Colorectal cancer, RAS wild-type

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 Travis Zack, MD, PhD
University of California San Francisco
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Note: the page has systemic regimens for the more general category of RAS wild-type colorectal cancer. Also note that most of the regimens were evaluated on patients tested for KRAS mutations only, and that the definition of wild-type has evolved over time. See individual regimen biomarker eligibility criteria for more details.

24 regimens on this page
35 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

Japanese Society for Cancer of the Colon and Rectum

NCCN

Perioperative therapy for oligometastatic disease

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (C) 1a. FOLFIRI & Cetuximab
1b. mFOLFOX6 & Cetuximab 		Inferior OS

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

14-day cycles until lesions deemed resectable or up to 12 cycles

References

  1. Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

FOLFIRI & Cetuximab

FOLFIRI & Cetuximab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Cetuximab

Regimen variant #1, weekly cetuximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (E-esc) 1a. FOLFIRI
1b. mFOLFOX6 		Superior OS (secondary endpoint)
Median OS: 30.9 vs 21 mo
(HR 0.54, 95% CI 0.33-0.88)

Superior rate of patients converted to resection for liver metastases (primary endpoint)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first:
    • Cycle 1: 400 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 8
    • Cycles 2 up to 12: 250 mg/m2 IV once per day on days 1 & 8

14-day cycles until lesions deemed resectable or up to 12 cycles


Regimen variant #2, bi-weekly cetuximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (E-esc) 1a. FOLFIRI
1b. mFOLFOX6 		Superior OS (secondary endpoint)
Median OS: 30.9 vs 21 mo
(HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

Targeted therapy

14-day cycles until lesions deemed resectable or up to 12 cycles

References

  1. Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

mFOLFOX6

mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen variant #1, 400/2800/85, resectable or suboptimally resectable

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Primrose et al. 2014 (New EPOC) 2007-2012 Phase 3 (C) mFOLFOX6 & Cetuximab Did not meet primary endpoint of PFS1
Median PFS: 22.2 vs 15.5 mo
(HR 0.85, 95% CI 0.64-1.15)

1Reported efficacy is based on the 2020 update.
Note: this trial was only open to KRAS wild-type patients with resectable or suboptimally resectable colorectal liver metastases.

Biomarker eligibility criteria

  • KRAS wild-type

Chemotherapy

14-day cycle for 6 cycles, then surgery, then 14-day cycle for 6 cycles


Regimen variant #2, 400/2800/85, unresectable

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (C) 1a. FOLFIRI & Cetuximab
1b. mFOLFOX6 & Cetuximab 		Inferior OS

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

14-day cycles until lesions deemed resectable or up to 12 cycles

References

  1. Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810
  2. New EPOC: Primrose J, Falk S, Finch-Jones M, Valle J, O'Reilly D, Siriwardena A, Hornbuckle J, Peterson M, Rees M, Iveson T, Hickish T, Butler R, Stanton L, Dixon E, Little L, Bowers M, Pugh S, Garden OJ, Cunningham D, Maughan T, Bridgewater J. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis: the New EPOC randomised controlled trial. Lancet Oncol. 2014 May;15(6):601-11. Epub 2014 Apr 7. Erratum in: Lancet Oncol. 2014 Jun;15(7):e253. link to original article PubMed ISRCTN22944367
    1. Update: Bridgewater JA, Pugh SA, Maishman T, Eminton Z, Mellor J, Whitehead A, Stanton L, Radford M, Corkhill A, Griffiths GO, Falk S, Valle JW, O'Reilly D, Siriwardena AK, Hornbuckle J, Rees M, Iveson TJ, Hickish T, Garden OJ, Cunningham D, Maughan TS, Primrose JN; New EPOC investigators. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):398-411. Epub 2020 Jan 31. link to original article link to PMC article PubMed

mFOLFOX6 & Cetuximab

mFOLFOX6 & Cetuximab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Cetuximab

Regimen variant #1, weekly cetuximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (E-esc) 1a. FOLFIRI
1b. mFOLFOX6 		Superior OS (secondary endpoint)
Median OS: 30.9 vs 21 mo
(HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first:
    • Cycle 1: 400 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 8
    • Cycles 2 up to 12: 250 mg/m2 IV once per day on days 1 & 8

14-day cycles until lesions deemed resectable or up to 12 cycles


Regimen variant #2, bi-weekly cetuximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03) 2008-2011 Phase 3 (E-esc) 1a. FOLFIRI
1b. mFOLFOX6 		Superior OS (secondary endpoint)
Median OS: 30.9 vs 21 mo
(HR 0.54, 95% CI 0.33-0.88)

Note: this trial was only open to KRAS wild-type patients with synchronous liver-confined unresectable metastases.

Chemotherapy

Targeted therapy

14-day cycles until lesions deemed resectable or up to 12 cycles

References

  1. Fudan 2012-03: Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY, Xu J. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol. 2013 Jun 1;31(16):1931-8. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT01564810

Advanced or metastatic disease, first-line

CapeOx & Panitumumab

CapeOx & Panitumumab: Capecitabine, Oxaliplatin, Panitumumab

Regimen

Study Evidence
Papaxoinis et al. 2018 (HE 6A/09) Phase 2

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

21-day cycles

References

  1. HE 6A/09: Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol. 2018 May 31;35(7):101. link to original article contains dosing details in manuscript PubMed NCT01215539

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) 2004-07 to 2005-11 Phase 3 (C) FOLFIRI & Cetuximab Inferior OS1

1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Biomarker eligibility criteria

  • CRYSTAL: none

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given second (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin

14-day cycles

References

  1. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains dosing details in manuscript PubMed NCT00154102
    1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed
    2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
    3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed

FOLFIRI & Bevacizumab

FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Heinemann et al. 2014 (FIRE-3) 2007-2012 Phase 3 (E-switch-ic) FOLFIRI & Cetuximab Did not meet primary endpoint of ORR

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin

Targeted therapy

  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given second
    • In FIRE-3, initial infusion is over 90 minutes, next over 60 minutes, and subsequently over 30 minutes

14-day cycles

References

  1. FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31.link to original article PubMed NCT00433927

FOLFIRI & Cetuximab

FOLFIRI & Cetuximab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) 2004-07 to 2005-11 Phase 3 (E-RT-esc) FOLFIRI Superior OS1 (secondary endpoint)
Median OS: 23.5 vs 19.5 mo
(HR 0.81, 95% CI 0.69-0.94)

Seems to have superior PFS (primary endpoint)
Median PFS: 8.9 vs 8 mo
(aHR 0.85, 95% CI 0.72-0.99)
Heinemann et al. 2014 (FIRE-3) 2007-2012 Phase 3 (E-switch-ooc) FOLFIRI & Bevacizumab Did not meet primary endpoint of ORR

1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Biomarker eligibility criteria

  • CRYSTAL: none
  • FIRE-3: Wild-type KRAS, Wild-type NRAS

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given second, 1 hour after completion of cetuximab, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given second, 1 hour after completion of cetuximab, with leucovorin

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first and completed at least 1 hour before FOLFIRI begins:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

  1. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains dosing details in manuscript PubMed NCT00154102
    1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed
    2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
    3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
  2. FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. link to original article PubMed NCT00433927

FOLFIRI & Cetuximab (L-Leucovorin)

FOLFIRI & Cetuximab: L-FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) 2004-07 to 2005-11 Phase 3 (E-RT-esc) FOLFIRI Superior OS1 (secondary endpoint)
Median OS: 23.5 vs 19.5 mo
(HR 0.81, 95% CI 0.69-0.94)
Heinemann et al. 2014 (FIRE-3) 2007-2012 Phase 3 (E-switch-ooc) FOLFIRI & Bevacizumab Did not meet primary endpoint of ORR

1Reported efficacy for CRYSTAL is based on the 2012 pooled update and is only for KRAS wild-type tumors.

Biomarker eligibility criteria

  • CRYSTAL: none
  • FIRE-3: Wild-type KRAS, Wild-type NRAS

Chemotherapy

  • Levoleucovorin (Fusilev) 200 mg/m2 IV over 2 hours once on day 1, given second, 1 hour after completion of cetuximab, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given second, 1 hour after completion of cetuximab, with L-leucovorin

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first and completed at least 1 hour before FOLFIRI begins:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

  1. CRYSTAL: Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. link to original article contains dosing details in manuscript PubMed NCT00154102
    1. Update: Van Cutsem E, Köhne CH, Láng I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011 May 20;29(15):2011-9. Epub 2011 Apr 18. link to original article contains dosing details in manuscript PubMed
    2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
    3. Biomarker analysis: Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH, Ciardiello F. Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015 Mar 1;33(7):692-700. Epub 2015 Jan 20. link to original article PubMed
  2. FIRE-3: Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Müller S, Link H, Niederle N, Rost A, Höffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Sep;15(10):1065-75. Epub 2014 Jul 31. link to original article PubMed NCT00433927

FOLFIRINOX

FOLFIRINOX: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, OXaliplatin
FOLFOXIRI: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Modest et al. 2019 (VOLFI) 2011-2016 Randomized Phase 2 (C) FOLFOXIRI & Panitumumab Inferior ORR

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

14-day cycle until POD or resectability or to max 12 cycles

References

  1. VOLFI: Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. link to original article contains dosing details in manuscript PubMed NCT01328171

FOLFOX4

FOLFOX4: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bokemeyer et al. 2008 (OPUS) 2005-2006 Randomized Phase 2 (C) FOLFOX4 & Cetuximab Inferior OS1
Douillard et al. 2010 (PRIME) 2006-2008 Phase 3 (C) FOLFOX4 & Panitumumab Seems to have inferior PFS2
Qin et al. 2018 (TAILOR-CRC) 2010-NR Phase 3 (C) FOLFOX4 & Cetuximab Seems to have inferior OS

1Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
2In PRIME, patients with KRAS wild-type tumors receiving this regimen seem to have inferior OS, based on the 2014 update. Conversely, in KRAS mutants, this regimen seems to have superior PFS.
Note: TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.

Chemotherapy

  • Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given first, with oxaliplatin on day 1
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given second (total dose per cycle: 2000 mg/m2)
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given first

14-day cycles

References

  1. OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains dosing details in manuscript PubMed NCT00125034
    1. Update: Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. link to original article PubMed
    2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
  2. PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed NCT00364013
    1. Biomarker analysis: Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article PubMed
    2. Update: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. link to original article PubMed
  3. TAILOR-CRC: Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. link to original article contains dosing details in abstract link to PMC article PubMed NCT01228734

FOLFOX4 & Cetuximab

FOLFOX4 & Cetuximab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bokemeyer et al. 2008 (OPUS) 2005-2006 Randomized Phase 2 (E-esc) FOLFOX4 Superior OS1 (secondary endpoint)
Median OS: 23.5 vs 19.5 mo
(HR 0.81, 95% CI 0.69-0.94)

Might have superior ORR (primary endpoint)
Qin et al. 2018 (TAILOR-CRC) 2010-NR Phase 3 (E-esc) FOLFOX4 Seems to have superior OS (secondary endpoint)
Median OS: 20.7 vs 17.8 mo
(HR 0.76, 95% CI 0.61-0.96)

Superior PFS (primary endpoint)
Median PFS: 9.2 vs 7.4 mo
(HR 0.69, 95% CI 0.54-0.89)

1Reported efficacy for OPUS is based on the 2012 pooled update and is only for KRAS wild-type tumors.
TAILOR required RAS wild-type (not just KRAS). Note that there is another trial named TAILOR in non-small cell lung cancer, so this one has been dubbed TAILOR-CRC.

Biomarker eligibility criteria

  • OPUS: none
  • TAILOR-CRC: Wild-type KRAS, Wild-type NRAS

Chemotherapy

  • Leucovorin (Folinic acid) 200 mg/m2 IV over 2 hours once per day on days 1 & 2, given second, with oxaliplatin on day 1
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 & 2, then 600 mg/m2 IV continuous infusion over 22 hours after each bolus, given third (total dose per cycle: 2000 mg/m2)
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1, given second

Targeted therapy

  • Cetuximab (Erbitux) given first, as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8

14-day cycles

References

  1. OPUS: Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):663-71. Epub 2008 Dec 29. link to original article contains dosing details in manuscript PubMed NCT00125034
    1. Update: Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011 Jul;22(7):1535-46. Epub 2011 Jan 12. link to original article PubMed
    2. Pooled update: Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Köhne CH. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012 Jul;48(10):1466-75. Epub 2012 Mar 23. link to original article PubMed
  2. TAILOR-CRC: Qin S, Li J, Wang L, Xu J, Cheng Y, Bai Y, Li W, Xu N, Lin LZ, Wu Q, Li Y, Yang J, Pan H, Ouyang X, Qiu W, Wu K, Xiong J, Dai G, Liang H, Hu C, Zhang J, Tao M, Yao Q, Wang J, Chen J, Eggleton SP, Liu T. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018 Oct 20;36(30):3031-9. Epub 2018 Sep 10. link to original article contains dosing details in abstract link to PMC article PubMed NCT01228734

FOLFOX4 & Panitumumab

FOLFOX4 & Panitumumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Panitumumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Douillard et al. 2010 (PRIME) 2006-2008 Phase 3 (E-RT-esc) FOLFOX4 Seems to have superior PFS (primary endpoint)
Median PFS: 9.6 vs 8 mo
(HR 0.80, 95% CI 0.66-0.97)

Seems to have superior OS1 (secondary endpoint)
Median OS: 23.8 vs 19.4 mo
(HR 0.83, 95% CI 0.70-0.98)

1In KRAS wild-type patients, this regimen seems to have superior OS, based on the exploratory analysis in the 2014 update.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

  • Panitumumab (Vectibix) 6 mg/kg IV once on day 1, given first
    • Infusion times are 1 hour for cycle 1, then if tolerated, 30 minutes for cycle 2 and later

14-day cycles

References

  1. PRIME: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010 Nov 1;28(31):4697-705. Epub 2010 Oct 4. link to original article PubMed NCT00364013
    1. Biomarker analysis: Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013 Sep 12;369(11):1023-34. link to original article PubMed
    2. Update: Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346-55. Epub 2014 Apr 8. link to original article PubMed

mFOLFOX6-B

mFOLFOX6-B: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Venook et al. 2017 (CALGB 80405) 2005-2012 Phase 3 (E-switch-ic) 1a. mFOLFOX6 & Cetuximab
1b. FOLFIRI & Cetuximab 		Did not meet primary endpoint of OS
2a. mFOLFOX6, Bevacizumab, Cetuximab
2b. FOLFIRI, Bevacizumab, Cetuximab 		Not reported
Schwartzberg et al. 2014 (PEAK) 2009-2011 Randomized Phase 2 (C) mFOLFOX6 & Panitumumab Seems to have inferior PFS1
Watanabe et al. 2023 (PARADIGMCRC) 2015-05 to 2022-01 Phase 3 (C) mFOLFOX6 & Panitumumab Seems to have inferior OS

1Reported efficacy for PEAK is based on the 2017 update.
Note: In CALGB 80405, the arm receiving bevacizumab and cetuximab was terminated early.

Chemotherapy

Targeted therapy

14-day cycles

References

  1. CALGB 80405: Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00265850
  2. PEAK: Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. link to original article PubMed NCT00819780
    1. Update: Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. link to original article link to PMC article PubMed
  3. PARADIGMCRC: Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. link to original article link to PMC article PubMed NCT02394795

mFOLFOX6 & Cetuximab

mFOLFOX6 & Cetuximab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Venook et al. 2017 (CALGB 80405) 2005-2012 Phase 3 (E-switch-ic) 1a. mFOLFOX6-B
1b. FOLFIRI & Bevacizumab 		Did not meet primary endpoint of OS
2a. mFOLFOX6, Bevacizumab, Cetuximab
2b. FOLFIRI, Bevacizumab, Cetuximab 		Not reported
Aranda et al. 2018 (MACRO-2) 2010-NR Non-randomized part of phase 2 RCT

Note: In CALGB 80405, the arm receiving bevacizumab and cetuximab was terminated early.

Biomarker eligibility criteria

  • CALGB 80405: Wild-type KRAS (codons 12 & 13)
  • MACRO-2: Wild-type KRAS (exons 3 & 4), Wild-type NRAS (exons 2 to 4)

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows, given first:
    • Cycle 1: 400 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 8
    • Cycle 2 onwards: 250 mg/m2 IV once per day on days 1 & 8

14-day cycles (see below)

Subsequent treatment

References

  1. CALGB 80405: Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 20;317(23):2392-2401. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00265850
  2. MACRO-2: Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. link to original article PubMed NCT01161316

mFOLFOX6 & Panitumumab

mFOLFOX6 & Panitumumab: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Panitumumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schwartzberg et al. 2014 (PEAK) 2009-2011 Randomized Phase 2 (E-switch-ooc) mFOLFOX6-B Seems to have superior PFS1 (primary endpoint)
Median PFS: 12.8 vs 10.1 mo
(HR 0.68, 95% CI 0.48-0.96)

Did not meet secondary endpoint of OS1
Median OS: 36.9 vs 28.9 mo
(HR 0.76, 95% CI 0.53-1.11)
Watanabe et al. 2023 (PARADIGMCRC) 2015-05 to 2022-01 Phase 3 (E-switch-ooc) mFOLFOX6-B Seems to have superior OS2 (primary endpoint)
Median OS: 37.9 vs 34.3 mo
(HR 0.82, 95.798% CI 0.68-0.99)
Rossini et al. 2022 (TRIPLETE) 2017-2021 Phase 3 (C) mFOLFOXIRI & Panitumumab Did not meet primary endpoint of ORR

1Reported efficacy for PEAK is based on the 2017 update.
2Reported efficacy is for patients with left-sided primary tumors, which was the primary analysis; efficacy results for the overall population were similar.

Biomarker eligibility criteria

  • TRIPLETE: Wild-type KRAS (exons 2 to 4), wild-type NRAS (exons 2 to 4), wild-type BRAF codon 600

Chemotherapy

Targeted therapy

14-day cycles

References

  1. PEAK: Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 2014 Jul 20;32(21):2240-7. Epub 2014 Mar 31. link to original article PubMed NCT00819780
    1. Update: Rivera F, Karthaus M, Hecht JR, Sevilla I, Forget F, Fasola G, Canon JL, Guan X, Demonty G, Schwartzberg LS. Final analysis of the randomised PEAK trial: overall survival and tumour responses during first-line treatment with mFOLFOX6 plus either panitumumab or bevacizumab in patients with metastatic colorectal carcinoma. Int J Colorectal Dis. 2017 Aug;32(8):1179-1190. Epub 2017 Apr 19. link to original article link to PMC article PubMed
  2. TRIPLETE: Rossini D, Antoniotti C, Lonardi S, Pietrantonio F, Moretto R, Antonuzzo L, Boccaccino A, Morano F, Brugia M, Pozzo C, Marmorino F, Bergamo F, Tamburini E, Passardi A, Randon G, Murgioni S, Borelli B, Buonadonna A, Giordano M, Fontanini G, Conca V, Formica V, Aglietta M, Bordonaro R, Aprile G, Masi G, Boni L, Cremolini C. Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO. J Clin Oncol. 2022 Sep 1;40(25):2878-2888. Epub 2022 Jun 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03231722
  3. PARADIGMCRC: Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. Erratum in: JAMA. 2023 Jun 27;329(24):2196. link to original article link to PMC article PubMed NCT02394795

mFOLFOXIRI & Cetuximab (L-Leucovorin)

mFOLFOXIRI & Cetuximab: modified L-FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Cetuximab

Regimen

Study Evidence
Cremolini et al. 2018 (MACBETH) Non-randomized part of phase 2 RCT

Note: 5-FU instructions are unusual in that no bolus is given.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

14-day cycle for 8 cycles

Subsequent treatment

References

  1. MACBETH: Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02295930

FOLFOXIRI & Panitumumab

FOLFOXIRI & Panitumumab: FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, IRInotecan, Panitumumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Modest et al. 2019 (VOLFI) 2011-2016 Randomized Phase 2 (E-esc) FOLFOXIRI Superior ORR (primary endpoint)

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Chemotherapy

Targeted therapy

14-day cycle until POD or resectability or to max 12 cycles

References

  1. VOLFI: Modest DP, Martens UM, Riera-Knorrenschild J, Greeve J, Florschütz A, Wessendorf S, Ettrich T, Kanzler S, Nörenberg D, Ricke J, Seidensticker M, Held S, Buechner-Steudel P, Atzpodien J, Heinemann V, Seufferlein T, Tannapfel A, Reinacher-Schick AC, Geissler M. FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109). J Clin Oncol. 2019 Dec 10;37(35):3401-3411. Epub 2019 Oct 14. link to original article contains dosing details in manuscript PubMed NCT01328171

Maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hagman et al. 2015 (Nordic ACT2) 2010-2012 Phase 3 (C) Erlotinib & Bevacizumab Did not meet primary endpoint of PFS

Biomarker eligibility criteria

  • Wild-type KRAS

Targeted therapy

21-day cycles

References

  1. Nordic ACT2: Hagman H, Frödin JE, Berglund Å, Sundberg J, Vestermark LW, Albertsson M, Fernebro E, Johnsson A. A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial. Ann Oncol. 2016 Jan;27(1):140-7. Epub 2015 Oct 19. link to original article contains dosing details in manuscript PubMed NCT01229813

Cetuximab monotherapy

Regimen variant #1, 250 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aranda et al. 2018 (MACRO-2) 2010-NR Randomized Phase 2 (E-de-esc) mFOLFOX6 & Cetuximab Non-inferior PFS9 (primary endpoint)

Note: regimen details are from ClinicalTrials.gov; they were not present in the abstract or the manuscript.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Preceding treatment

Targeted therapy

7-day cycles


Regimen variant #2, 500 mg/m2 q2wk

Study Evidence
Cremolini et al. 2018 (MACBETH) Randomized Phase 2

Note: this was a non-comparative study.

Biomarker eligibility criteria

  • Wild-type KRAS, Wild-type NRAS

Preceding treatment

Targeted therapy

14-day cycles

References

  1. MACBETH: Cremolini C, Antoniotti C, Lonardi S, Aprile G, Bergamo F, Masi G, Grande R, Tonini G, Mescoli C, Cardellino GG, Coltelli L, Salvatore L, Corsi DC, Lupi C, Gemma D, Ronzoni M, Dell'Aquila E, Marmorino F, Di Fabio F, Mancini ML, Marcucci L, Fontanini G, Zagonel V, Boni L, Falcone A. Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer: a randomized phase 2 clinical trial. JAMA Oncol. 2018 Apr 1;4(4):529-536. link to original article link to PMC article PubMed NCT02295930
  2. MACRO-2: Aranda E, García-Alfonso P, Benavides M, Sánchez Ruiz A, Guillén-Ponce C, Safont MJ, Alcaide J, Gómez A, López R, Manzano JL, Méndez Ureña M, Sastre J, Rivera F, Grávalos C, García T, Martín-Valadés JI, Falcó E, Navalón M, González Flores E, Ma García Tapiador A, Ma López Muñoz A, Barrajón E, Reboredo M, García Teijido P, Viudez A, Cárdenas N, Díaz-Rubio E; Spanish Cooperative Group for the Treatment of Digestive Tumours. First-line mFOLFOX plus cetuximab followed by mFOLFOX plus cetuximab or single-agent cetuximab as maintenance therapy in patients with metastatic colorectal cancer: phase II randomised MACRO2 TTD study. Eur J Cancer. 2018 Sep;101:263-272. Epub 2018 Jul 24. link to original article PubMed NCT01161316

Advanced or metastatic disease, second-line

FOLFIRI

FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Peeters et al. 2010 (20050181) 2006-2008 Phase 3 (C) FOLFIRI & Panitumumab Seems to have inferior PFS1

1Reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.

Biomarker eligibility criteria

  • None

Prior treatment criteria

  • First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin

14-day cycles

References

  1. 20050181: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. link to original article contains dosing details in manuscript PubMed NCT00339183
    1. Update: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. link to original article PubMed

FOLFIRI & Panitumumab

FOLFIRI & Panitumumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Panitumumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Peeters et al. 2010 (20050181) 2006-2008 Phase 3 (E-esc) FOLFIRI Seems to have superior PFS1 (co-primary endpoint)
Median PFS: 6.7 vs 4.9 mo
(HR 0.82, 95% CI 0.69-0.97)

1Reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.

Biomarker eligibility criteria

  • None

Prior treatment criteria

  • First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

  • Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given second, with irinotecan
  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given third (total dose per cycle: 2800 mg/m2)
  • Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given second, with leucovorin

Targeted therapy

14-day cycles

References

  1. 20050181: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tzekova V, Collins S, Oliner KS, Rong A, Gansert J. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 1;28(31):4706-13. Epub 2010 Oct 4. link to original article contains dosing details in manuscript PubMed NCT00339183
    1. Update: Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, Punt CJ, Strickland AH, Wilson G, Ciuleanu TE, Roman L, Van Cutsem E, Tian Y, Sidhu R. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jan;25(1):107-16. Erratum in: Ann Oncol. 2014 Mar;25(3):757. link to original article PubMed

Irinotecan monotherapy

Example orders

Regimen variant #1, 180 mg/m2 q2wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shi et al. 2019 (CRC009) 2009-2011 Phase 3 (C) Irinotecan & CMAB009 Inferior PFS50%

Prior treatment criteria

  • Exposure to FOLFOX, with progression or discontinuation due to toxicity

Chemotherapy

14-day cycles


Regimen variant #2, 300 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seymour et al. 2013 (PICCOLO) 2006-12-04 to 2008-08-31 Phase 3 (C) 1. Irinotecan & Panitumumab Did not meet primary endpoint of OS
Median OS: 10.9 vs 10.4 mo
(HR 0.99, 95% CI 0.81-1.20)
2. Irinotecan & Cyclosporine Not reported

Note: In some trials, this starting dose was intended for patients who were at least 70 years old, had ECOG performance status 2 or more, or had prior pelvic radiation.

Prior treatment criteria

  • First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

21-day cycles


Regimen variant #3, 350 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seymour et al. 2013 (PICCOLO) 2006-12-04 to 2008-08-31 Phase 3 (C) 1. Irinotecan & Panitumumab Did not meet primary endpoint of OS
Median OS: 10.9 vs 10.4 mo
(HR 0.99, 95% CI 0.81-1.20)
2. Irinotecan & Cyclosporine Not reported

Prior treatment criteria

  • First-line fluoropyrimidine-based chemotherapy, with progression

Chemotherapy

Supportive therapy

21-day cycles

References

  1. PICCOLO: Seymour MT, Brown SR, Middleton G, Maughan T, Richman S, Gwyther S, Lowe C, Seligmann JF, Wadsley J, Maisey N, Chau I, Hill M, Dawson L, Falk S, O'Callaghan A, Benstead K, Chambers P, Oliver A, Marshall H, Napp V, Quirke P. Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. Lancet Oncol. 2013 Jul;14(8):749-59. Epub 2013 May 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00389870
  2. CRC009: Shi Y, Li J, Xu J, Sun Y, Wang L, Cheng Y, Liu W, Sun G, Chen Y, Bai L, Zhang Y, He X, Luo Y, Wang Z, Liu Y, Yao Q, Li Y, Qin S, Hu X, Bi F, Zheng R, Ouyang X. CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients: promising findings from a prospective, open-label, randomized, phase III trial. Cancer Commun (Lond). 2019 May 24;39(1):28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01550055

Irinotecan & Cetuximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sobrero et al. 2008 (EPIC) 2003-2006 Phase 3 (E-esc) Irinotecan Did not meet primary endpoint of OS

Prior treatment criteria

  • First-line fluoropyrimidine and oxaliplatin treatment, with progression or discontinuation due to toxicity

Chemotherapy

  • Irinotecan (Camptosar) by the following criteria:
    • Standard patients: 350 mg/m2 IV over 90 minutes once on day 1
    • If aged 70 years old or more, ECOG performance status 2 or more, or prior pelvic radiation: 300 mg/m2 IV over 90 minutes once on day 1

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

21-day cycles

References

  1. EPIC: Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, Vega-Villegas ME, Eng C, Steinhauer EU, Prausova J, Lenz HJ, Borg C, Middleton G, Kröning H, Luppi G, Kisker O, Zubel A, Langer C, Kopit J, Burris HA 3rd. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008 May 10;26(14):2311-9. Epub 2008 Apr 7. link to original article contains dosing details in manuscript PubMed NCT00063141

Advanced or metastatic disease, subsequent lines of therapy

Cetuximab monotherapy

Example orders

Regimen variant #1, weekly

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Saltz et al. 2004 2001 Phase 2 (RT)
Cunningham et al. 2004 (BOND) 2001-07 to 2002-05 Phase 3 (C) Irinotecan & Cetuximab Inferior TTP
Lenz et al. 2006 (SALVAGE) NR Phase 2
Jonker et al. 2007 (NCIC-CTG CO.17) 2003-2005 Phase 3 (E-RT-esc) Best supportive care Superior OS (primary endpoint)
Median OS: 6.1 vs 4.6 mo
(HR 0.77, 95% CI 0.64-0.92)
Siu et al. 2013 (NCIC-CTG/AGITG CO.20) 2008-2011 Phase 3 (C) Brivanib & Cetuximab Did not meet primary endpoint of OS
Price et al. 2014 (ASPECCT) 2010-2012 Phase 3 (C) Panitumumab Non-inferior OS

Prior treatment criteria

  • Saltz et al. 2004: Exposure to irinotecan-containing therapy, with clinical failure
  • BOND: Exposure to irinotecan-containing therapy, with progression
  • SALVAGE: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine
  • NCIC-CTG CO.17: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine or contraindication to these drugs
  • NCIC-CTG/AGITG CO.20: Exposure to a fluoropyrimidine and exposure to irinotecan and oxaliplatin or contraindication to these drugs

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once on day 1

Supportive therapy

7-day cycles


Regimen variant #2, bi-weekly

Study Evidence
Tabernero et al. 2009 Phase 1

Note: no primary reference could be found for this exact dosing in monotherapy; in the phase I trial it is described as "the most convenient and feasible dose".

Targeted therapy

  • Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
    • If tolerated, subsequent doses can be given over 1 hour

Supportive therapy

14-day cycles

References

  1. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004 Apr 1;22(7):1201-8. Epub 2004 Mar 1. link to original article PubMed
  2. BOND: Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains dosing details in manuscript PubMed
  3. SALVAGE: Lenz HJ, Van Cutsem E, Khambata-Ford S, Mayer RJ, Gold P, Stella P, Mirtsching B, Cohn AL, Pippas AW, Azarnia N, Tsuchihashi Z, Mauro DJ, Rowinsky EK. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006 Oct 20;24(30):4914-21. link to original article contains dosing details in manuscript PubMed
  4. NCIC-CTG CO.17: Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, Berry SR, Krahn M, Price T, Simes RJ, Tebbutt NC, van Hazel G, Wierzbicki R, Langer C, Moore MJ. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007 Nov 15;357(20):2040-8. link to original article contains dosing details in manuscript PubMed NCT00079066
    1. Subgroup analysis: Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757-65. link to original article PubMed
    2. Subgroup analysis: Asmis TR, Powell E, Karapetis CS, Jonker DJ, Tu D, Jeffery M, Pavlakis N, Gibbs P, Zhu L, Dueck DA, Whittom R, Langer C, O'Callaghan CJ. Comorbidity, age and overall survival in cetuximab-treated patients with advanced colorectal cancer (ACRC)--results from NCIC-CTG CO.17: a phase III trial of cetuximab versus best supportive care. Ann Oncol. 2011 Jan;22(1):118-26. Epub 2010 Jul 5. link to original article contains dosing details in manuscript PubMed
  5. Phase I: Tabernero J, Ciardiello F, Rivera F, Rodriguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study. Ann Oncol. 2010 Jul;21(7):1537-45. Epub 2009 Nov 25. link to original article PubMed
  6. NCIC-CTG/AGITG CO.20: Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013 Jul 1;31(19):2477-84. Epub 2013 May 20. link to original article contains dosing details in manuscript PubMed NCT00640471
  7. ASPECCT: Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed NCT01001377
    1. Update: Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. link to original article PubMed

Irinotecan & Cetuximab

Regimen variant #1, 125/250, irinotecan 2 weeks on, 1 week off

FDA-recommended dose

Note: In contrast to BOND, some guidelines list irinotecan as being given on days 1 & 8 of a 21-day cycle. No primary reference could be found for this. Note also that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

21-day cycles


Regimen variant #2, 125/250, irinotecan 4 weeks on, 2 weeks off

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2004 (BOND) 2001-07 to 2002-05 Phase 3 (E-RT-esc) Cetuximab Superior TTP (secondary endpoint)

Superior ORR (primary endpoint)

Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Prior treatment criteria

  • BOND: Exposure to irinotecan-containing therapy, with progression

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8, 15, 22, 29, 36
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36

Supportive therapy

42-day cycles


Regimen variant #3, 150/500, bi-weekly

Study Dates of enrollment Evidence
Osumi et al. 2018 2011-2014 Phase 2

Prior treatment criteria

  • Exposure to fluoropyrimidine‐ and oxaliplatin‐based chemotherapy, with treatment failure

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
    • Subsequent doses are given over 60 minutes

Supportive therapy

14-day cycles


Regimen variant #4, 180/250, bi-weekly, with response adaptation

Study Dates of enrollment Evidence
Van Cutsem et al. 2012 (EVEREST) 2004-2005 Non-randomized part of phase 1/2 RCT

Prior treatment criteria

  • Exposure to irinotecan-containing chemotherapy

Chemotherapy

Targeted therapy

21-day course

Subsequent treatment


Regimen variant #5, 180/500, bi-weekly

Study Dates of enrollment Evidence
Martín-Martorell et al. 2008 2005-2007 Phase 2

Prior treatment criteria

  • One previous line of chemotherapy

Chemotherapy

Targeted therapy

  • Cetuximab (Erbitux) 500 mg/m2 IV over 2 hours once on day 1
    • If tolerated, subsequent doses can be given over 1 hour

Supportive therapy

14-day cycles


Regimen variant #6, 350/250, q3wk irinotecan

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cunningham et al. 2004 (BOND) 2001-07 to 2002-05 Phase 3 (E-RT-esc) Cetuximab Superior TTP (secondary endpoint)

Superior ORR (primary endpoint)

Note that the FDA-recommended dosing is for the cetuximab component; no comment is made about irinotecan dosing.

Prior treatment criteria

  • BOND: Exposure to irinotecan-containing therapy, with progression

Chemotherapy

  • Irinotecan (Camptosar) by the following criteria:
    • Standard patients: 350 mg/m2 IV over 90 minutes once on day 1
    • If aged 70 years old or more, ECOG performance status 2 or more, or prior pelvic radiation: 300 mg/m2 IV over 90 minutes once on day 1

Targeted therapy

  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

21-day cycles

References

  1. BOND: Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. link to original article contains dosing details in manuscript PubMed
  2. Martín-Martorell P, Roselló S, Rodríguez-Braun E, Chirivella I, Bosch A, Cervantes A. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008 Aug 5;99(3):455-8. link to original article contains dosing details in manuscript link to PMC article PubMed
  3. EVEREST: Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X, Vlassak S, Schlichting M, Ciardiello F. Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study. J Clin Oncol. 2012 Aug 10;30(23):2861-8. Epub 2012 Jul 2. link to original article contains dosing details in abstract PubMed
  4. Osumi H, Shinozaki E, Mashima T, Wakatsuki T, Suenaga M, Ichimura T, Ogura M, Ota Y, Nakayama I, Takahari D, Chin K, Miki Y, Yamaguchi K. Phase II trial of biweekly cetuximab and irinotecan as third-line therapy for pretreated KRAS exon 2 wild-type colorectal cancer. Cancer Sci. 2018 Aug;109(8):2567-2575. Epub 2018 Jul 13. link to original article link to PMC article contains dosing details in manuscript PubMed UMIN000019893

Panitumumab monotherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2007 (20020408) 2004-01 to 2005-06 Phase 3 (E-RT-esc) Best supportive care Superior PFS (primary endpoint)
Median PFS: 8 vs 7.3 wks
(HR 0.54, 95% CI 0.44-0.66)
Price et al. 2014 (ASPECCT) 2010-2012 Phase 3 (E-RT-switch-ic) Cetuximab Non-inferior OS (primary endpoint)
Median OS: 10.4 vs 10 mo
(HR 0.97, 95% CI 0.84-1.11)
Kim et al. 2016 (20100007) 2011-2013 Phase 3 (E-RT-esc) Best supportive care Superior OS (primary endpoint)1
Median OS: 10 vs 6.9 mo
(HR 0.72, 95% CI 0.55-0.94)

1Reported efficacy for 20100007 is based on the 2018 update.

Prior treatment criteria

  • 20020408 & 20100007: Exposure to irinotecan, oxaliplatin, and a fluoropyrimidine

Targeted therapy

14-day cycles

References

  1. 20020408: Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, Van Laethem JL, Maurel J, Richardson G, Wolf M, Amado RG. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007 May 1;25(13):1658-64. link to original article contains dosing details in manuscript PubMed NCT00113763
  2. ASPECCT: Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Zhang K, Murugappan S, Sidhu R. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014 May;15(6):569-79. Epub 2014 Apr 14. link to original article PubMed NCT01001377
    1. Update: Price T, Kim TW, Li J, Cascinu S, Ruff P, Suresh AS, Thomas A, Tjulandin S, Guan X, Peeters M. Final results and outcomes by prior bevacizumab exposure, skin toxicity, and hypomagnesaemia from ASPECCT: randomized phase 3 non-inferiority study of panitumumab versus cetuximab in chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer. Eur J Cancer. 2016 Nov;68:51-59. Epub 2016 Oct 5. link to original article PubMed
  3. 20100007: Kim TW, Elme A, Kusic Z, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Bilic A, Manojlovic N, Dong J, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016 Nov 8;115(10):1206-1214. Epub 2016 Oct 13. link to original article link to PMC article PubMed NCT01412957
    1. Update: Kim TW, Elme A, Park JO, Udrea AA, Kim SY, Ahn JB, Valencia RV, Krishnan S, Manojlovic N, Guan X, Lofton-Day C, Jung AS, Vrdoljak E. Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2018 Sep;17(3):206-214. Epub 2018 Mar 21. link to original article PubMed
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