Metastatic Colorectal Cancer — MSI / MMR-stratified

Sequencing for metastatic colorectal cancer by mismatch-repair status: MSI-H/dMMR disease starts with checkpoint immunotherapy (single-agent or dual blockade), while MSS/pMMR disease follows a chemotherapy-backbone pathway.

Mismatch-repair / MSI status?

• MSI-H / dMMR → Checkpoint regimen?
• MSS / pMMR → FOLFOX (or CAPOX) + bevacizumab

Checkpoint regimen?

• Single-agent checkpoint → Pembrolizumab monotherapy
• Dual checkpoint blockade → Nivolumab + ipilimumab

1L: Pembrolizumab monotherapy

Single-agent checkpoint blockade doubled PFS vs chemotherapy in 1L MSI-H/dMMR mCRC, with far less toxicity.

Evidence: KEYNOTE-177

• Progression on immunotherapy → FOLFOX ± bevacizumab (chemotherapy backbone if immunotherapy fails)

1L: Nivolumab + ipilimumab

Dual checkpoint blockade offers deep, durable responses; balance higher immune-related toxicity against efficacy.

Evidence: CheckMate-8HW

• Progression on immunotherapy → FOLFOX ± bevacizumab (chemotherapy backbone if immunotherapy fails)

2L: FOLFOX ± bevacizumab (chemotherapy backbone if immunotherapy fails)

A minority progress on immunotherapy; fall back to the standard cytotoxic backbone with an anti-angiogenic.

1L: FOLFOX (or CAPOX) + bevacizumab

MSS/pMMR disease does not respond to checkpoint monotherapy; a doublet + anti-angiogenic (or anti-EGFR for left-sided RAS wild-type) is standard.

• Progression → FOLFIRI + bevacizumab

2L: FOLFIRI + bevacizumab

Switch the cytotoxic backbone at progression; later lines include regorafenib and trifluridine/tipiracil.