Colon cancer, KRAS wild-type

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Neeta K. Venepalli, MD, MBA
University of Illinois at Chicago
Chicago, IL

Note: the page has adjuvant and perioperative regimens specific to KRAS wild-type colon cancer as well as systemic regimens for the more general category of KRAS wild-type colorectal cancer.

16 regimens on this page
25 variants on this page

Contents


Guidelines

ESMO

Japanese Society for Cancer of the Colon and Rectum

NCCN

Adjuvant therapy

mFOLFOX6 & Cetuximab

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mFOLFOX6 & Cetuximab: modified FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Evidence Comparator Comparative Efficacy
Alberts et al. 2012 (N0147) Phase III (E) mFOLFOX6 Might have inferior DFS

Some guidelines do not recommend using cetuximab as adjuvant therapy outside of a clinical trial.

Preceding treatment

Chemotherapy

  • Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m2)
  • Folinic acid (Leucovorin) 400 mg/m2 IV over 2 hours once on day 1
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
  • 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 on day 8
    • Cycles 2 to 12: 250 mg/m2 IV over 2 hours once per day on days 1 & 8

14-day cycle for 12 cycles

References

  1. N0147: Alberts SR, Sargent DJ, Nair S, Mahoney MR, Mooney M, Thibodeau SN, Smyrk TC, Sinicrope FA, Chan E, Gill S, Kahlenberg MS, Shields AF, Quesenberry JT, Webb TA, Farr GH Jr, Pockaj BA, Grothey A, Goldberg RM. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA. 2012 Apr 4;307(13):1383-93. link to original article contains verified protocol link to PMC article PubMed

Perioperative therapy for oligometastatic disease

FOLFIRI & Cetuximab

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FOLFIRI & Cetuximab: FOLinic acid, Fluorouracil, IRInotecan, Cetuximab

Variant #1, weekly cetuximab

Study Evidence Comparator Comparative Efficacy
Ye et al. 2013 Phase III (E) FOLFIRI Seems to have superior 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

Variant #2, bi-weekly cetuximab

Study Evidence Comparator Comparative Efficacy
Ye et al. 2013 Phase III (E) FOLFIRI Seems to have superior 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. 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 verified protocol PubMed

mFOLFOX6 & Cetuximab

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mFOLFOX6 & Cetuximab: modified FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Variant #1, weekly cetuximab

Study Evidence Comparator Comparative Efficacy
Ye et al. 2013 Phase III (E) mFOLFOX6 Seems to have superior 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

Variant #2, bi-weekly cetuximab

Study Evidence Comparator Comparative Efficacy
Ye et al. 2013 Phase III (E) mFOLFOX6 Seems to have superior 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. 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 verified protocol PubMed

Advanced or metastatic disease, first-line

CapeOx & Panitumumab

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CapeOx & Panitumumab: Capecitabine, Oxaliplatin, Panitumumab

Regimen

Study Evidence
Papaxoinis et al. 2018 Phase II

Chemotherapy

21-day cycles

References

  1. 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 verified protocol PubMed

FOLFIRI & Cetuximab

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FOLFIRI & Cetuximab: FOLinic acid, Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) Phase III (E-RT) FOLFIRI Superior OS (*)
Heinemann et al. 2014 (FIRE-3) Phase III (E) FOLFIRI & Bevacizumab Seems not superior

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

Chemotherapy

  • Folinic acid (Leucovorin) 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
  • 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 verified protocol PubMed
    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 verified protocol 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

FOLFIRI & Cetuximab (L-Leucovorin)

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FOLFIRI & Cetuximab: L-FOLinic acid, Fluorouracil, IRInotecan, Cetuximab

Regimen

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2009 (CRYSTAL) Phase III (E-RT) FOLFIRI Superior OS (*)
Heinemann et al. 2014 (FIRE-3) Phase III (E) FOLFIRI & Bevacizumab Seems not superior

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

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
  • 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 verified protocol PubMed
    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 verified protocol 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

FOLFOX4 & Cetuximab

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FOLFOX4 & Cetuximab: FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Evidence Comparator Comparative Efficacy
Bokemeyer et al. 2008 (OPUS) Randomized Phase II (E) FOLFOX4 Superior OS (*)
Qin et al. 2018 (TAILOR-CRC) Phase III (E) FOLFOX4 Seems to have superior OS

Reported 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.

Chemotherapy

  • Folinic acid (Leucovorin) 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
  • 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 on day 8, given first
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1 & 8, 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 verified protocol PubMed
    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: 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 protocol PubMed

FOLFOX4 & Panitumumab

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FOLFOX4 & Panitumumab: FOLinic acid, Fluorouracil, OXaliplatin, Panitumumab

Regimen

Study Evidence Comparator Comparative Efficacy
Douillard et al. 2010 (PRIME) Phase III (E-RT) FOLFOX4 Seems to have superior OS (*)

Note: in KRAS wild-type patients, this regimen seems to have superior OS, based on the 2014 update.

Chemotherapy

  • 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 (total dose per cycle: 2000 mg/m2)
  • Folinic acid (Leucovorin) 200 mg/m2 IV over 2 hours once per day on days 1 & 2
  • Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
  • 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
    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 & Cetuximab

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mFOLFOX6 & Cetuximab: modified FOLinic acid, Fluorouracil, OXaliplatin, Cetuximab

Regimen

Study Evidence Comparator Comparative Efficacy
Venook et al. 2017 (CALGB 80405) Phase III (C) mFOLFOX6 & Bevacizumab Seems not superior
Aranda et al. 2018 (MACRO-2) Non-randomized portion of RCT

Chemotherapy

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 verified protocol PubMed
  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 (TTD). 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

mFOLFOXIRI & Cetuximab (L-Leucovorin)

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

Regimen

Study Evidence
Cremolini et al. 2018 (MACBETH) Non-randomized portion of RCT

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

Chemotherapy

14-day cycle for 8 cycles

Subsequent treatment

  • If deemed resectable: Surgery
  • If deemed unresectable: Cetuximab versus Bevacizumab maintenance

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 verified protocol link to PMC article PubMed

Maintenance after first-line therapy

Cetuximab monotherapy

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Variant #1, 250 mg/m2 weekly

Study Evidence Comparator Comparative Efficacy
Aranda et al. 2018 (MACRO-2) Randomized Phase II (E) mFOLFOX6 & Cetuximab Non-inferior PFS

Note: regimen details were not available in the abstract.

Preceding treatment

Chemotherapy

7-day cycles

Variant #2, 500 mg/m2 q2wk

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

Note: this was a non-comparative study.

Preceding treatment

Chemotherapy

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
  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 (TTD). 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

Advanced or metastatic disease, second-line

FOLFIRI & Panitumumab

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FOLFIRI & Panitumumab: FOLinic acid, Fluorouracil, IRInotecan, Panitumumab

Regimen

Study Evidence Comparator Comparative Efficacy
Peeters et al. 2010 (20050181) Phase III (E) FOLFIRI Seems to have superior PFS (*)

Note: reported efficacy is for wild-type KRAS, only, and is based on the 2014 update.

Chemotherapy

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 verified protocol PubMed
    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 & Cetuximab

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Regimen

Study Evidence Comparator Comparative Efficacy
Sobrero et al. 2008 (EPIC) Phase III (E) Irinotecan Seems not superior

Chemotherapy

  • Irinotecan (Camptosar) 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
  • 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
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive medications

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 verified protocol PubMed

Advanced or metastatic disease, subsequent lines of therapy

Cetuximab monotherapy

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Example orders

Variant #1, weekly

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Cunningham et al. 2004 (BOND) Phase III (C) Irinotecan & Cetuximab Inferior TTP
Lenz et al. 2006 (SALVAGE) Phase II
Jonker et al. 2007 (NCIC CTG CO.17) Phase III (E-RT) Best supportive care Superior OS
Siu et al. 2013 (NCIC CTG/AGITG CO.20) Phase III (C) Brivanib & Cetuximab Seems not superior
Price et al. 2014 (ASPECCT) Phase III (C) Panitumumab Non-inferior OS

Chemotherapy

  • 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
    • Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles

Variant #2, bi-weekly

Study Evidence
Tabernero et al. 2009 Phase I

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".

Chemotherapy

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

Supportive medications

14-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 verified protocol PubMed
  2. 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 verified protocol PubMed
  3. 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 verified protocol PubMed
    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 verified protocol PubMed
  4. 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
  5. 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 verified protocol PubMed
  6. 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
    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 SD article PubMed

Irinotecan & Cetuximab

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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

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1 & 8
  • 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
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive medications

21-day cycles

Variant #2, 125/250, irinotecan 4 weeks on, 2 weeks off

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Cunningham et al. 2004 (BOND) Phase III (E-RT) Cetuximab Superior TTP

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

Chemotherapy

  • Irinotecan (Camptosar) 125 mg/m2 IV over 90 minutes once per day on days 1, 8, 15, 22
  • 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
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36

Supportive medications

42-day cycles

Variant #3, 150/500, bi-weekly

Study Evidence
Osumi et al. 2018 Phase II

Chemotherapy

Supportive medications

14-day cycles

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

Study Evidence
Van Cutsem et al. 2012 (EVEREST) Non-randomized portion of RCT

Chemotherapy

21-day course

Subsequent treatment

  • Grade 0 or 1 skin reaction: Continue standard dose versus escalate dose of cetuximab to 500 mg/m2
  • Grade 2 or worse skin reaction: Continue standard dose

Variant #5, 180/500, bi-weekly

Study Evidence
Martín-Martorell et al. 2008 Phase II

Chemotherapy

Supportive medications

14-day cycles

Variant #6, 350/250, q3wk irinotecan

FDA-recommended dose
Study Evidence Comparator Comparative Efficacy
Cunningham et al. 2004 (BOND) Phase III (E-RT) Cetuximab Superior TTP

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

Chemotherapy

  • Irinotecan (Camptosar) 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
  • 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
    • Subsequent cycles: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15

Supportive medications

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 verified protocol 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 verified protocol 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 protocol 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 verified protocol PubMed

Panitumumab monotherapy

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Example orders

Regimen

Study Evidence Comparator Comparative Efficacy
Van Cutsem et al. 2007 (20020408) Phase III (E-RT) Best supportive care Superior PFS
Price et al. 2014 (ASPECCT) Phase III (E-RT) Cetuximab Non-inferior OS
Kim et al. 2016 (20100007) Phase III (E-RT) Best supportive care Seems to have superior OS (*)

Note: reported efficacy for 20100007 is based on the 2018 update.

Chemotherapy

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 verified protocol PubMed
  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
    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 SD 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
    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