Colon cancer, RAS wild-type

Page editor		Section editor
	Ryan Nguyen, DO University of Illinois at Chicago Chicago, IL LinkedIn		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.

• 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

back to top

mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Alberts et al. 2012 (N0147)	Phase III (C)	mFOLFOX6 & Cetuximab	Might have superior DFS

Preceding treatment

• Surgery, within 10 weeks

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, given second (total dose per cycle: 2800 mg/m²)
• Folinic acid (Leucovorin) 400 mg/m² IV over 2 hours once on day 1, given first, with oxaliplatin
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given first, with folinic acid

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

mFOLFOX6 & Cetuximab

back to top

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

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Alberts et al. 2012 (N0147)	Phase III (E-esc)	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 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

back to top

FOLFIRI: FOLinic acid, Fluorouracil, IRInotecan

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (C)	FOLFIRI & Cetuximab	Seems to have inferior 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 (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

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 verified protocol PubMed

FOLFIRI & Cetuximab

back to top

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

Variant #1, weekly cetuximab

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (E-esc)	FOLFIRI	Seems to have superior OS

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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 (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 until lesions deemed resectable or up to 12 cycles

Variant #2, bi-weekly cetuximab

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (E-esc)	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 (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 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 verified protocol PubMed

mFOLFOX6

back to top

mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Variant #1, 400/2800/85, resectable or suboptimally resectable

Study	Evidence	Comparator	Comparative Efficacy
Primrose et al. 2014 (New EPOC)	Phase III (C)	mFOLFOX6 & Cetuximab	Seems to have superior PFS

Note: this trial was only open to KRAS wild-type patients with resectable or suboptimally resectable colorectal liver metastases.

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV 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 (total dose per cycle: 2800 mg/m²)
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

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

Variant #2, 400/2800/85, unresectable

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (C)	mFOLFOX6 & Cetuximab	Seems to have inferior OS

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

Chemotherapy

• Folinic acid (Leucovorin) 400 mg/m² IV 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 (total dose per cycle: 2800 mg/m²)
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

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 verified protocol PubMed
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

mFOLFOX6 & Cetuximab

back to top

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

Variant #1, weekly cetuximab

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (E-esc)	mFOLFOX6	Seems to have superior OS

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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 (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 until lesions deemed resectable or up to 12 cycles

Variant #2, bi-weekly cetuximab

Study	Evidence	Comparator	Comparative Efficacy
Ye et al. 2013 (Fudan 2012-03)	Phase III (E-esc)	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 (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 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 verified protocol PubMed

Advanced or metastatic disease, first-line

CapeOx & Panitumumab

back to top

CapeOx & Panitumumab: Capecitabine, Oxaliplatin, Panitumumab

Regimen

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m² IV once on day 1
• Panitumumab (Vectibix) 9 mg/kg IV once on day 1

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 verified protocol PubMed

FOLFIRI & Bevacizumab

back to top

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

Regimen

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

Chemotherapy

• Folinic acid (Leucovorin) 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
• 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

FOLFIRI & Cetuximab

back to top

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-esc)	FOLFIRI	Superior OS (*)
Heinemann et al. 2014 (FIRE-3)	Phase III (E-switch-ooc)	FOLFIRI & Bevacizumab	Did not meet primary endpoint of ORR

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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)

back to top

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-esc)	FOLFIRI	Superior OS (*)
Heinemann et al. 2014 (FIRE-3)	Phase III (E-switch-ooc)	FOLFIRI & Bevacizumab	Did not meet primary endpoint of ORR

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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

back to top

FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Bokemeyer et al. 2008 (OPUS)	Randomized Phase II (C)	FOLFOX4 & Cetuximab	Inferior OS (*)
Douillard et al. 2010 (PRIME)	Phase III (C)	FOLFOX4 & Panitumumab	Seems to have superior PFS (*)
Qin et al. 2018 (TAILOR-CRC)	Phase III (C)	FOLFOX4 & Cetuximab	Seems to have inferior OS

Note: in 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. 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 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 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. 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
3. 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 & Cetuximab

back to top

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

Regimen

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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

back to top

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

Regimen

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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

back to top

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	Did not meet primary endpoint of OS
Aranda et al. 2018 (MACRO-2)	Non-randomized portion of RCT

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV bolus once on day 1, then 2400 mg/m² IV continuous infusion over 46 hours (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 (see below)

Subsequent treatment

• MACRO-2, after 8 cycles: continued mFOLFOX6 & Cetuximab until progression versus cetuximab maintenance

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)

back to top

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

Regimen

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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

Chemotherapy

• Fluorouracil (5-FU) 1200 mg/m²/day IV continuous infusion over 48 hours, started on day 1, given fourth (total dose per cycle: 2400 mg/m²)
• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1, given third, with oxaliplatin
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1, given third, with L-leucovorin
• Irinotecan (Camptosar) 130 mg/m² IV over 60 minutes once on day 1, given second
• Cetuximab (Erbitux) 500 mg/m² IV over 60 minutes once on day 1, given first

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

FOLFOXIRI & Panitumumab

back to top

FOLFOXIRI & Panitumumab: FOLinic acid, Fluorouracil, OXaliplatin, IRInotecan, Panitumumab

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Modest et al. 2019 (VOLFI)	Randomized Phase II (E-esc)	FOLFOXIRI	Superior ORR

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Chemotherapy

• Fluorouracil (5-FU) 3000 mg/m²/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 6000 mg/m²)
• Levoleucovorin (Fusilev) 200 mg/m² IV over 2 hours once on day 1
• Oxaliplatin (Eloxatin) 85 mg/m² IV over 2 hours once on day 1
• Irinotecan (Camptosar) 150 mg/m² IV over 60 minutes once on day 1
• Panitumumab (Vectibix) 6 mg/kg² IV over 60 minutes once on day 1

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 PubMed

Maintenance after first-line therapy

Cetuximab monotherapy

back to top

Variant #1, 250 mg/m² weekly

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Note: regimen details were not available in the abstract.

Preceding treatment

• mFOLFOX6 & Cetuximab x 8

Chemotherapy

• Cetuximab (Erbitux) 250 mg/m² IV once on day 1

7-day cycles

Variant #2, 500 mg/m² q2wk

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

Note: this was a non-comparative study.

Preceding treatment

• mFOLFOXIRI & Cetuximab x 8

Chemotherapy

• Cetuximab (Erbitux) 500 mg/m² IV once on day 1

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

back to top

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

Regimen

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

Biomarker eligibility criteria

Wild-type KRAS, Wild-type NRAS

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

Chemotherapy

• Folinic acid (Leucovorin) 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
• Panitumumab (Vectibix) 6 mg/kg IV over 60 minutes once on day 1, given first

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 monotherapy

back to top

Example orders

• Example orders for Irinotecan (Camptosar) in colon cancer

Variant #1, 300 mg/m² q3wk

Study	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	Phase III (C)	Irinotecan & Panitumumab	Did not meet primary endpoint of OS

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. Patients in N9841 had not previously received irinotecan or oxaliplatin.

Chemotherapy

• Irinotecan (Camptosar) 300 mg/m² IV over 90 minutes once on day 1

21-day cycles

Variant #2, 350 mg/m² q3wk

Study	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2013 (PICCOLO)	Phase III (C)	1. Irinotecan & Cyclosporine 2. Irinotecan & Panitumumab	Did not meet primary endpoint of OS

Chemotherapy

• Irinotecan (Camptosar) 350 mg/m² IV over 90 minutes once on day 1

Supportive medications

• (varied depending on reference):
• "Standard regimens of antiemetics, Atropine (Atropen), and intensive Loperamide (Imodium)," but no prophylactic Atropine (Atropen) allowed on cycle 1 day 1

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 verified protocol PubMed

Irinotecan & Cetuximab

back to top

Regimen

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

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

Best supportive care

back to top

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Van Cutsem et al. 2007 (20020408)	Phase III (C)	Panitumumab	Inferior PFS
Jonker et al. 2007 (NCIC CTG CO.17)	Phase III (C)	Cetuximab	Inferior OS
Kim et al. 2016 (20100007)	Phase III (C)	Panitumumab	Inferior OS

No treatment except for supportive care.

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. 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
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

Cetuximab monotherapy

back to top

Example orders

• Example orders for Cetuximab (Erbitux) in colon cancer

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-esc)	Best supportive care	Superior OS
Siu et al. 2013 (NCIC CTG/AGITG CO.20)	Phase III (C)	Brivanib & Cetuximab	Did not meet primary endpoint of OS
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

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

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

• 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: 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

back to top

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

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

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-esc)	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, 150/500, bi-weekly

Study	Evidence
Osumi et al. 2018	Phase II

Chemotherapy

• Irinotecan (Camptosar) 150 mg/m² IV once on day 1
• Cetuximab (Erbitux) 500 mg/m² IV over 2 hours once on day 1
  • Subsequent doses are given over 60 minutes

Supportive medications

• Antihistamine prior to Cetuximab (Erbitux)

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

• Irinotecan (Camptosar) 180 mg/m² IV over 30 minutes once per day on days 1 & 15
• Cetuximab (Erbitux) 400 mg/m² IV once on day 1, then 250 mg/m² IV once per day on days 8 & 15

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

• 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

Variant #6, 350/250, q3wk irinotecan

FDA-recommended dose

Study	Evidence	Comparator	Comparative Efficacy
Cunningham et al. 2004 (BOND)	Phase III (E-RT-esc)	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

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

back to top

Example orders

• Example orders for Panitumumab (Vectibix) in colon cancer

Regimen

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

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

Chemotherapy

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

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