KRAS Inhibitor Clinical Trial Landscape

What is KRAS and Why Does It Matter?

KRAS (Kirsten RAS) is one of the most frequently mutated oncogenes in human cancer — present in approximately 25% of all malignancies. In pancreatic ductal adenocarcinoma (PDAC), KRAS mutations exceed 90%. In non-small cell lung cancer (NSCLC), KRAS mutations are found in ~25% of cases (predominantly G12C and G12D). In colorectal cancer, KRAS mutations occur in ~35-40% of cases.

For four decades, KRAS was considered "undruggable" — its smooth protein surface offered no obvious binding pocket for small molecules. The 2013 discovery of an allosteric binding pocket near the switch II region, combined with covalent chemistry targeting the G12C cysteine mutation, finally unlocked KRAS as a therapeutic target. Sotorasib became the first approved KRAS inhibitor in May 2021.

Approved KRAS Inhibitors

Current KRAS Inhibitor Landscape (2026)

The KRAS field has evolved rapidly from single-agent G12C inhibitors to combination strategies, next-generation G12C agents, and entirely new target approaches (G12D, G12V, pan-KRAS, SOS1 inhibition). The major axes of current development:

KRAS G12C — Second-Generation and Combinations

First-generation single-agent response rates in NSCLC (sotorasib: ~37%, adagrasib: ~43%) highlighted the need for combinations to overcome adaptive resistance. Current Phase 3 programs pair KRAS G12C inhibitors with PD-(L)1 checkpoint blockade, chemotherapy, or anti-EGFR antibodies to address the RAS pathway reactivation that limits monotherapy durability.

• Olomorasib (LY3537982, Eli Lilly/Loxo) — next-gen G12C inhibitor with superior potency. Phase 3 vs. standard chemo-IO in first-line KRAS G12C NSCLC (NCT06119581) and in combination with standard of care (NCT06890598).
• Divarasib (GDC-6036, Roche/Genentech) — Phase 3 vs. docetaxel in second-line NSCLC (NCT06497556) and in combination with cetuximab in colorectal cancer (NCT06793215).
• Calderasib (MK-1084, Merck) — Phase 3 with pembrolizumab in resected NSCLC adjuvant setting (NCT07431827) and first-line combination (NCT06345729).
• Adagrasib (Krazati, Mirati/BMS) — Phase 3 + pembrolizumab + chemotherapy first-line NSCLC (NCT06875310).

KRAS G12C — Colorectal Cancer

Unlike NSCLC, KRAS G12C colorectal cancer (CRC) shows poor single-agent response due to EGFR-driven adaptive feedback. Combining KRAS G12C inhibitors with anti-EGFR antibodies (cetuximab, panitumumab) has demonstrated meaningful activity — the combination is now being validated in Phase 3:

• Sotorasib + panitumumab (Amgen) — Phase 3 vs. standard second-line therapy in KRAS G12C CRC (NCT05198934, NCT06252649).
• Divarasib + cetuximab (Roche) — Phase 3 (NCT06793215).
• Amivantamab + FOLFIRI (Janssen) — amivantamab targets EGFR/MET; Phase 3 in KRAS-mutant CRC including G12C (NCT06662786, NCT06750094).

Pan-KRAS and Multi-Mutation Inhibitors

Revolution Medicines is leading the development of pan-RAS inhibitors that target multiple KRAS mutations simultaneously — including G12D, the dominant mutation in pancreatic cancer:

• RMC-6236 (Revolution Medicines) — pan-RAS(ON) inhibitor targeting multiple KRAS/HRAS/NRAS mutations. Phase 1/2 in PDAC and NSCLC. Expected to enter Phase 3 in pancreatic cancer.
• RMC-9805 (Revolution Medicines) — KRAS G12D-selective. Phase 1 in KRAS G12D-mutant solid tumors, particularly PDAC.
• D-1553 + IN10018 (InxMed) — combination of a KRAS G12C inhibitor (D-1553) with a FAK inhibitor (IN10018). Phase 3 in NSCLC (NCT07174908).

SOS1 Inhibitors — Upstream RAS Pathway

SOS1 is a guanine nucleotide exchange factor (GEF) that activates RAS by exchanging GDP for GTP. Blocking SOS1 reduces KRAS activation upstream — and importantly, can complement direct KRAS inhibitors by blocking the adaptive re-activation that drives resistance:

• BI-3406 / BI 1701963 (Boehringer Ingelheim) — SOS1::KRAS interaction inhibitor in combination with MEK inhibitor trametinib. Phase 1/2 in KRAS-mutant solid tumors.
• BAY3498264 (Bayer) — SOS1 inhibitor in combination with sotorasib. Phase 1 (NCT-sotorasib + BAY3498264).

Key Phase 3 KRAS Inhibitor Trials (2026)

The KRAS Inhibitor Competitive Landscape by Indication

NSCLC (Lung Cancer) — 38+ Active Trials

NSCLC is the primary battleground for KRAS inhibition. KRAS G12C mutations occur in ~13% of all NSCLC — a large addressable population in one of oncology's biggest markets. The competitive dynamic in 2026 is: which KRAS G12C inhibitor (with which combination partner) will become standard first-line therapy? Olomorasib (Eli Lilly), divarasib (Roche), and calderasib (Merck) are all competing to displace adagrasib and sotorasib in earlier lines of therapy. The key differentiating data points will come from first-line combination trials — results expected 2026-2027.

Colorectal Cancer — 14+ Active Trials

KRAS G12C colorectal cancer has a narrow but well-defined opportunity. Anti-EGFR combinations (sotorasib + panitumumab, adagrasib + cetuximab) have demonstrated meaningful activity where monotherapy failed. The CodeBreaK 300 data from Amgen established sotorasib + panitumumab as an active regimen. Phase 3 confirmatory trials are now running for multiple combinations. Amivantamab (bispecific EGFR/MET antibody from Janssen) provides an alternative approach targeting the same EGFR feedback mechanism.

Pancreatic Cancer (PDAC) — 10+ Active Trials

PDAC is the highest-stakes battleground for non-G12C KRAS inhibition. KRAS mutations drive ~90% of PDAC cases, predominantly G12D (~45%) and G12V (~30%). No approved KRAS-targeted therapy exists for PDAC. Revolution Medicines' RMC-6236 (pan-RAS) and RMC-9805 (KRAS G12D) are the leading programs, with Phase 2/3 expansion anticipated in 2026. If pan-KRAS inhibition works in PDAC, it would be a transformative advance in a disease with a 5-year survival rate below 13%.

Generation-by-Generation: KRAS Inhibitor Evolution

Key Sponsors in KRAS Inhibitor Development

Frequently asked questions