View source for Colorectal cancer, MSI-H or dMMR

<span id="BackToTop"></span>
<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
[[#top|Back to Top]]
</div>
{{#lst:Editorial board transclusions|gi}}
<big>Note: this page has regimens specific to MSI-H/dMMR colon cancer. 
*See the [[Colorectal_cancer|'''main colorectal cancer page''']] for general regimens.</big>
{| class="wikitable" style="float:right; margin-right: 5px;"
|-
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
|}
{{TOC limit|limit=3}}
=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 [https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428 NCCN Guidelines - Colon Cancer].''
=Advanced or metastatic disease, first-line=
==Atezolizumab monotherapy {{#subobject:egac61|Regimen=1}}==
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:abgc1l|Variant=1}}===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://www.clinicaltrials.gov/study/NCT02997228 Awaiting publication (COMMIT)]
|2017-ongoing
| style="background-color:#1a9851" |Phase 3 (C)
|1. [[#mFOLFOX6-B|mFOLFOX6-B]]<br>2. [[#mFOLFOX6.2C_Atezolizumab.2C_Bevacizumab_666|mFOLFOX6, Atezolizumab, Bevacizumab]]
| style="background-color:#d3d3d3" |In progress
|-
|}
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. The mFOLFOX6-B arm was closed early.''
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Atezolizumab (Tecentriq)]]
</div></div>
===References===
#'''COMMIT:''' [https://clinicaltrials.gov/study/NCT02997228 NCT02997228]
==FOLFIRI {{#subobject:ebcf30|Regimen=1}}==
FOLFIRI: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:abe1bd|Variant=1}}===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
|2016-2018
| style="background-color:#1a9851" |Phase 3 (C)
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
|-
|}
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Chemotherapy====
*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given second''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> IV over 30 to 90 minutes once on day 1, '''given first, with leucovorin'''
'''14-day cycles'''
</div></div>
===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. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33264544/ PubMed] [https://clinicaltrials.gov/study/NCT02563002 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. [https://doi.org/10.1016/s1470-2045(21)00064-4 link to orginal article] [https://pubmed.ncbi.nlm.nih.gov/33812497/ PubMed]
## '''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. [https://doi.org/10.1016/s1470-2045(22)00197-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533375/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427471/ PubMed]
# '''CheckMate 8HW:''' [https://clinicaltrials.gov/study/NCT04008030 NCT04008030]
==FOLFIRI & Bevacizumab {{#subobject:80d6b8|Regimen=1}}==
FOLFIRI & Bevacizumab: '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>IRI</u>'''notecan, Bevacizumab
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:28b67a|Variant=1}}===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
|2016-2018
| style="background-color:#1a9851" |Phase 3 (C)
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
|-
|}
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Chemotherapy====
*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given first, with irinotecan'''
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours, '''given third''' (total dose per cycle: 2800 mg/m<sup>2</sup>)
*[[Irinotecan (Camptosar)]] 180 mg/m<sup>2</sup> 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'''
</div></div>
===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. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33264544/ PubMed] [https://clinicaltrials.gov/study/NCT02563002 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. [https://doi.org/10.1016/s1470-2045(21)00064-4 link to orginal article] [https://pubmed.ncbi.nlm.nih.gov/33812497/ PubMed]
## '''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. [https://doi.org/10.1016/s1470-2045(22)00197-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533375/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427471/ PubMed]
==mFOLFOX6 {{#subobject:e4bda7|Regimen=1}}==
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:db877a|Variant=1}}===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
|2016-2018
| style="background-color:#1a9851" |Phase 3 (C)
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
|-
|}
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Chemotherapy====
*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV once on day 1
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
'''14-day cycles'''
</div></div>
===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. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33264544/ PubMed] [https://clinicaltrials.gov/study/NCT02563002 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. [https://doi.org/10.1016/s1470-2045(21)00064-4 link to orginal article] [https://pubmed.ncbi.nlm.nih.gov/33812497/ PubMed]
## '''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. [https://doi.org/10.1016/s1470-2045(22)00197-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533375/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427471/ PubMed]
# '''ATOMIC:''' [https://clinicaltrials.gov/study/NCT02912559 NCT02912559]
==mFOLFOX6-B {{#subobject:b74416|Regimen=1}}==
mFOLFOX6-B: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid (Leucovorin), '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:db572g|Variant=1}}===
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
|2016-2018
| style="background-color:#1a9851" |Phase 3 (C)
|[[#Pembrolizumab_monotherapy|Pembrolizumab]]
| style="background-color:#fee08b" |Might have inferior OS<sup>1</sup>
|-
|}
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Chemotherapy====
*[[Leucovorin (Folinic acid)]] 400 mg/m<sup>2</sup> IV over 2 hours once on day 1
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 to 48 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
====Targeted therapy====
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once on day 1
'''14-day cycles'''
</div></div>
===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. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33264544/ PubMed] [https://clinicaltrials.gov/study/NCT02563002 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. [https://doi.org/10.1016/s1470-2045(21)00064-4 link to orginal article] [https://pubmed.ncbi.nlm.nih.gov/33812497/ PubMed]
## '''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. [https://doi.org/10.1016/s1470-2045(22)00197-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533375/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427471/ PubMed]
==Pembrolizumab monotherapy {{#subobject:5aa59d|Regimen=1}}==
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:3af038|Variant=1}}===
{| class="wikitable" style="color:white; background-color:#404040"
|<small>'''FDA-recommended dose'''</small>
|-
|}
{| class="wikitable sortable" style="width: 100%; text-align:center;" 
!style="width: 20%"|Study
!style="width: 20%"|Dates of enrollment
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
!style="width: 20%"|Comparator
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
|-
|[https://doi.org/10.1056/nejmoa2017699 André et al. 2020 (KEYNOTE-177)]
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-301-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
|-
|} -->
|2016-2018
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
|Investigator's choice of:<br>1a. [[#mFOLFOX6|mFOLFOX6]]<br>1b. [[#mFOLFOX6-B|mFOLFOX6-B]]<br>1c. [[#mFOLFOX6_.26_Cetuximab_888|mFOLFOX6 & Cetuximab]]<br>1d. [[#FOLFIRI|FOLFIRI]]<br>1e. [[#FOLFIRI_.26_Bevacizumab|FOLFIRI & Bevacizumab]]<br>1f. [[#FOLFIRI_.26_Cetuximab_888|FOLFIRI & Cetuximab]]
| style="background-color:#d9ef8b" |Superior PFS (co-primary endpoint)<br>Median PFS: 16.5 vs 8.2 mo<br>(HR 0.60, 95% CI 0.45-0.80)<br><br>Might have superior OS<sup>1</sup> (co-primary endpoint)<br>Median OS: NYR vs 36.7 mo <br>(HR 0.74, 95% CI 0.53-1.03)
|-
|}
''<sup>1</sup>Reported efficacy is based on the 2022 update.''<br>
''Inclusion criteria: ECOG PS 0 or 1''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*MSI-H/dMMR mCRC as determined locally
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
'''21-day cycle for up to 2 years'''
</div></div>

===References===
<!-- #'''Abstract:''' Andre T, Shiu KK, KIM TW, Jensen BV, Jensen LH, Punt CJA, Smith DM, Garcia-Carbonero R, Benavides M, Gibbs P, Fouchardiere CDL, Rivera F, Elez E, Bendell JC, Le DT, Yoshino T, Yang P, Farooqui MZH, Marinello P, Diaz LA. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. J Clin Oncol 38: 2020 (suppl; abstr LBA4) [https://meetinglibrary.asco.org/record/186928 Link to abstract] -->
# '''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. [https://doi.org/10.1056/nejmoa2017699 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33264544/ PubMed] [https://clinicaltrials.gov/study/NCT02563002 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. [https://doi.org/10.1016/s1470-2045(21)00064-4 link to orginal article] [https://pubmed.ncbi.nlm.nih.gov/33812497/ PubMed]
## '''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. [https://doi.org/10.1016/s1470-2045(22)00197-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533375/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427471/ PubMed]

=Advanced or metastatic disease, subsequent lines of therapy=
==Ipilimumab & Nivolumab {{#subobject:517ff0|Regimen=1}}==
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:3a481c|Variant=1}}===
{| class="wikitable" style="width: 60%; text-align:center;" 
!style="width: 33%"|Study
!style="width: 33%"|Dates of enrollment
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
|-
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ Overman et al. 2017 (CheckMate 142)]
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-282-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
|-
|} -->
|2014-2016
| style="background-color:#91cf61" |Phase 2 (RT)
|-
|}
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Ipilimumab (Yervoy)]] as follows:
**Cycles 1 to 4: 1 mg/kg IV once on day 1
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
'''21-day cycle for 4 cycles, then 14-day cycles'''
</div></div>
===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. [https://doi.org/10.1016/S1470-2045(17)30422-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28734759/ PubMed] [https://clinicaltrials.gov/study/NCT02060188 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. [https://doi.org/10.1200/JCO.2017.76.9901 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29355075/ PubMed]
## '''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. [https://doi.org/10.1016/j.annonc.2022.06.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35764271/ PubMed]

==Nivolumab monotherapy {{#subobject:ac98g4|Regimen=1}}==
<div class="toccolours" style="background-color:#eeeeee">
===Regimen {{#subobject:91abt2|Variant=1}}===
{| class="wikitable" style="width: 60%; text-align:center;" 
!style="width: 33%"|Study
!style="width: 33%"|Dates of enrollment
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
|-
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ Overman et al. 2017 (CheckMate 142)]
|2014-2016
| style="background-color:#91cf61" |Phase 2 (RT)
|-
|}
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*dMMR or MSI-H colorectal cancer.
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Nivolumab (Opdivo)]] 3 mg/kg IV once on day 1
'''14-day cycles'''
</div></div>
===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. [https://doi.org/10.1016/S1470-2045(17)30422-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207072/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28734759/ PubMed] [https://clinicaltrials.gov/study/NCT02060188 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. [https://doi.org/10.1200/JCO.2017.76.9901 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29355075/ PubMed]
## '''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. [https://doi.org/10.1016/j.annonc.2022.06.008 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35764271/ PubMed]
==Pembrolizumab monotherapy {{#subobject:ac2c94|Regimen=1}}==
<div class="toccolours" style="background-color:#eeeeee">
===Regimen variant #1, flat dose {{#subobject:fe5344|Variant=1}}===
{| class="wikitable sortable" style="width: 60%; text-align:center;" 
!style="width: 33%"|Study
!style="width: 33%"|Dates of enrollment
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
|-
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7031958/ Le et al. 2019 (KEYNOTE-164)]
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-332-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
|-
|} -->
|2015-2017
| style="background-color:#91cf61" |Phase 2 (RT)
|-
|}
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*dMMR or MSI-H tumors
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Pembrolizumab (Keytruda)]] 200 mg IV once on day 1
'''21-day cycle for up to 35 cycles (2 years)'''
</div></div><br>
<div class="toccolours" style="background-color:#eeeeee">
===Regimen variant #2, weight-based {{#subobject:B34AD4|Variant=1}}===
{| class="wikitable sortable" style="width: 60%; text-align:center;" 
!style="width: 33%"|Study
!style="width: 33%"|Dates of enrollment
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
|-
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ Le et al. 2015 (KEYNOTE-016)]
|2013-09 to 2016-09
| style="background-color:#91cf61" |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.''
<div class="toccolours" style="background-color:#fdcdac">
====Biomarker eligibility criteria====
*dMMR or MSI-H tumors
</div>
<div class="toccolours" style="background-color:#b3e2cd">
====Immunotherapy====
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
'''14-day cycles'''
</div></div>

===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. [https://doi.org/10.1056/NEJMoa1500596 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26028255/ PubMed] [https://clinicaltrials.gov/study/NCT01876511 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. [http://science.sciencemag.org/content/357/6349/409.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28596308/ PubMed]
<!-- #'''Abstract:''' Dung T. Le, Takayuki Yoshino, Dirk Jäger, Thierry Andre, Johanna C. Bendell, Ruixue Wang... SoonMo Peter Kang, Minori Koshiji, Luis A. Diaz. KEYNOTE-164: Phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma. J Clin Oncol [https://doi.org/10.1200/jco.2016.34.4_suppl.tps787 abstract TPS787] and [https://doi.org/10.1200/JCO.2016.34.15_suppl.TPS3631 abstract TPS3631] -->
#'''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. [https://doi.org/10.1200/jco.19.02107 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7031958/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31725351/ PubMed] [https://clinicaltrials.gov/study/NCT02460198 NCT02460198]
[[Category:Colon cancer regimens]]
[[Category:Biomarker-specific pages]]
[[Category:Colorectal cancers]]