Metastatic Colorectal Cancer: Systemic Therapy

Metastatic Colorectal Cancer: overview

This algorithm organizes systemic therapy for metastatic colorectal cancer by biomarker, with mismatch repair status, RAS and BRAF status, tumor sidedness, HER2 amplification and KRAS G12C as the key branch points.

For dMMR or MSI-high disease, first-line immunotherapy is preferred: pembrolizumab (KEYNOTE-177) or nivolumab with or without ipilimumab (CheckMate 8HW), the latter producing a large progression-free survival gain over chemotherapy. RAS and BRAF wild-type, left-sided tumors receive FOLFOX or FOLFIRI plus cetuximab or panitumumab (CRYSTAL). RAS-mutant or right-sided tumors receive FOLFOX or FOLFIRI plus bevacizumab. BRAF V600E tumors are treated with encorafenib plus cetuximab (BEACON). For HER2-amplified disease, options are tucatinib plus trastuzumab (MOUNTAINEER) or trastuzumab deruxtecan (DESTINY-CRC02), which was active including in RAS-mutant tumors. KRAS G12C tumors may receive sotorasib plus panitumumab (CodeBreaK 300) or adagrasib plus cetuximab (KRYSTAL-1). Biomarker-agnostic later-line options are regorafenib (CORRECT), trifluridine/tipiracil with or without bevacizumab (SUNLIGHT, where adding bevacizumab improved overall survival), and fruquintinib (FRESCO-2).

Trials behind this algorithm

KEYNOTE-177 Andre T et al, NEJM, 2020; PMID: 33264544
CheckMate 8HW Andre T et al, NEJM, 2024; PMID: 39602630
CRYSTAL trial Van Cutsem E et al, NEJM, 2009; PMID: 19339720
BEACON CRC Kopetz S et al, NEJM, 2019; PMID: 31566309
MOUNTAINEER Strickler JH et al, Lancet Oncol, 2023; PMID: 37142372
DESTINY-CRC02 Raghav K et al, Lancet Oncol, 2024; PMID: 39116902
KRYSTAL-1 (CRC) Yaeger R et al, NEJM, 2022; PMID: 36546659
CORRECT Grothey A et al, Lancet, 2013; PMID: 23177514
SUNLIGHT Prager GW et al, NEJM, 2023; PMID: 37133585

Background reading: Colorectal cancer board review notes.

Metastatic Colorectal Cancer: the algorithm in words

Starting point: Metastatic colorectal cancer by biomarker. Full background: Colorectal cancer notes.

dMMR / MSI-high (first-line): IO: Pembrolizumab (KEYNOTE-177); Dual-IO: Nivolumab ± ipilimumab (CheckMate 8HW).
RAS/BRAF-wt · left (first-line): Anti-EGFR: FOLFOX/FOLFIRI + cetuximab/panitumumab (CRYSTAL).
RAS-mut or right-sided (first-line): Anti-VEGF: FOLFOX/FOLFIRI + bevacizumab (first-line).
BRAF V600E (first-line): Targeted: Encorafenib + cetuximab (BEACON).
HER2-amplified (second-line): Dual anti-HER2: Tucatinib + trastuzumab (MOUNTAINEER); ADC: Trastuzumab deruxtecan (DESTINY-CRC02).
KRAS G12C (second-line): Targeted: Sotorasib + panitumumab (CodeBreaK 300); Targeted: Adagrasib + cetuximab (KRYSTAL-1).
Later-line (agnostic) (later-line): TKI: Regorafenib (CORRECT); Cytotoxic: Trifluridine/tipiracil ± bev (SUNLIGHT); TKI: Fruquintinib (FRESCO-2).