQoL analysis: Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. link to original article PubMed
    2. Update: Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
  2. PRONOUNCE: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00948675
  3. IFCT-GFPC-1101: Souquet PJ, Audigier-Valette C, Molinier O, Cortot A, Margery J, Moreau L, Gervais R, Barlesi F, Pichon E, Zalcman G, Dumont P, Girard N, Poudenx M, Mazières J, Cadranel J, Debieuvre D, Dauba J, Langlais A, Morin F, Moro-Sibilot D, Westeel V, Pérol M. Tailoring maintenance chemotherapy upon response to induction chemotherapy as compared with pemetrexed continuation maintenance in advanced non-squamous NSCLC patients: Results of the IFCT-GFPC-1101 multicenter randomized phase III trial. Lung Cancer. 2022 Feb;164:84-90. Epub 2021 Nov 30. link to original article PubMed NCT01631136

Pemetrexed & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patel et al. 2013 (PointBreak) 2008-2012 Non-randomized part of phase 3 RCT
Seto et al. 2019 (COMPASS) 2010-2015 Phase 3 (E-esc) Bevacizumab Might have superior OS (primary endpoint)
Median OS: 23.3 vs 19.6 mo
(HR 0.87, 95% CI 0.73-1.05)

Preceding treatment

Chemotherapy

Targeted therapy

Supportive therapy

  • Premedications, Folic acid (Folate), and vitamin supplementation per pemetrexed label
  • Erythropoietic agents or granulocyte colony-stimulating factors allowed per ASCO & NCCN guidelines

21-day cycles

References

  1. PointBreak: Patel JD, Socinski MA, Garon EB, Reynolds CH, Spigel DR, Olsen MR, Hermann RC, Jotte RM, Beck T, Richards DA, Guba SC, Liu J, Frimodt-Moller B, John WJ, Obasaju CK, Pennella EJ, Bonomi P, Govindan R. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Dec 1;31(34):4349-57. Epub 2013 Oct 21. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00762034
    1. Dataset: Project Data Sphere
  2. COMPASS: Seto T, Azuma K, Yamanaka T, Sugawara S, Yoshioka H, Wakuda K, Atagi S, Iwamoto Y, Hayashi H, Okamoto I, Saka H, Mitsuoka S, Fujimoto D, Nishino K, Horiike A, Daga H, Sone T, Yamamoto N, Nakagawa K, Nakanishi Y. Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non-Small-Cell Lung Cancer: COMPASS (WJOG5610L). J Clin Oncol. 2020 Mar 10;38(8):793-803. Epub 2019 Dec 27. link to original article contains dosing details in abstract PubMed UMIN000004194

Advanced or metastatic disease, subsequent lines of therapy

Note: this section includes regimens that were tested in second-line and beyond.

Docetaxel monotherapy

Regimen variant #1, 75 mg/m2 q3wk, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gerber et al. 2018 (SUNRISE) 2013-2016 Phase 3 (C) Docetaxel & Bavituximab Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borghaei et al. 2015 (CheckMate 057) 2012-2015 Phase 3 (C) Nivolumab Inferior OS
Cortot et al. 2020 (ULTIMATE) 2013-05-31 to 2014-08-13 Phase 3 (C) Paclitaxel & Bevacizumab Inferior PFS
Steendam et al. 2021 (NVALT-18) 2016-2018 Phase 3 (C) Docetaxel & Erlotinib Superior OS
Awaiting publication (CARMEN-LC03) 2020-ongoing Phase 3 (C) Tusamitamab ravtansine TBD if different co-primary endpoints of PFS/OS

Biomarker eligibility criteria

  • CARMEN-LC03: CEACAM5+

Chemotherapy

21-day cycles

References

  1. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article link to PMC article PubMed NCT01673867
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article link to PMC article PubMed
    2. HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed
    3. Pooled update: Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wójcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, García MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Mar 1;39(7):723-733. Epub 2021 Jan 15. link to original article link to PMC article PubMed
  2. SUNRISE: Gerber DE, Horn L, Boyer M, Sanborn R, Natale R, Palmero R, Bidoli P, Bondarenko I, Germonpre P, Ghizdavescu D, Kotsakis A, Lena H, Losonczy G, Park K, Su WC, Tang M, Lai J, Kallinteris NL, Shan JS, Reck M, Spigel DR. Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. Ann Oncol. 2018 Jul 1;29(7):1548-1553. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01999673
  3. ULTIMATE: Cortot AB, Audigier-Valette C, Molinier O, Le Moulec S, Barlesi F, Zalcman G, Dumont P, Pouessel D, Poulet C, Fontaine-Delaruelle C, Hiret S, Dixmier A, Renault PA, Becht C, Raffy O, Dayen C, Mazieres J, Pichon E, Langlais A, Morin F, Moro-Sibilot D, Besse B. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study. Eur J Cancer. 2020 May;131:27-36. Epub 2020 Apr 8. link to original article contains dosing details in abstract PubMed NCT01763671
  4. NVALT-18: Steendam CMJ, Peric R, van Walree NC, Youssef M, Schramel FMNH, Brocken P, van Putten JWG, van der Noort V, Veerman GDM, Koolen SLW, Groen HJM, Dingemans AC, Mathijssen RHJ, Smit EF, Aerts JGJV; NVALT Study Group. Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma. Lung Cancer. 2021 Oct;160:44-49. Epub 2021 Aug 4. link to original article contains dosing details in abstract PubMed NCT02775006
  5. CARMEN-LC03: NCT04154956

Gefitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Urata et al. 2016 (WJOG 5108L) 2009-2012 Phase 3 (E-switch-ic) Erlotinib Inconclusive whether non-inferior PFS

Targeted therapy

Continued indefinitely

References

  1. WJOG 5108L: Urata Y, Katakami N, Morita S, Kaji R, Yoshioka H, Seto T, Satouchi M, Iwamoto Y, Kanehara M, Fujimoto D, Ikeda N, Murakami H, Daga H, Oguri T, Goto I, Imamura F, Sugawara S, Saka H, Nogami N, Negoro S, Nakagawa K, Nakanishi Y. Randomized phase III study comparing gefitinib with erlotinib in patients with previously treated advanced lung adenocarcinoma: WJOG 5108L. J Clin Oncol. 2016 Sep 20;34(27):3248-57. Epub 2016 Mar 28. link to original article contains dosing details in manuscript PubMed UMIN000002014

Nintedanib & Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hanna et al. 2016 (LUME-Lung 2) 2008-2011 Phase 3 (E-esc) Pemetrexed Seems to have superior PFS (primary endpoint)
Median PFS: 4.4 vs 3.6 mo
(HR 0.83, 95% CI 0.70-0.99)

Targeted therapy

Chemotherapy

21-day cycles

References

  1. LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed NCT00806819

Nivolumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Borghaei et al. 2015 (CheckMate 057) 2012-2015 Phase 3 (E-RT-switch-ooc) Docetaxel Superior OS (primary endpoint)
Median OS: 12.2 vs 9.4 mo
(HR 0.73, 96% CI 0.59-0.89)

Immunotherapy

  • Nivolumab (Opdivo) 3 mg/kg IV once on day 1
    • Notably, on 2016-09-13 the FDA recommended that dosing for this indication be changed to 240 mg with the same schedule based on updated pharmacokinetic data.

14-day cycles

References

  1. CheckMate 057: Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Epub 2015 Sep 27. link to original article link to PMC article PubMed NCT01673867
    1. Pooled update: Horn L, Spigel DR, Vokes EE, Holgado E, Ready N, Steins M, Poddubskaya E, Borghaei H, Felip E, Paz-Ares L, Pluzanski A, Reckamp KL, Burgio MA, Kohlhäeufl M, Waterhouse D, Barlesi F, Antonia S, Arrieta O, Fayette J, Crinò L, Rizvi N, Reck M, Hellmann MD, Geese WJ, Li A, Blackwood-Chirchir A, Healey D, Brahmer J, Eberhardt WEE. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol. 2017 Dec 10;35(35):3924-3933. Epub 2017 Oct 12. link to original article link to PMC article PubMed
    2. HRQoL analysis: Reck M, Brahmer J, Bennett B, Taylor F, Penrod JR, DeRosa M, Dastani H, Spigel DR, Gralla RJ. Evaluation of health-related quality of life and symptoms in patients with advanced non-squamous non-small cell lung cancer treated with nivolumab or docetaxel in CheckMate 057. Eur J Cancer. 2018 Oct;102:23-30. Epub 2018 Aug 10. link to original article PubMed
    3. Pooled update: Borghaei H, Gettinger S, Vokes EE, Chow LQM, Burgio MA, de Castro Carpeno J, Pluzanski A, Arrieta O, Frontera OA, Chiari R, Butts C, Wójcik-Tomaszewska J, Coudert B, Garassino MC, Ready N, Felip E, García MA, Waterhouse D, Domine M, Barlesi F, Antonia S, Wohlleber M, Gerber DE, Czyzewicz G, Spigel DR, Crino L, Eberhardt WEE, Li A, Marimuthu S, Brahmer J. Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non-Small-Cell Lung Cancer. J Clin Oncol. 2021 Mar 1;39(7):723-733. Epub 2021 Jan 15. link to original article link to PMC article PubMed

Paclitaxel & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortot et al. 2020 (ULTIMATE) 2013-05-31 to 2014-08-13 Phase 3 (E-esc) Docetaxel Superior PFS (primary endpoint)
Median PFS: 5.4 vs 3.9 mo
(HR 0.61, 95% CI 0.44-0.86)

Chemotherapy

Targeted therapy

28-day cycles

References

  1. ULTIMATE: Cortot AB, Audigier-Valette C, Molinier O, Le Moulec S, Barlesi F, Zalcman G, Dumont P, Pouessel D, Poulet C, Fontaine-Delaruelle C, Hiret S, Dixmier A, Renault PA, Becht C, Raffy O, Dayen C, Mazieres J, Pichon E, Langlais A, Morin F, Moro-Sibilot D, Besse B. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study. Eur J Cancer. 2020 May;131:27-36. Epub 2020 Apr 8. link to original article contains dosing details in abstract PubMed NCT01763671

Pemetrexed monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hanna et al. 2016 (LUME-Lung 2) 2008-2011 Phase 3 (C) Nintedanib & Pemetrexed Seems to have inferior PFS

Chemotherapy

Supportive therapy

21-day cycles

References

  1. LUME-Lung 2: Hanna NH, Kaiser R, Sullivan RN, Aren OR, Ahn MJ, Tiangco B, Voccia I, Pawel JV, Kovcin V, Agulnik J, Gaschler-Markefski B, Barrueco J, Sikken P, Schloss C, Kim JH; LUME-Lung 2 Study group. Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial. Lung Cancer. 2016 Dec;102:65-73. Epub 2016 Oct 27. link to original article PubMed NCT00806819

Sorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paz-Ares et al. 2015 (MISSION) 2009-NR Phase 3 (E-esc) Placebo Did not meet primary endpoint of OS

Note: although the primary endpoinat (OS) was negative overall, the authors note that the subgroup of patients with known EGFR mutations treated with sorafenib had significantly superior survival (p=0.002).

Targeted therapy

Continued indefinitely

References

  1. MISSION: Paz-Ares L, Hirsh V, Zhang L, de Marinis F, Yang JC, Wakelee HA, Seto T, Wu YL, Novello S, Juhász E, Arén O, Sun Y, Schmelter T, Ong TJ, Peña C, Smit EF, Mok TS. Monotherapy administration of sorafenib in patients with non-small cell lung cancer (MISSION) trial: A phase III, multicenter, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly nonsquamous non-small-cell lung cancer after 2 or 3 previous treatment regimens. J Thorac Oncol. 2015 Dec;10(12):1745-53. link to original article contains dosing details in manuscript PubMed NCT00863746
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