Colorectal cancer, MSI-H or dMMR

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Note: this page has regimens specific to MSI-H/dMMR colon cancer. 
*See the main colorectal cancer page for general regimens.
Last updated on 2024-12-02:11 regimens on this page
12 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Colon Cancer.
=Neoadjuvant therapy=
==Ipilimumab & Nivolumab==
===Regimen===
Study 	Dates of enrollment 	Evidence
Chalabi et al. 2024 (NICHE-2)	2017-07-04 to 2022-07-18	Phase 2
====Immunotherapy====
*Ipilimumab (Yervoy) 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) 3 mg/kg IV once per day on days 1 & 15
One course
====Subsequent treatment====
*Surgery
===References===
#NICHE-2: Chalabi M, Verschoor YL, Tan PB, Balduzzi S, Van Lent AU, Grootscholten C, Dokter S, Büller NV, Grotenhuis BA, Kuhlmann K, Burger JW, Huibregtse IL, Aukema TS, Hendriks ER, Oosterling SJ, Snaebjornsson P, Voest EE, Wessels LF, Beets-Tan RG, Van Leerdam ME, Schumacher TN, van den Berg JG, Beets GL, Haanen JB. Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer. N Engl J Med. 2024 Jun 6;390(21):1949-1958. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03026140
=Advanced or metastatic disease, first-line=
==Atezolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Awaiting publication (COMMIT)	2017-ongoing 	Phase 3 (E-switch-ooc)	1. mFOLFOX6-B2. mFOLFOX6, Atezolizumab, Bevacizumab	TBD if different primary endpoint of PFS
Note: The mFOLFOX6-B arm was closed early.
====Immunotherapy====
*Atezolizumab (Tecentriq)
14-day cycle for up to 48 cycles
===References===
#COMMIT: NCT02997228
==FOLFIRI==
FOLFIRI: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
André et al. 2020 (KEYNOTE-177)	2016-2018 	Phase 3 (C)	Pembrolizumab	Might have shorter OS1Median OS: 36.7 vs NYR mo(HR 1.35, 95% CI 0.97-1.89)Shorter PFSMedian PFS: 8.2 vs 16.5 mo(HR 1.67, 95% CI 1.25-2.22)
1Reported efficacy is based on the 2022 update.
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given second (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
14-day cycles
===References===
# KEYNOTE-177: André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563002
## HRQoL analysis: Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. Epub 2021 Apr 1. link to orginal article EuroPMC
## Update: Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May 1;23(5):659-670. Epub 2022 Apr 12. link to original article link to PMC article EuroPMC
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article EuroPMC NCT04008030
==FOLFIRI & Bevacizumab==
FOLFIRI & Bevacizumab: FOLinic acid (Leucovorin), Fluorouracil, IRInotecan, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
André et al. 2020 (KEYNOTE-177)	2016-2018 	Phase 3 (C)	Pembrolizumab	Might have shorter OS1Median OS: 36.7 vs NYR mo(HR 1.35, 95% CI 0.97-1.89)Shorter PFSMedian PFS: 8.2 vs 16.5 mo(HR 1.67, 95% CI 1.25-2.22)
1Reported efficacy is based on the 2022 update.
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
====Chemotherapy====
*Leucovorin (Folinic acid) 400 mg/m2 IV over 2 hours once on day 1, given first, with irinotecan
*Fluorouracil (5-FU) 400 mg/m2 IV bolus once on day 1, then 2400 mg/m2 IV continuous infusion over 46 to 48 hours, given third (total dose per cycle: 2800 mg/m2)
*Irinotecan (Camptosar) 180 mg/m2 IV over 30 to 90 minutes once on day 1, given first, with leucovorin
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1, given second
14-day cycles
===References===
# KEYNOTE-177: André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563002
## HRQoL analysis: Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. Epub 2021 Apr 1. link to orginal article EuroPMC
## Update: Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May 1;23(5):659-670. Epub 2022 Apr 12. link to original article link to PMC article EuroPMC
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article EuroPMC NCT04008030
==mFOLFOX6==
mFOLFOX6: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
André et al. 2020 (KEYNOTE-177)	2016-2018 	Phase 3 (C)	Pembrolizumab	Might have shorter OS1Median OS: 36.7 vs NYR mo(HR 1.35, 95% CI 0.97-1.89)Shorter PFSMedian PFS: 8.2 vs 16.5 mo(HR 1.67, 95% CI 1.25-2.22)
1Reported efficacy is based on the 2022 update.
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
====Chemotherapy====
*Leucovorin (Folinic acid) 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 over 2 hours once on day 1
14-day cycles
===References===
# KEYNOTE-177: André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563002
## HRQoL analysis: Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. Epub 2021 Apr 1. link to orginal article EuroPMC
## Update: Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May 1;23(5):659-670. Epub 2022 Apr 12. link to original article link to PMC article EuroPMC
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article EuroPMC NCT04008030
# ATOMIC: NCT02912559
==mFOLFOX6-B==
mFOLFOX6-B: modified FOLinic acid (Leucovorin), Fluorouracil, OXaliplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
André et al. 2020 (KEYNOTE-177)	2016-2018 	Phase 3 (C)	Pembrolizumab	Might have shorter OS1Median OS: 36.7 vs NYR mo(HR 1.35, 95% CI 0.97-1.89)Shorter PFSMedian PFS: 8.2 vs 16.5 mo(HR 1.67, 95% CI 1.25-2.22)
1Reported efficacy is based on the 2022 update.
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
====Chemotherapy====
*Leucovorin (Folinic acid) 400 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 to 48 hours (total dose per cycle: 2800 mg/m2)
*Oxaliplatin (Eloxatin) 85 mg/m2 IV over 2 hours once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 5 mg/kg IV once on day 1
14-day cycles
===References===
# KEYNOTE-177: André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563002
## HRQoL analysis: Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. Epub 2021 Apr 1. link to orginal article EuroPMC
## Update: Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May 1;23(5):659-670. Epub 2022 Apr 12. link to original article link to PMC article EuroPMC
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article EuroPMC NCT04008030
==Ipilimumab & Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Andre et al. 2024 (CheckMate 8HW)	2019-08 to 2023-04 	Phase 3 (E-switch-ooc)	Investigator's choice of:1a. FOLFIRI1b. FOLFIRI & Bevacizumab1c. FOLFIRI & Cetuximab1d. mFOLFOX61e. mFOLFOX6-B1f. mFOLFOX6 & Cetuximab	Longer PFS (primary endpoint)PFS24: 72% vs 14%(RMST24: 19.2 vs 8.6 mo)
Andre et al. 2024 (CheckMate 8HW)	2019-08 to 2023-04 	Phase 3 (E-switch-ooc)	2. Nivolumab 	Longer PFS1 (primary endpoint)Median PFS: NYR vs 39.3 mo(HR 0.62, 95% CI 0.48-0.81)
1Reported efficacy is based on the 2025 update.
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 4: 240 mg IV once on day 1
**Cycle 5 onwards: 480 mg IV once on day 1
21-day cycle for 4 cycles, then 28-day cycles
===References===
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04008030
##Update: André T, Elez E, Lenz HJ, Jensen LH, Touchefeu Y, Van Cutsem E, Garcia-Carbonero R, Tougeron D, Mendez GA, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Manzano Mozo JL, Dahan L, Tortora G, Chalabi M, Goekkurt E, Braghiroli MI, Joshi R, Cil T, Aubin F, Cela E, Chen T, Lei M, Jin L, Blum SI, Lonardi S. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025 Jan. Epub ahead of print. link to original article link to EuroPMC
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Andre et al. 2024 (CheckMate 8HW)	2019-08 to 2023-04 	Phase 3 (C)	Investigator's choice of:1a. FOLFIRI1b. FOLFIRI & Bevacizumab1c. FOLFIRI & Cetuximab1d. mFOLFOX61e. mFOLFOX6-B1f. mFOLFOX6 & Cetuximab	Not directly compated
Andre et al. 2024 (CheckMate 8HW)	2019-08 to 2023-04 	Phase 3 (C)	2. Ipilimumab & Nivolumab 	Shorter PFS1 (primary endpoint)Median PFS: 39.3 vs NYR mo(HR 1.61, 95% CI 1.23-2.08)
1Reported efficacy is based on the 2025 update.
====Immunotherapy====
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 6: 240 mg IV once on day 1
**Cycle 7 onwards: 480 mg IV once on day 1
14-day cycle for 6 cycles, then 28-day cycles
===References===
#CheckMate 8HW: Andre T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Lenz HJ, Manzano Mozo JL, Tortora G, Garcia-Carbonero R, Dahan L, Chalabi M, Joshi R, Goekkurt E, Braghiroli MI, Cil T, Cela E, Chen T, Lei M, Dixon M, Abdullaev S, Lonardi S; CheckMate 8HW Investigators. Nivolumab plus Ipilimumab in Microsatellite-Instability-High Metastatic Colorectal Cancer. N Engl J Med. 2024 Nov 28;391(21):2014-2026. link to original article EuroPMC NCT04008030
##Update: André T, Elez E, Lenz HJ, Jensen LH, Touchefeu Y, Van Cutsem E, Garcia-Carbonero R, Tougeron D, Mendez GA, Schenker M, de la Fouchardiere C, Limon ML, Yoshino T, Li J, Manzano Mozo JL, Dahan L, Tortora G, Chalabi M, Goekkurt E, Braghiroli MI, Joshi R, Cil T, Aubin F, Cela E, Chen T, Lei M, Jin L, Blum SI, Lonardi S. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025 Jan. Epub ahead of print. link to original article dosing details in manuscript have been reviewed by our editors link to EuroPMC
==Pembrolizumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
André et al. 2020 (KEYNOTE-177)	2016-2018 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. mFOLFOX61b. mFOLFOX6-B1c. mFOLFOX6 & Cetuximab1d. FOLFIRI1e. FOLFIRI & Bevacizumab1f. FOLFIRI & Cetuximab	Longer PFS (co-primary endpoint)Median PFS: 16.5 vs 8.2 mo(HR 0.60, 95% CI 0.45-0.80)Might have longer OS1 (co-primary endpoint)Median OS: NYR vs 36.7 mo (HR 0.74, 95% CI 0.53-1.03)
1Reported efficacy is based on the 2022 update.
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
====Eligibility criteria====
*ECOG PS 0 or 1
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 2 years
===References===
# KEYNOTE-177: André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02563002
## HRQoL analysis: Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 May;22(5):665-677. Epub 2021 Apr 1. link to orginal article EuroPMC
## Update: Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fourchardiere C, Rivera F, Elez E, Le DT, Yoshino T, Zhong WY, Fogelman D, Marinello P, Andre T; KEYNOTE-177 Investigators. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May 1;23(5):659-670. Epub 2022 Apr 12. link to original article link to PMC article EuroPMC
=Advanced or metastatic disease, subsequent lines of therapy=
==Ipilimumab & Nivolumab==
===Regimen===
Study 	Dates of enrollment	Evidence
Overman et al. 2017 (CheckMate 142)	2014-2016 	Phase 2 (RT)
Note: This regimen is described in Overman et al. 2018, not the original publication by Overman et al. 2017.
====Immunotherapy====
*Ipilimumab (Yervoy) as follows:
**Cycles 1 to 4: 1 mg/kg IV over 90 minutes once on day 1
*Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1
21-day cycle for 4 cycles, then 14-day cycles
===References===
#CheckMate 142: Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. Epub 2017 Jul 19. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. link to original article link to PMC article does not contain dosing details EuroPMC NCT02060188
## Update: Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779. Epub 2018 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: André T, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Abdullaev S, Memaj A, Lei M, Dixon M, Kopetz S, Overman MJ. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol. 2022 Oct;33(10):1052-1060. Epub 2022 Jun 25. link to original article EuroPMC
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Overman et al. 2017 (CheckMate 142)	2014-2016 	Phase 2 (RT)
====Biomarker eligibility criteria====
*dMMR or MSI-H colorectal cancer.
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
===References===
#CheckMate 142: Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017 Sep;18(9):1182-1191. Epub 2017 Jul 19. Erratum in: Lancet Oncol. 2017 Sep;18(9):e510. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02060188
## Update: Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Svrcek M, Moss RA, Ledeine JM, Cao ZA, Kamble S, Kopetz S, André T. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779. Epub 2018 Jan 20. link to original article EuroPMC
## Update: André T, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, Morse MA, Van Cutsem E, McDermott R, Hill A, Sawyer MB, Hendlisz A, Neyns B, Abdullaev S, Memaj A, Lei M, Dixon M, Kopetz S, Overman MJ. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol. 2022 Oct;33(10):1052-1060. Epub 2022 Jun 25. link to original article EuroPMC
==Pembrolizumab monotherapy==
===Regimen variant #1, flat dose===
Study 	Dates of enrollment	Evidence
Le et al. 2019 (KEYNOTE-164)	2015-2017 	Phase 2 (RT)
====Biomarker eligibility criteria====
*dMMR or MSI-H tumors
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===Regimen variant #2, weight-based===
Study 	Dates of enrollment	Evidence
Le et al. 2015 (KEYNOTE-016)	2013-09 to 2016-09 	Phase 2
Note: this study only demonstrated a clear benefit for mismatch repair-deficient colorectal cancers. Please be aware that the FDA-approved, recommended pembrolizumab dose in the package insert is 200 mg for adults, 2 mg/kg (maximum dose 200 mg) for children, given every 3 weeks.
====Biomarker eligibility criteria====
*dMMR or MSI-H tumors
====Immunotherapy====
*Pembrolizumab (Keytruda) 10 mg/kg IV over 30 minutes once on day 1
14-day cycles
===References===
#KEYNOTE-016: Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01876511
##Update: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. link to original article link to PMC article EuroPMC
#KEYNOTE-164: Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, Burge M, O'Neil B, Kavan P, Yoshino T, Guimbaud R, Taniguchi H, Elez E, Al-Batran SE, Boland PM, Crocenzi T, Atreya CE, Cui Y, Dai T, Marinello P, Diaz LA Jr, André T. Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J Clin Oncol. 2020 Jan 1;38(1):11-19. Epub 2019 Nov 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02460198
Category:Colon cancer regimens
Category:Biomarker-specific pages
Category:Colorectal cancers