KRAS G12C-mutant colorectal cancer: the decisions you may face

Cancer page →Second-opinion finder →

3 treatment settings, 3 with more than one named option. Each section lays out the options the standard of care names, what each is for, the trials behind them with their recorded results, the side effects and cautions on record, and questions to ask. Built from the cancer page's standard-of-care rows; nothing here is advice for your case.

Advanced, first line

Metastatic, previously treated

5 optionsCompare side by side →

Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan.

Guideline

NCCN Guidelines: Colon Cancer

The options, in plain words

SotorasibApprovedSmall-molecule inhibitor (KRAS G12C)

Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.

PanitumumabApprovedMonoclonal antibody (anti-EGFR)

Panitumumab is a fully human EGFR antibody, the preferred first-line partner for chemotherapy in left-sided, RAS-normal bowel cancer after the PARADIGM trial.

AdagrasibApprovedSmall-molecule inhibitor (KRAS G12C)

Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.

CetuximabApprovedMonoclonal antibody (anti-EGFR)

Cetuximab is a chimeric antibody that blocks the EGFR growth receptor. It is used with FOLFIRI or FOLFOX in RAS wild-type, left-sided bowel cancer, with encorafenib in BRAF V600E disease, with KRAS G12C inhibitors, and with radiation or chemotherapy in head and neck cancer; RAS-mutant tumours gain nothing and may be harmed, so RAS testing comes first.

KRAS & RAS inhibitorsApproved

Drugs against the most common cancer gene, considered impossible to target until sotorasib in 2021.

First drugs for a 40-year-old target

The evidence behind it

CodeBreaK 300 Phase 3 NCT05198934 2023160 peopleevidence 85
Tests Sotorasib
KRAS G12C colorectal cancer, previously treated: sotorasib + panitumumab vs standard of care
PFS HR 0.49.
Progression-free survival (BICR), sotorasib 960 mg + panitumumab (months): Sotorasib 960 mg + panitumumab 5.6 (n=53) vs Trifluridine-tipiracil or regorafenib 2.2 (n=54) · HR 0.49 · source
Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 Phase 1/2 NCT03785249731 peopleevidence 27
Tests Cetuximab
A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation KRYSTAL-1
No headline result recorded yet.

The main trade-offs on record

Sotorasib all recorded rates →

Side effect	Any grade	Grade 3+
Hepatotoxicity · CodeBreaK 100	25%	12%
Interstitial lung disease · CodeBreaK 100	2.2%	1.1%
Diarrhoea · CodeBreaK 100	42%	-
Musculoskeletal pain · CodeBreaK 100	35%	-

No adjustment for mild impairment; hepatotoxicity is common and worse after recent immunotherapy.

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

Adagrasib all recorded rates →

Side effect	Any grade	Grade 3+
Hepatotoxicity · KRYSTAL-1 NSCLC	37%	10%
Dyspnoea · KRYSTAL-1 NSCLC	35%	10%
Fatigue · KRYSTAL-1 NSCLC	59%	7%
Musculoskeletal pain · KRYSTAL-1 NSCLC	41%	7%

Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.

Rates from the label or pivotal trial as recorded on the product page; each grade 3+ figure links to its source.

KRAS & RAS inhibitors

Modest durability as monotherapy
Adaptive RTK feedback requires combinations

Questions to ask about this decision

Between Sotorasib, Panitumumab, Adagrasib and the other options, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in CodeBreaK 300 and Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
Which side effects of Sotorasib or Adagrasib are most likely for me, which are reversible, and which would make us stop?
Why: The recorded rates below come from labels and trials; your own risk depends on dose, other medicines and your health.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Colon Cancer), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (metastatic, previously treated), which of the standard options do you recommend and why?
Why: Guideline options include: Sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1) after fluoropyrimidine, oxaliplatin and irinotecan.
Am I a candidate for Sotorasib, Panitumumab, Adagrasib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of CodeBreaK 300 and Phase 1/2 Study of MRTX849 in Patients With Cancer Having a KRAS G12C Mutation KRYSTAL-1 apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Advanced, first line

Metastatic, first line

4 optionsCompare side by side →

FOLFOX, FOLFIRI or CAPOX with bevacizumab, as for any RAS-mutant colorectal cancer; anti-EGFR antibodies are not used; KRAS G12C combinations are under test first line (CodeBreaK 301).

Guideline

NCCN Guidelines: Colon Cancer

The options, in plain words

FOLFOX (5-FU, leucovorin, oxaliplatin)Standard of careCytotoxic regimen

FOLFOX is the workhorse chemotherapy combination for bowel cancer, used after surgery to cure and in advanced disease as the backbone that targeted drugs are added to.

FOLFIRI (5-FU, leucovorin, irinotecan)Standard of careCytotoxic regimen

FOLFIRI is the other backbone bowel-cancer chemotherapy, swapping oxaliplatin for irinotecan. Used first or second line and, since 2026, with the BRAF combination.

CAPOX (capecitabine, oxaliplatin)Standard of careCytotoxic regimen

CAPOX pairs the oral fluoropyrimidine capecitabine with intravenous oxaliplatin as a pill-based alternative to FOLFOX. For low-risk stage III colon cancer three months after surgery works as well as six and halves nerve damage; it is also standard in gastric cancer, with hand-foot syndrome as its price.

BevacizumabApprovedMonoclonal antibody (anti-VEGF)

Bevacizumab is a humanised antibody that soaks up VEGF-A, the signal tumours use to grow new blood vessels. Approved in 2004, it partners chemotherapy in colorectal, ovarian, cervical, lung, kidney and liver cancer and glioblastoma, and adds to trifluridine/tipiracil in late-line bowel cancer; hypertension, protein in the urine and bleeding are its characteristic side effects.

The evidence behind it

Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal Phase 3 NCT06252649450 peopleevidence 48
Phase 3 Multicenter, Randomized, Open-label, Active-controlled Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb for Treatment-naïve Subjects With Metastatic Colorectal Cancer With KRAS p.G12C Mutation (CodeBreaK 301)
No headline result recorded yet.

The main trade-offs on record

No side-effect rates or interaction flags are recorded for these options yet. The side-effect lookup and interaction checker cover the products that have them.

Questions to ask about this decision

Between FOLFOX (5-FU, leucovorin, oxaliplatin), FOLFIRI (5-FU, leucovorin, irinotecan), CAPOX (capecitabine, oxaliplatin) and the other options, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Colon Cancer), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (metastatic, first line), which of the standard options do you recommend and why?
Why: Guideline options include: FOLFOX, FOLFIRI or CAPOX with bevacizumab, as for any RAS-mutant colorectal cancer; anti-EGFR antibodies are not used; KRAS G12C combinations are under test first line (CodeBreaK 301).
Am I a candidate for FOLFOX (5-FU, leucovorin, oxaliplatin), FOLFIRI (5-FU, leucovorin, irinotecan), CAPOX (capecitabine, oxaliplatin) or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-naïve Participants With Metastatic Colorectal apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

Third line and beyond

Later lines

3 optionsCompare side by side →

Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors.

Guideline

NCCN Guidelines: Colon Cancer

The options, in plain words

Trifluridine/tipiracilApprovedCytotoxic chemotherapy (oral nucleoside)

An oral chemotherapy pill for bowel cancer that has stopped responding to everything else; with bevacizumab it extends life by about three months.

FruquintinibApprovedSmall-molecule kinase inhibitor (VEGFR1-3)

A Chinese-discovered pill that blocks the blood-vessel receptors, approved in 2023 for bowel cancer after all standard treatments.

RegorafenibApprovedSmall-molecule multi-kinase inhibitor

A sorafenib successor that became the first second-line drug proven to prolong life in liver cancer (2017).

The evidence behind it

SUNLIGHT Phase 3 NCT04737187 2023492 peopleevidence 93
Tests Trifluridine/tipiracil
Refractory metastatic colorectal cancer: trifluridine/tipiracil + bevacizumab vs trifluridine/tipiracil
OS 10.8 vs 7.5 months, HR 0.61.
Overall survival (months): Trifluridine/tipiracil + bevacizumab 10.8 (n=246) vs Trifluridine/tipiracil 7.5 (n=246) · HR 0.61 · source
FRESCO-2 Phase 3 NCT04322539 2023691 peopleevidence 94
Tests Fruquintinib
Refractory metastatic colorectal cancer after all standard therapies: fruquintinib vs placebo
OS 7.4 vs 4.8 months, HR 0.66.
Overall survival (months): Fruquintinib 7.4 (n=461) vs Placebo 4.8 (n=230) · HR 0.66 · source

The main trade-offs on record

Regorafenib all recorded rates →

Take with a low-fat breakfast (under 30% fat).
Not recommended in severe impairment; hepatotoxicity is a boxed warning.

Questions to ask about this decision

Between Trifluridine/tipiracil, Fruquintinib and Regorafenib, which do you recommend for me, and what about my case would make you choose differently?
Why: Guidelines list several reasonable options; the choice turns on details of your tumour, your health and your priorities.
What is each option trying to achieve: cure, long control, or relief of symptoms, and over what time?
Why: The aim shapes how much side effect and disruption is worth accepting.
How closely do I match the people in SUNLIGHT and FRESCO-2, and does that change what the results mean for me?
Why: Trial populations are selected; age, fitness, prior treatment and biomarkers all affect how far results carry.
What happens if I delay, or decline this step for now? Is the decision reversible?
Why: Some decisions can wait for a second opinion or a trial slot; others cannot. Knowing which is part of the choice.
Does your recommendation follow the current guideline (NCCN Guidelines: Colon Cancer), and if it departs from it, why?
Why: Departures from guidelines are sometimes right for an individual; they should be explained.
For my situation (later lines), which of the standard options do you recommend and why?
Why: Guideline options include: Trifluridine-tipiracil with bevacizumab (SUNLIGHT), fruquintinib (FRESCO-2) or regorafenib; clinical trials of next-generation RAS inhibitors.
Am I a candidate for Trifluridine/tipiracil, Fruquintinib, Regorafenib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of SUNLIGHT and FRESCO-2 apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Add these to your appointment list, or take the full question set for this cancer.

How to read this page. Options and results come from OnCo records with their sources; the settings are the standard-of-care rows on the cancer page, and the lines of therapy are on the sequencing grid. Where a setting names one path, the choice is usually about timing, trials and where to be treated: see expert centres. OnCo is orientation, not medical advice.