Colorectal cancer, KRAS-mutated

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Note: the page has regimens specific to BRAF-mutated colon cancer. 
*See the main colorectal cancer page for general regimens.
Last updated on 2024-07-23:5 regimens on this page
8 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.
=Advanced or metastatic disease, KRAS inhibitor-naive=
==Regorafenib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	1. Sotorasib & Panitumumab; 240 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 3.9 mo(HR 1.72, 95% CI 1.08-2.78)
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	2. Sotorasib & Panitumumab; 960 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 5.6 mo(HR 2.04, 95% CI 1.25-3.33)
====Targeted therapy====
*Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21
28-day cycles
===References===
#CodeBreaK 300: Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, Karamouzis MV, Ruiz-Garcia E, Kim TW, Kuboki Y, Meriggi F, Cunningham D, Yeh KH, Chan E, Chao J, Saportas Y, Tran Q, Cremolini C, Pietrantonio F. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Dec 7;389(23):2125-2139. Epub 2023 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05198934
==Sotorasib & Panitumumab==
===Regimen variant #1, 240 mg/day sotorasib===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (E-RT-switch-ooc)	1a. Trifluridine and tipiracil1b. Regorafenib 	Longer PFS (primary endpoint)Median PFS: 3.9 vs 2.2 mo(HR 0.58, 95% CI 0.36-0.93)
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (E-RT-switch-ooc)	2. Sotorasib & Panitumumab; 960 mg/day sotorasib	Not reported
====Biomarker eligibility criteria====
*KRAS p.G12C mutation
====Targeted therapy====
*Sotorasib (Lumakras) 240 mg PO once per day on days 1 to 14
*Panitumumab (Vectibix) 6 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, 960 mg/day sotorasib===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (E-RT-switch-ooc)	1a. Trifluridine and tipiracil1b. Regorafenib 	Longer PFS (primary endpoint)Median PFS: 5.6 vs 2.2 mo(HR 0.49, 95% CI 0.30-0.80)
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (E-RT-switch-ooc)	2. Sotorasib & Panitumumab; 240 mg/day sotorasib	Not reported
====Biomarker eligibility criteria====
*KRAS p.G12C mutation
====Targeted therapy====
*Sotorasib (Lumakras) 960 mg PO once per day on days 1 to 14
*Panitumumab (Vectibix) 6 mg/kg IV once on day 1
14-day cycles
===References===
#CodeBreaK 300: Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, Karamouzis MV, Ruiz-Garcia E, Kim TW, Kuboki Y, Meriggi F, Cunningham D, Yeh KH, Chan E, Chao J, Saportas Y, Tran Q, Cremolini C, Pietrantonio F. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Dec 7;389(23):2125-2139. Epub 2023 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05198934
==Trifluridine and tipiracil monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	1. Sotorasib & Panitumumab; 240 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 3.9 mo(HR 1.72, 95% CI 1.08-2.78)
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	2. Sotorasib & Panitumumab; 960 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 5.6 mo(HR 2.04, 95% CI 1.25-3.33)
Note: This was the Japanese dosing variant.
====Chemotherapy====
*Trifluridine and tipiracil (Lonsurf) 35 mg/m2 (maximum dose of 75 mg) PO twice per day on days 1 to 5, 8 to 12
28-day cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	1. Sotorasib & Panitumumab; 240 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 3.9 mo(HR 1.72, 95% CI 1.08-2.78)
Fakih et al. 2023 (CodeBreaK 300)	2022-04-19 to 2023-03-14	Phase 3 (C)	2. Sotorasib & Panitumumab; 960 mg/day sotorasib	Shorter PFS (primary endpoint)Median PFS: 2.2 vs 5.6 mo(HR 2.04, 95% CI 1.25-3.33)
====Chemotherapy====
*Trifluridine and tipiracil (Lonsurf) 35 mg/m2 (maximum dose of 80 mg) PO twice per day on days 1 to 5, 8 to 12
28-day cycles
===References===
#CodeBreaK 300: Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, Karamouzis MV, Ruiz-Garcia E, Kim TW, Kuboki Y, Meriggi F, Cunningham D, Yeh KH, Chan E, Chao J, Saportas Y, Tran Q, Cremolini C, Pietrantonio F. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Dec 7;389(23):2125-2139. Epub 2023 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT05198934
=Advanced or metastatic disease, subsequent lines of therapy=
==Adagrasib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Yaeger et al. 2022 (KRYSTAL-1CRC)	Not reported 	Phase 1/2
====Biomarker eligibility criteria====
*KRAS p.G12C mutation
====Targeted therapy====
*Adagrasib (Krazati) 600 mg PO twice per day
Continued indefinitely
===References===
#KRYSTAL-1CRC: Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, Leal TA, Bekaii-Saab TS, Paweletz CP, Heavey GA, Christensen JG, Velastegui K, Kheoh T, Der-Torossian H, Klempner SJ. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Jan 5;388(1):44-54. Epub 2022 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03785249
==Adagrasib & Cetuximab==
===Regimen variant #1, weekly cetuximab===
Study 	Dates of enrollment	Evidence
Yaeger et al. 2022 (KRYSTAL-1CRC)	Not reported 	Phase 1/2 (RT)
====Biomarker eligibility criteria====
*KRAS p.G12C mutation
====Targeted therapy====
*Adagrasib (Krazati) 600 mg PO twice per day
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg IV once on day 1
**Cycle 2 onwards: 250 mg IV once on day 1
7-day cycles
===Regimen variant #2, bi-weekly cetuximab===
Study 	Dates of enrollment	Evidence
Yaeger et al. 2022 (KRYSTAL-1CRC)	Not reported 	Phase 1/2 (RT)
====Biomarker eligibility criteria====
*KRAS p.G12C mutation
====Targeted therapy====
*Adagrasib (Krazati) 600 mg PO twice per day
*Cetuximab (Erbitux) 500 mg IV once on day 1
14-day cycles
===References===
#KRYSTAL-1CRC: Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, Leal TA, Bekaii-Saab TS, Paweletz CP, Heavey GA, Christensen JG, Velastegui K, Kheoh T, Der-Torossian H, Klempner SJ. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023 Jan 5;388(1):44-54. Epub 2022 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03785249
Category:Colon cancer regimens
Category:Biomarker-specific pages
Category:Colorectal cancers