Non-small cell lung cancer, EGFR-mutated

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 Amit Kulkarni, MBBS
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 Travis Osterman, DO, MS, FAMIA
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Note: these are regimens tested in biomarker-specific populations, please see the main NSCLC page for other regimens.

46 regimens on this page
63 variants on this page


Guidelines

IASLC

Adjuvant therapy

Cisplatin & Vinorelbine

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CVb: Cisplatin & Vinorelbine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Zhong et al. 2017 (ADJUVANT/CTONG1104) 2011-2014 Phase III (C) Gefinitib Inferior DFS

Biomarker Eligibility Criteria

  • Biomarker: EGFR exon 19 deletion and exon 21 L858R activating mutations

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. ADJUVANT/CTONG1104: Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Epub 2017 Nov 21. link to original article contains protocol PubMed

Gefitinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Zhong et al. 2017 (ADJUVANT/CTONG1104) 2011-2014 Phase III (E-switch-ooc) Cisplatin & Vinorelbine Superior DFS

Biomarker Eligibility Criteria

  • Biomarker: EGFR exon 19 deletion and exon 21 L858R activating mutations

Preceding treatment

Targeted therapy

24-month course

References

  1. Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, Shen Y, Liu YY, Chen C, Cheng Y, Xu L, Wang J, Fei K, Li XF, Li J, Huang C, Liu ZD, Xu S, Chen KN, Xu SD, Liu LX, Yu P, Wang BH, Ma HT, Yan HH, Yang XN, Zhou Q, Wu YL; ADJUVANT investigators. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Jan;19(1):139-148. Epub 2017 Nov 21. link to original article contains protocol PubMed

Osimertinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wu et al. 2020 (ADAURA) 2015-2019 Phase III (E-esc) Placebo Superior DFS

Biomarker eligibility criteria

  • EGFR exon 19 deletion or p.L858R mutation, alone or in combination with other EGFR mutations

Precediing treatment

Targeted therapy

3-year course

References

  1. ADAURA: Wu YL, Tsuboi M, He J, John T, Grohe C, Majem M, Goldman JW, Laktionov K, Kim SW, Kato T, Vu HV, Lu S, Lee KY, Akewanlop C, Yu CJ, de Marinis F, Bonanno L, Domine M, Shepherd FA, Zeng L, Hodge R, Atasoy A, Rukazenkov Y, Herbst RS; ADAURA Investigators. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Oct 29;383(18):1711-1723. Epub 2020 Sep 19. link to original article contains verified protocol PubMed NCT02511106

Advanced or metastatic disease, EGFR inhibitor-naive

Afatinib monotherapy

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Regimen variant #1, 30 mg/day

FDA-recommended dose

This is the FDA-recommended dose for patients with "severe renal impairment".

Targeted therapy

Continued indefinitely

Regimen variant #2, 40 mg/day

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2012 (LUX-Lung 2) 2007-2009 Phase II ORR: 61%
Sequist et al. 2013 (LUX-Lung 3) 2009-2011 Phase III (E-RT-switch-ooc) Cisplatin & Pemetrexed Superior PFS
Wu et al. 2014 (LUX-Lung 6) 2010-2011 Phase III (E-switch-ooc) Cisplatin & Gemcitabine Superior PFS
Park et al. 2016 (LUX-Lung 7) 2011-2013 Randomized Phase II (E-switch-ic) Gefitinib Seems to have superior PFS

Biomarker Eligibility Criteria

  • Biomarker:
    • activating EGFR mutations within exons 18–21 (LUX LUNG-2)
    • activating EGFR mutation with 19 deletions in exon 19, L858R, 3 insertions in exon 20, L861Q, G719S, G719A, G719C, T790M and S768I (LUX-LUNG 3, LUX-LUNG 6)
    • activating EGFR mutation with exon 19 deletion and/or L858R (LUX-LUNG 7)

Targeted therapy

  • Afatinib (Gilotrif) 40 mg PO once per day, given 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")
    • In LUX-Lung 3, patients could be increased to 50 mg PO once per day if they did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

Continued indefinitely

References

  1. LUX-Lung 2: Yang JC, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SH, Yu CJ, Chang GC, Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012 May;13(5):539-48. Epub 2012 Mar 26. link to original article contains verified protocol PubMed NCT00525148
    1. Pooled analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article PubMed
  2. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains verified protocol PubMed NCT00949650
    1. Subgroup analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
    2. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    3. Pooled analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article PubMed
    4. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  3. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains verified protocol PubMed NCT01121393
    1. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    2. Pooled analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article PubMed
    3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  4. LUX-Lung 7: Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. Epub 2016 Apr 12. link to original article contains protocol PubMed NCT01466660

Carboplatin & Docetaxel

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DCb: Docetaxel & Carboplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase III (C) Erlotinib Inferior PFS

Biomarker Eligibility Criteria

  • Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21

Chemotherapy

21-day cycles

References

  1. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed

Carboplatin & Gemcitabine

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GC: Gemcitabine & Carboplatin
GCa: Gemcitabine & Carboplatin
GCb: Gemcitabine & Carboplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase III (C) Erlotinib Inferior PFS
Zhou et al. 2011 (OPTIMAL) 2008-2009 Phase III (C) Erlotinib Inferior PFS

Biomarker Eligibility Criteria

  • Biomarker: EGFR activating mutation with exon 19 deletion or p.L858R mutation in exon 21

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. OPTIMAL: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. Epub 2011 Jul 23. link to original article PubMed NCT00874419
    1. Update: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article contains verified protocol PubMed
  2. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed

Carboplatin & Gemcitabine/Erlotinib

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wu et al. 2013 (FASTACT-2) 2009-2010 Phase III (E-esc) Carboplatin & Gemcitabine Seems to have superior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

Targeted therapy

28-day cycle for 4 cycles

References

  1. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed

Carboplatin & Paclitaxel

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

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Maemondo et al. 2010 (NEJ002) 2006-2009 Phase III (C) Gefitinib Inferior PFS

Chemotherapy

21-day cycle for at least 3 cycles

References

  1. NEJ002: Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8. link to original article contains verified protocol PubMed UMIN000000376
    1. HRQoL analysis: Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863-70. Epub 2012 May 11. link to original article link to PMC article PubMed
    2. Update: Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013 Jan;24(1):54-9. Epub 2012 Sep 11. link to original article PubMed

Cisplatin & Docetaxel

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

Regimen variant #1, 75/75

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase III (C) Erlotinib Inferior PFS

Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation.

Chemotherapy

21-day cycle for up to 4 cycles

Regimen variant #2, 80/60

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mitsudomi et al. 2009 (WJTOG3405) 2006-2009 Phase III (C) Gefitinib Inferior PFS

Patients in WJTOG3405 had EGFR exon 19 deletion or p.L858R mutation.

Chemotherapy

21-day cycle for 3 to 6 cycles

References

  1. WJTOG3405: Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Thoracic Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8. Epub 2009 Dec 18. link to original article contains verified protocol PubMed UMIN000000539
    1. Update: Yoshioka H, Shimokawa M, Seto T, Morita S, Yatabe Y, Okamoto I, Tsurutani J, Satouchi M, Hirashima T, Atagi S, Shibata K, Saito H, Toyooka S, Yamamoto N, Nakagawa K, Mitsudomi T. Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. Ann Oncol. 2019 Dec 1;30(12):1978-1984. link to original article PubMed
  2. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed

Cisplatin & Gemcitabine

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

Regimen variant #1, 75/1000

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wu et al. 2014 (LUX-Lung 6) 2010-2011 Phase III (C) Afatinib Inferior PFS

Tumor specimen was required to be EGFR mutation-positive.

Chemotherapy

21-day cycle for up to 6 cycles

Regimen variant #2, 75/1250

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase III (C) Erlotinib Inferior PFS
Wu et al. 2015 (ENSURE) 2011-2012 Phase III (C) Erlotinib Inferior PFS

Note: Patients in EURTAC had EGFR exon 19 deletion or p.L858R mutation in exon 21.

Chemotherapy

21-day cycle for up to 4 cycles

References

  1. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
  2. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains verified protocol PubMed NCT01121393
    1. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    2. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  3. ENSURE: Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, Xia F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015 Sep;26(9):1883-9. Epub 2015 Jun 23. link to original article contains verified protocol PubMed NCT01342965

Cisplatin & Gemcitabine/Erlotinib

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Wu et al. 2013 (FASTACT-2) 2009-2010 Phase III (E-esc) Cisplatin & Gemcitabine Seems to have superior OS

Note: this cohort was enriched for EGFR mutations and only those patients with an activating EGFR gene mutation were noted to have a treatment benefit in favor of the experimental arm.

Chemotherapy

Targeted therapy

28-day cycle for 4 cycles

References

  1. FASTACT-2: Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, Srimuninnimit V, Sriuranpong V, Sandoval-Tan J, Zhu Y, Liao M, Zhou C, Pan H, Lee V, Chen YM, Sun Y, Margono B, Fuerte F, Chang GC, Seetalarom K, Wang J, Cheng A, Syahruddin E, Qian X, Ho J, Kurnianda J, Liu HE, Jin K, Truman M, Bara I, Mok T. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013 Jul;14(8):777-86. Epub 2013 Jun 17. link to original article contains protocol PubMed

Cisplatin & Pemetrexed

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

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Sequist et al. 2013 (LUX-Lung 3) 2009-2011 Phase III (C) Afatinib Inferior PFS
Shi et al. 2017 (CONVINCE) 2013-2014 Phase III (C) See link See link

Note: Patients in LUX-Lung 3 had adenocarcinoma with activating mutations in EGFR. Patients in CONVINCE had stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

  • CONVINCE: Optional pemetrexed maintenance

References

  1. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains verified protocol PubMed NCT00949650
    1. Subgroup analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains verified protocol PubMed
    2. Update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  2. CONVINCE: Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article contains verified protocol PubMed NCT01719536

Dacomitinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Ramalingam et al. 2012 (A7471028) 2008-2010 Randomized Phase II (E-switch-ic) Erlotinib Seems to have superior PFS
Ramalingam et al. 2014 (ARCHER 1009) 2011-2013 Phase III (E-switch-ic) Erlotinib Did not meet primary endpoint of PFS
Wu et al. 2017 (ARCHER 1050) 2013-2015 Phase III (E-RT-switch-ic) Gefitinib Seems to have superior OS (*)

Note: Efficacy for ARCHER 1050 is based on the 2018 update.

Targeted therapy

Continued indefinitely

References

  1. A7471028: Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. Epub 2012 Jul 2. link to original article PubMed NCT00769067
  2. ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15.link to original article PubMed NCT01360554
  3. ARCHER 1050: Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. Epub 2017 Sep 25. link to original article PubMed
    1. Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Wu YL. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250. Epub 2018 Jun 4. link to original article PubMed

Erlotinib monotherapy

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Regimen variant #1, 150 mg/d

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Rossell et al. 2012 (EURTAC) 2007-2011 Phase III (E-RT-switch-ooc) 1. Carboplatin & Docetaxel
2. Carboplatin & Gemcitabine
3. Cisplatin & Docetaxel
4. Cisplatin & Gemcitabine 		Superior PFS
Zhou et al. 2011 (OPTIMAL) 2008-2009 Phase III (E-switch-ooc) Carboplatin & Gemcitabine Superior PFS
Ramalingam et al. 2012 (A7471028) 2008-2010 Randomized Phase II (C) Dacomitinib Seems to have inferior PFS
Yang et al. 2017 (CTONG 0901) 2009-2014 Phase III (C) Gefitinib Did not meet primary endpoint of PFS
Seto et al. 2014 (JO25567) 2011-2012 Randomized Phase II (C) Erlotinib & Bevacizumab Inferior PFS
Wu et al. 2015 (ENSURE) 2011-2012 Phase III (E-switch-ooc) Cisplatin & Gemcitabine Superior PFS
Ramalingam et al. 2014 (ARCHER 1009) 2011-2013 Phase III (C) Dacomitinib Did not meet primary endpoint of PFS
Soria et al. 2017 (FLAURA) 2014-2016 Phase III (C) Osimertinib Seems to have inferior OS (*)
Saito et al. 2019 (NEJ026) 2015-2016 Phase III (C) Erlotinib & Bevacizumab Seems to have inferior PFS
Kelly et al. 2019 (SOLAR) 2016-2017 Phase III (C) Naquotinib Did not meet primary endpoint of PFS
Nakagawa et al. 2019 (RELAY) 2016-2018 Phase III (C) Erlotinib & Ramucirumab Inferior PFS

Note: these are all trials restricted to patients with EGFR-mutated lung cancer. Some trials of erlotinib in unselected populations nevertheless had high rates of EGFR-mutated lung cancers, due to the nature of the populations studied. See the main NSCLC page for these trials. Reported efficacy for FLAURA is based on the 2019 update.

Targeted therapy

Continued indefinitely

Regimen variant #2, low-dose

Study Evidence
Yeo et al. 2010 Retrospective

Targeted therapy

Continued indefinitely

References

  1. Retrospective: Yeo WL, Riely GJ, Yeap BY, Lau MW, Warner JL, Bodio K, Huberman MS, Kris MG, Tenen DG, Pao W, Kobayashi S, Costa DB. Erlotinib at a dose of 25 mg daily for non-small cell lung cancers with EGFR mutations. J Thorac Oncol. 2010 Jul;5(7):1048-53. link to PMC article PubMed
  2. OPTIMAL: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. Epub 2011 Jul 23. link to original article contains protocol PubMed NCT00874419
    1. Update: Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol. 2015 Sep;26(9):1877-83. Epub 2015 Jul 3. link to original article PubMed
  3. EURTAC: Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group; Groupe Français de Pneumo-Cancérologie; Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. Epub 2012 Jan 26. link to original article contains protocol PubMed
  4. A7471028: Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, Seog Heo D, Rosell R, Talbot DC, Frank R, Letrent SP, Ruiz-Garcia A, Taylor I, Liang JQ, Campbell AK, O'Connell J, Boyer M. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2012 Sep 20;30(27):3337-44. Epub 2012 Jul 2. link to original article link to PMC article contains protocol PubMed NCT00769067
  5. JO25567: Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Erratum in: Lancet Oncol. 2014 Oct;15(11):e475. link to original article contains protocol PubMed JapicCTI-111390
  6. ARCHER 1009: Ramalingam SS, Jänne PA, Mok T, O'Byrne K, Boyer MJ, Von Pawel J, Pluzanski A, Shtivelband M, Docampo LI, Bennouna J, Zhang H, Liang JQ, Doherty JP, Taylor I, Mather CB, Goldberg Z, O'Connell J, Paz-Ares L. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1369-78. Epub 2014 Oct 15. link to original article contains protocol PubMed NCT01360554
  7. ENSURE: Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, Lu S, Cheng Y, Han B, Chen L, Huang C, Qin S, Zhu Y, Pan H, Liang H, Li E, Jiang G, How SH, Fernando MC, Zhang Y, Xia F, Zuo Y. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015 Sep;26(9):1883-9. Epub 2015 Jun 23. link to original article contains verified protocol PubMed NCT01342965
  8. CTONG 0901: Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, Wang Z, Xu CR, Su J, Wang BC, Jiang BY, Bai XY, Zhong WZ, Yang XN, Wu YL. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017 Feb 28;116(5):568-574. Epub 2017 Jan 19. link to original article contains protocol link to PMC article PubMed NCT01024413
  9. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains verified protocol PubMed NCT02296125
    1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
    2. Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article PubMed
  10. NEJ026: Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. Epub 2019 Apr 8. link to original article contains protocol PubMed UMIN000017069
  11. SOLAR: Kelly RJ, Shepherd FA, Krivoshik A, Jie F, Horn L. A phase 3, randomized, open-label study of ASP8273 versus erlotinib or gefitinib in patients with advanced stage IIIB/IV non-small cell lung cancer. Ann Oncol. 2019 Jul 1;30(7):1127-1133. Epub 2019 May 9. link to original article link to PMC article PubMed NCT02588261
  12. RELAY: Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. Epub 2019 Oct 4. link to original article contains protocol PubMed NCT02411448

Erlotinib & Bevacizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Seto et al. 2014 (JO25567) 2011-2012 Randomized Phase II (E-esc) Erlotinib Superior PFS
Saito et al. 2019 (NEJ026) 2015-2016 Phase III (E-esc) Erlotinib Seems to have superior PFS

Targeted therapy

21-day cycles

References

  1. JO25567: Seto T, Kato T, Nishio M, Goto K, Atagi S, Hosomi Y, Yamamoto N, Hida T, Maemondo M, Nakagawa K, Nagase S, Okamoto I, Yamanaka T, Tajima K, Harada R, Fukuoka M, Yamamoto N. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014 Oct;15(11):1236-44. Epub 2014 Aug 27. Erratum in: Lancet Oncol. 2014 Oct;15(11):e475. link to original article contains protocol PubMed JapicCTI-111390
  2. NEJ026: Saito H, Fukuhara T, Furuya N, Watanabe K, Sugawara S, Iwasawa S, Tsunezuka Y, Yamaguchi O, Okada M, Yoshimori K, Nakachi I, Gemma A, Azuma K, Kurimoto F, Tsubata Y, Fujita Y, Nagashima H, Asai G, Watanabe S, Miyazaki M, Hagiwara K, Nukiwa T, Morita S, Kobayashi K, Maemondo M. Erlotinib plus bevacizumab versus erlotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2019 May;20(5):625-635. Epub 2019 Apr 8. link to original article contains protocol PubMed UMIN000017069

Erlotinib & Ramucirumab

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Nakagawa et al. 2019 (RELAY) 2016-2018 Phase III (E-RT-esc) Erlotinib Superior PFS

Note: the FDA-recommended dose is only provided for ramucirumab.

Targeted therapy

14-day cycles

References

  1. RELAY: Nakagawa K, Garon EB, Seto T, Nishio M, Ponce Aix S, Paz-Ares L, Chiu CH, Park K, Novello S, Nadal E, Imamura F, Yoh K, Shih JY, Au KH, Moro-Sibilot D, Enatsu S, Zimmermann A, Frimodt-Moller B, Visseren-Grul C, Reck M; RELAY Study Investigators. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Dec;20(12):1655-1669. Epub 2019 Oct 4. link to original article contains protocol PubMed NCT02411448

GCP

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GCP: Gefitinib, Carboplatin, Pemetrexed

Regimen variant #1, 4 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Noronha et al. 2019 2016-2018 Phase III (E-esc) Gefitinib Superior OS

Targeted therapy

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • Gefitinib & Pemetrexed maintenance

Regimen variant #2, 6 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hosomi et al. 2019 (NEJ009) 2011-2015 Phase III (E-esc) Gefitinib Seems to have superior OS

Targeted therapy

Chemotherapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Gefitinib & Pemetrexed maintenance

References

  1. NEJ009: Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, Minato K, Takamura K, Hagiwara K, Kobayashi K, Nukiwa T, Inoue A; North-East Japan Study Group. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 2020 Jan 10;38(2):115-123. Epub 2019 Nov 4. link to original article contains verified protocol PubMed
  2. Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, Kadam N, Daware N, Bhattacharjee A, Shah S, Yadav A, Trivedi V, Behel V, Dutt A, Banavali SD, Prabhash K. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. Epub 2019 Aug 14. link to original article contains verified protocol PubMed

Gefitinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Mitsudomi et al. 2009 (WJTOG3405) 2006-2009 Phase III (E-switch-ooc) Cisplatin & Docetaxel Superior PFS
Maemondo et al. 2010 (NEJ002) 2006-2009 Phase III (E-switch-ooc) Carboplatin & Paclitaxel Superior PFS
Urata et al. 2016 (WJOG 5108L) 2009-2012 Phase III (C) Erlotinib Inconclusive whether non-inferior PFS
Yang et al. 2017 (CTONG 0901) 2009-2014 Phase III (C) Erlotinib Did not meet primary endpoint of PFS
Douillard et al. 2014 (IFUM) 2010-2012 Phase IV (RT) ORR: 70% (95% CI: 60.5–78)
Park et al. 2016 (LUX-Lung 7) 2011-2013 Randomized Phase II (C) Afatinib Seems to have inferior PFS
Hosomi et al. 2019 (NEJ009) 2011-2015 Phase III (C) GCP Seems to have inferior OS
Cheng et al. 2016 (JMIT) 2012-2013 Randomized Phase II (C) P+G Seems to have inferior PFS
Patil et al. 2017 2012-2016 Phase III (E-switch-ooc) Carboplatin & Pemetrexed, then Pem maint. Superior PFS
Wu et al. 2017 (ARCHER 1050) 2013-2015 Phase III (C) Dacomitinib Seems to have inferior OS (*)
Soria et al. 2017 (FLAURA) 2014-2016 Phase III (C) Osimertinib Seems to have inferior OS (*)
Noronha et al. 2019 2016-2018 Phase III (C) GCP Inferior OS

Note: these are all trials restricted to EGFR-mutated lung cancer, with the exception of WJOG 5108L, which nevertheless had 72% EGFR-mutated patients. Reported efficacy for ARCHER 1050 is based on the 2018 update. Reported efficacy for FLAURA is based on the 2019 update.

Targeted therapy

Continued indefinitely

References

  1. WJTOG3405: Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, Satouchi M, Tada H, Hirashima T, Asami K, Katakami N, Takada M, Yoshioka H, Shibata K, Kudoh S, Shimizu E, Saito H, Toyooka S, Nakagawa K, Fukuoka M; West Japan Thoracic Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010 Feb;11(2):121-8. Epub 2009 Dec 18. link to original article contains verified protocol PubMed UMIN000000539
    1. Update: Yoshioka H, Shimokawa M, Seto T, Morita S, Yatabe Y, Okamoto I, Tsurutani J, Satouchi M, Hirashima T, Atagi S, Shibata K, Saito H, Toyooka S, Yamamoto N, Nakagawa K, Mitsudomi T. Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. Ann Oncol. 2019 Dec 1;30(12):1978-1984. link to original article PubMed
  2. NEJ002: Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8. link to original article contains verified protocol PubMed UMIN000000376
    1. HRQoL analysis: Oizumi S, Kobayashi K, Inoue A, Maemondo M, Sugawara S, Yoshizawa H, Isobe H, Harada M, Kinoshita I, Okinaga S, Kato T, Harada T, Gemma A, Saijo Y, Yokomizo Y, Morita S, Hagiwara K, Nukiwa T. Quality of life with gefitinib in patients with EGFR-mutated non-small cell lung cancer: quality of life analysis of North East Japan Study Group 002 Trial. Oncologist. 2012;17(6):863-70. Epub 2012 May 11. link to original article link to PMC article PubMed
    2. Update: Inoue A, Kobayashi K, Maemondo M, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol. 2013 Jan;24(1):54-9. Epub 2012 Sep 11. link to original article PubMed
  3. IFUM: Douillard JY, Ostoros G, Cobo M, Ciuleanu T, McCormack R, Webster A, Milenkova T. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: a phase-IV, open-label, single-arm study. Br J Cancer. 2014 Jan 7;110(1):55-62. Epub 2013 Nov 21. link to original article contains verified protocol link to PMC article PubMed
  4. LUX-Lung 7: Park K, Tan EH, O'Byrne K, Zhang L, Boyer M, Mok T, Hirsh V, Yang JC, Lee KH, Lu S, Shi Y, Kim SW, Laskin J, Kim DW, Arvis CD, Kölbeck K, Laurie SA, Tsai CM, Shahidi M, Kim M, Massey D, Zazulina V, Paz-Ares L. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. Epub 2016 Apr 12. link to original article contains protocol PubMed NCT01466660
  5. 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 verified protocol PubMed
  6. JMIT: Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JC. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016 Sep 20;34(27):3258-66. Epub 2016 Aug 9. link to original article contains verified protocol PubMed NCT01469000
  7. CTONG 0901: Yang JJ, Zhou Q, Yan HH, Zhang XC, Chen HJ, Tu HY, Wang Z, Xu CR, Su J, Wang BC, Jiang BY, Bai XY, Zhong WZ, Yang XN, Wu YL. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer. 2017 Feb 28;116(5):568-574. Epub 2017 Jan 19. link to original article contains protocol link to PMC article PubMed NCT01024413
  8. Patil VM, Noronha V, Joshi A, Choughule AB, Bhattacharjee A, Kumar R, Goud S, More S, Ramaswamy A, Karpe A, Pande N, Chandrasekharan A, Goel A, Talreja V, Mahajan A, Janu A, Purandare N, Prabhash K. Phase III study of gefitinib or pemetrexed with carboplatin in EGFR-mutated advanced lung adenocarcinoma. ESMO Open. 2017 Apr 27;2(1):e000168. link to original article link to PMC article PubMed
  9. ARCHER 1050: Wu YL, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Tsuji F, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Nadanaciva S, Sandin R, Mok TS. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017 Nov;18(11):1454-1466. Epub 2017 Sep 25. link to original article contains verified protocol PubMed
    1. Update: Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, Lee M, Linke R, Rosell R, Corral J, Migliorino MR, Pluzanski A, Sbar EI, Wang T, White JL, Wu YL. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J Clin Oncol. 2018 Aug 1;36(22):2244-2250. Epub 2018 Jun 4. link to original article PubMed
  10. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains verified protocol PubMed NCT02296125
    1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
    2. Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article PubMed
  11. NEJ009: Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, Takahashi K, Fujita Y, Harada T, Minato K, Takamura K, Hagiwara K, Kobayashi K, Nukiwa T, Inoue A; North-East Japan Study Group. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. J Clin Oncol. 2020 Jan 10;38(2):115-123. Epub 2019 Nov 4. link to original article contains verified protocol PubMed
  12. Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, Janu A, Purandare N, Kumar R, More S, Goud S, Kadam N, Daware N, Bhattacharjee A, Shah S, Yadav A, Trivedi V, Behel V, Dutt A, Banavali SD, Prabhash K. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. J Clin Oncol. 2020 Jan 10;38(2):124-136. Epub 2019 Aug 14. link to original article contains verified protocol PubMed

Gefitinib & Pemetrexed

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P+G: Pemetrexed and Gefitinib

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Cheng et al. 2016 (JMIT) 2012-2013 Randomized Phase II (E-esc) Gefitinib Seems to have superior PFS

Targeted therapy

Chemotherapy

21-day cycles

References

  1. JMIT: Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, Kim JH, Wang X, Enatsu S, Puri T, Orlando M, Yang JC. Randomized phase II trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol. 2016 Sep 20;34(27):3258-66. Epub 2016 Aug 9. link to original article contains verified protocol PubMed NCT01469000

Icotinib monotherapy

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Shi et al. 2017 (CONVINCE) 2013-2014 Phase III (E-switch-ooc) Cisplatin & Pemetrexed x 4, then Pemetrexed maintenance Superior PFS

Note: this drug is only approved in China; eligible patients had stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations.

Targeted therapy

Continued indefinitely

References

  1. CONVINCE: Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article contains verified protocol PubMed NCT01719536

Osimertinib monotherapy

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Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Soria et al. 2017 (FLAURA) 2014-2016 Phase III (E-RT-switch-ic) 1. Erlotinib
2. Gefitinib 		Seems to have superior OS (*)

Patients were required to have EGFR exon 19 deletion or p.L858R mutation. Reported efficacy is based on the 2019 update.

Targeted therapy

Continued indefinitely

References

  1. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains verified protocol PubMed NCT02296125
    1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
    2. Update: Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y, Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R, Saggese M, Rukazenkov Y, Soria JC; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41-50. Epub 2019 Nov 21. link to original article PubMed


Advanced or metastatic disease, EGFR inhibitor-exposed

Afatinib monotherapy

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Regimen

Study Evidence Efficacy
Katakami et al. 2013 (LUX-Lung 4) Phase II ORR: 8% (95% CI: 3-18)

In LUX-Lung 4, 72.6% of patients were EGFR mutation positive. This was third or fourth line therapy for participants, who had progressed while receiving erlotinib and/or gefitinib and had received one or two previous lines of chemotherapy, including at least one platinum-based regimen.

Targeted therapy

Continued indefinitely

References

  1. LUX-Lung 4: Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, Ichinose Y, Koboyashi K, Takeda K, Kiura K, Nishio K, Seki Y, Ebisawa R, Shahidi M, Yamamoto N. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013 Sep 20;31(27):3335-41. Epub 2013 Jul 1. link to original article contains verified protocol PubMed

Afatinib & Bevacizumab

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Regimen

Study Years of enrollment Evidence
Hata et al. 2018 2014-2017 Phase II

Targeted therapy

21-day cycles

References

  1. Hata A, Katakami N, Kaji R, Yokoyama T, Kaneda T, Tamiya M, Inoue T, Kimura H, Yano Y, Tamura D, Morita S, Negoro S; Hanshin Oncology Group F. Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study). Cancer. 2018 Oct 1;124(19):3830-3838. Epub 2018 Sep 7. link to original article PubMed

Afatinib & Cetuximab

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Regimen

Study Evidence Efficacy
Janjigian et al. 2014 (BI 1200.71) Phase Ib ORR: 29%

Targeted therapy

14-day cycles

References

  1. BI 1200.71: Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, Riely GJ, Wang B, Fu Y, Chand VK, Miller VA, Pao W. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014 Sep;4(9):1036-45. Epub 2014 Jul 29. link to original article link to PMC article contains verified protocol PubMed

Cisplatin & Pemetrexed

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Soria et al. 2015 (IMPRESS) 2012-2013 Phase III (C) Cisplatin, Pemetrexed, Gefitinib Did not meet primary endpoint of PFS

Patients enrolled in IMPRESS were EGFR mutation positive and had progression after first-line gefitinib.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

References

  1. IMPRESS: Soria JC, Wu YL, Nakagawa K, Kim SW, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Lee DH, Liu Y, Yoh K, Zhou JY, Shi X, Webster A, Jiang H, Mok TS. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015 Aug;16(8):990-8. Epub 2015 Jul 6. link to original article contains verified protocol PubMed NCT01544179
    1. Update: Mok TSK, Kim SW, Wu YL, Nakagawa K, Yang JJ, Ahn MJ, Wang J, Yang JC, Lu Y, Atagi S, Ponce S, Shi X, Rukazenkov Y, Haddad V, Thress KS, Soria JC. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J Clin Oncol. 2017 Dec 20;35(36):4027-4034. Epub 2017 Oct 2. link to original article PubMed

Osimertinib monotherapy for Leptomeningeal metastasis (LM)

Regimen

Study Evidence Efficacy
Yang et al. 2020 (BLOOM) Phase I BICR- LM ORR (62%), DoR 15.2 months

Investigator- LM ORR (41%), DoR 8.3 months

Patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy. BICR- Blinded Independent Central Review, DoR- Duration of Response, ORR-Objective response rate

Targeted therapy

Continued indefinitely

References.

  1. Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, Brown AP, Collins B, Chmielecki J, Vishwanathan K, Mendoza-Naranjo A, Ahn MJ. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. 2020 Feb 20;38(6):538-547. doi: 10.1200/JCO.19.00457. Epub 2019 Dec 6. link to original article PubMed

Advanced or metastatic disease, EGFR p.T790M mutation

Carboplatin & Pemetrexed

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2016 (AURA3) 2014-2015 Phase III (C) Osimertinib Inferior PFS

Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol link to PMC article PubMed NCT02151981
    1. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
    2. Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Aug 27:S0923-7534(20)42155-6. Epub ahead of print. link to original article PubMed

Cisplatin & Pemetrexed

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mok et al. 2016 (AURA3) 2014-2015 Phase III (C) Osimertinib Inferior PFS

Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.

Chemotherapy

Supportive medications

21-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol link to PMC article PubMed NCT02151981
    1. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
    2. Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Aug 27:S0923-7534(20)42155-6. Epub ahead of print. link to original article PubMed

Docetaxel & Bevacizumab

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Nie et al. 2018 (QingdaoCH20161101) 2015-2016 Phase III (C) Osimertinib Inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. Enrolled patients had EGFR p.T790M mutations.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. QingdaoCH20161101: Nie K, Zhang Z, Zhang C, Geng C, Zhang L, Xu X, Liu S, Wang S, Zhuang X, Lan K, Ji Y. Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:5-11. Epub 2018 Apr 17. link to original article contains protocol PubMed NCT02959749

Osimertinib monotherapy

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Regimen

FDA-recommended dose


Study Years of enrollment Evidence Comparator Comparative Efficacy
Jänne et al. 2015 (AURA) 2013-NR Phase 1, >20 pts in this dosing cohort (RT)
Goss et al. 2016 (AURA2) 2014 Phase II (RT)
Mok et al. 2016 (AURA3) 2014-2015 Phase III (E-RT-switch-ooc) 1. Carboplatin & Pemetrexed
2. Cisplatin & Pemetrexed 		Superior PFS
Nie et al. 2018 (QingdaoCH20161101) 2015-2016 Phase III (E-switch-ooc) Docetaxel & Bevacizumab Superior PFS

Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy, and were required to have presence of an EGFR p.T790M mutation.

Targeted therapy

Continued indefinitely

References

  1. Phase 1: Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. link to original article contains verified protocol PubMed
  2. AURA2: Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. Epub 2016 Oct 14. link to original article PubMed
  3. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains verified protocol link to PMC article PubMed NCT02151981
    1. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
    2. Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Aug 27:S0923-7534(20)42155-6. Epub ahead of print. link to original article PubMed
  4. QingdaoCH20161101: Nie K, Zhang Z, Zhang C, Geng C, Zhang L, Xu X, Liu S, Wang S, Zhuang X, Lan K, Ji Y. Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:5-11. Epub 2018 Apr 17. link to original article contains protocol PubMed NCT0295974
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