Colon cancer, RAS wild-type

Section editor
	Neeta K. Venepalli, MD, MBA 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.

• See the main colon cancer page for general regimens.

2 regimens on this page 2 variants on this page

Guidelines

ESMO

• 2016: ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. PubMed
• 2013: Early Colon Cancer: ESMO Clinical Practice Guidelines PubMed
• 2013: Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. PubMed

Japanese Society for Cancer of the Colon and Rectum

• 2016: Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer PubMed

NCCN

• NCCN Guidelines - Colon Cancer

Adjuvant therapy

mFOLFOX6 & Cetuximab

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

Regimen

Study	Evidence	Comparator	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

• Surgery, within 10 weeks

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 1200 mg/m²/day IV continuous infusion over 46 to 48 hours on days 1 to 2 (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	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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1
• 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
  • Subsequent cycles: 250 mg/m² IV once per day on days 1 & 8

14-day cycles

Treatment continued until lesions deemed resectable or progression or toxicity, or maximum of 12 cycles.

Variant #2, bi-weekly cetuximab

Study	Evidence	Comparator	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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Irinotecan (Camptosar) 180 mg/m² IV once on day 1
• Cetuximab (Erbitux) 500 mg/m² IV once on day 1, given first

14-day cycles

Treatment continued until lesions deemed resectable or progression or toxicity, or maximum of 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	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

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

14-day cycles

Treatment continued until lesions deemed resectable or progression or toxicity, or maximum of 12 cycles.

Variant #2, bi-weekly cetuximab

Study	Evidence	Comparator	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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours on days 1 to 2 (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1
• Cetuximab (Erbitux) 500 mg/m² IV once on day 1, given first

14-day cycles

Treatment continued until lesions deemed resectable or progression or toxicity, or maximum of 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

FOLFIRI & Cetuximab

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

Regimen

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Van Cutsem et al. 2009 (CRYSTAL)	Phase III (E)	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, started during irinotecan infusion
  • Alternatively, Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV over 30 to 90 minutes once on day 1, given 1 hour after completion of cetuximab
• 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 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: Abstract: E. Van Cutsem, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D. Cunningham, I. Celik, C. Kohne. Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with treatment outcome. 2010 ASCO Annual Meeting abstract 3570. link to abstract
   2. 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
   3. Update: Bokemeyer C, Cutsem EV, 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. 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	Efficacy
Bokemeyer et al. 2008 (OPUS)	Phase III (E)	FOLFOX4	Superior OS (*)

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus, then 600 mg/m²/day IV continuous infusion over 22 hours once per day on days 1 & 2 (total dose per cycle: 2000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2, before 5-FU
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, concurrent with leucovorin
• Cetuximab (Erbitux) as follows:
  • Cycle 1 day 1: 400 mg/m² IV over 2 hours once, given first
  • Thereafter: 250 mg/m² IV over 60 minutes once per week, 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. Pooled Update: Bokemeyer C, Cutsem EV, 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

FOLFOX4 & Panitumumab

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

Regimen

Study	Evidence	Comparator	Efficacy
Douillard et al. 2010 (PRIME)	Phase III (E)	FOLFOX4	See note

Note: in KRAS wild-type patients, this regimen seems to have superior PFS. Conversely, in KRAS mutants, this regimen seems to have inferior PFS.

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 600 mg/m²/day IV continuous infusion over 22 hours; both bolus and continuous infusion given on days 1 & 2
• 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

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

Advanced or metastatic disease, second-line

FOLFIRI & Panitumumab

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

Regimen

Study	Evidence	Comparator	Efficacy
Peeters et al. 2010	Phase III (E)	FOLFIRI	Superior PFS

Note: efficacy is for wild-type KRAS, only.

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, started during irinotecan infusion on day 1
• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 to 48 hours on days 1 to 2, given last (total dose per cycle: 2800 mg/m²)
• Irinotecan (Camptosar) 180 mg/m² IV over 30 to 90 minutes once on day 1, given first
• Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1

14-day cycles

References

1. 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

Irinotecan & Cetuximab

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Regimen

Study	Evidence	Comparator	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

• Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)

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

• Example orders for Cetuximab (Erbitux) in colon cancer

Variant #1, weekly

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2004 (BOND)	Phase III (C)	Cetuximab & Irinotecan	Inferior TTP
Lenz et al. 2006 (SALVAGE)	Phase II
Jonker et al. 2007 (NCIC CTG CO.17)	Phase III (E)	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) 400 mg/m² IV over 2 hours once on day 1 of cycle 1, then 250 mg/m² IV over 60 minutes once per week

Supportive medications

• Varies depending on reference
• Antihistamine (such as Diphenhydramine (Benadryl) 50 mg IV) prior to at least the first infusion of Cetuximab (Erbitux)

Given until progression of disease or unacceptable toxicity

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

• Antihistamine prior to Cetuximab (Erbitux)

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: 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

Irinotecan & Cetuximab

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Variant #1, q3wk irinotecan

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2004 (BOND)	Phase III (E)	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

• Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)

21-day cycles

Variant #2, irinotecan 4 weeks on, 2 weeks off

FDA-recommended dose

Study	Evidence	Comparator	Efficacy
Cunningham et al. 2004 (BOND)	Phase III (E)	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

• Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)

42-day cycles

Variant #3, 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

• Antihistamine prior to at least the first infusion of Cetuximab (Erbitux)

21-day cycles

Variant #4, escalated dose cetuximab

Study	Evidence
Martín-Martorell et al. 2008	Phase II

Chemotherapy

• Irinotecan (Camptosar) 180 mg/m² IV over 30 minutes once on day 1
• 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

• Antihistamine prior to Cetuximab (Erbitux)
• Dexamethasone (Decadron) & Ondansetron (Zofran) prior to Irinotecan (Camptosar)

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. 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. Dose escalation study: 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 PubMed

Panitumumab monotherapy

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Example orders

• Example orders for Panitumumab (Vectibix) in colon cancer

Regimen

Study	Evidence	Comparator	Efficacy
Van Cutsem et al. 2007	Phase III (E)	Best supportive care	Superior PFS
Price et al. 2014 (ASPECCT)	Phase III (E)	Cetuximab	Non-inferior OS
Kim et al. 2016 (20100007)	Phase III (E)	Best supportive care	Superior OS

Chemotherapy

• Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1

14-day cycles

References

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