KRAS G12C Cancer Clinical Trials — 2026 Pipeline Tracker

Phase 3 KRAS G12C Trials — Active 2026

The table below covers the pivotal registration-intent studies currently underway. These trials will define the standard of care in KRAS G12C NSCLC and colorectal cancer through 2027 and beyond.

Source: ClinicalTrials.gov. Table reflects trials with registration intent as of Q1 2026. For a live, continuously updated list, set up a DataLookout alert.

From "Undruggable" to Standard of Care: The KRAS Story

For four decades after its discovery in 1982, KRAS was considered the most important and most intractable oncogene in cancer. Mutations in KRAS drive roughly 25% of all human cancers — more than any other single oncogene. Yet every attempt to inhibit it directly failed. The protein's surface lacked obvious drug-binding pockets, its affinity for GTP was in the picomolar range (far too tight for competitive inhibitors), and efforts to target its membrane localization or downstream effectors produced more toxicity than efficacy.

The breakthrough came from a structural insight: the G12C substitution — glycine to cysteine at codon 12 — creates a reactive thiol group adjacent to a shallow pocket (the "switch-II pocket," or S-IIP) that only exists in the GDP-bound, inactive form of the protein. Covalent inhibitors designed to dock into this pocket and form an irreversible bond with Cys12 could lock KRAS in its inactive state permanently. The AMSGEN team's discovery of AMG-510 (later sotorasib) demonstrated this was pharmacologically achievable, triggering a wave of competitive programs that has produced today's pipeline.

First-Generation Approvals: Sotorasib and Adagrasib

Sotorasib (Lumakras, Amgen) received accelerated FDA approval in May 2021 for previously treated KRAS G12C NSCLC — the first approved therapy directly targeting a KRAS mutation. Full approval followed in January 2023 based on CodeBreaK 200, a randomized Phase 3 trial showing PFS benefit vs docetaxel (5.6 vs 4.5 months; HR 0.66). The modest absolute benefit highlighted the limitations of KRAS G12C inhibitor monotherapy in the post-immunotherapy setting.

Adagrasib (Krazati, Mirati/BMS) gained accelerated FDA approval in December 2022 based on KRYSTAL-1, a Phase 2 single-arm trial showing 43% ORR and 8.5 months median duration of response in previously treated NSCLC. Adagrasib's longer half-life (~23 hours) enables once-daily dosing and — critically — the drug penetrates the blood-brain barrier, producing responses in CNS metastases in early data. In January 2024, adagrasib received a second FDA approval in combination with cetuximab for KRAS G12C colorectal cancer, based on KRYSTAL-1 colorectal cohort data showing 35% ORR (compared to ~10% for prior sotorasib monotherapy data in CRC).

Despite these approvals, neither agent has displaced chemotherapy or immunotherapy as a primary treatment in most NSCLC patients with KRAS G12C. Response rates in the 36–43% range and median PFS of 5–8 months fall short of EGFR inhibitor benchmarks in EGFR-mutant NSCLC. The field has recognized this gap and shifted R&D focus toward two approaches: next-generation inhibitors with improved potency, and rational combination strategies. See also: NSCLC clinical trials tracker and EGFR-mutant lung cancer trials.

The Calderasib Era: Merck's Next-Generation Bet

Calderasib (MK-1084) is the most advanced next-generation KRAS G12C inhibitor in clinical development as of 2026. Developed by Merck, calderasib is a covalent switch-II pocket inhibitor with higher potency and a more favorable pharmacokinetic profile than first-generation agents. Early Phase 1/2 data presented at ASCO and ESMO showed response rates in the 45–55% range in previously treated NSCLC — a meaningful step up from sotorasib and adagrasib monotherapy benchmarks.

Merck has initiated two Phase 3 programs with calderasib. NCT06345729 tests calderasib plus pembrolizumab versus docetaxel with or without pembrolizumab in second-line or later KRAS G12C NSCLC — a direct attempt to establish a combination immunotherapy backbone that could shift the standard of care. The pembrolizumab pairing is mechanistically motivated: KRAS G12C inhibition reduces immunosuppressive signaling in the tumor microenvironment, potentially synergizing with PD-1 blockade. NCT07190248 takes a broader platform approach, testing calderasib in multiple combination regimens in NSCLC, including novel doublet and triplet combinations that will be evaluated in parallel arms.

If calderasib's Phase 3 data mature favorably, it would represent a direct threat to both sotorasib and adagrasib's established positions — and establish Merck as the dominant player in the KRAS G12C NSCLC treatment paradigm, complementing their existing pembrolizumab franchise.

Olomorasib: Eli Lilly's Entry and the Race for Second-Line Dominance

Olomorasib (LY3537982) is Eli Lilly's KRAS G12C inhibitor candidate, also positioned as a next-generation agent with potency advantages over first-generation drugs. Preclinical data demonstrated greater depth of target engagement, and early clinical data showed a competitive response rate profile. Lilly has advanced olomorasib into a Phase 3 randomized trial (NCT06890598) comparing olomorasib plus standard of care versus standard of care alone in KRAS G12C NSCLC.

The combination-with-SoC design is distinct from Merck's immunotherapy-backbone approach, testing whether olomorasib's activity is additive or synergistic with established regimens rather than requiring a full immunotherapy pairing. This gives Lilly a differentiated clinical development strategy and could position olomorasib in settings where pembrolizumab combination is not appropriate (e.g., patients with autoimmune contraindications to checkpoint inhibitors).

Colorectal KRAS G12C: A Different Disease, Different Biology

Colorectal cancer harboring KRAS G12C — approximately 4% of all CRC cases — presents a fundamentally different therapeutic challenge than NSCLC. The reason is EGFR-driven feedback reactivation: when KRAS G12C is inhibited in colorectal tumor cells, EGFR signaling rapidly re-engages the RAS/MAPK pathway through upstream receptor tyrosine kinase activation, effectively bypassing the KRAS block within hours. This intrinsic resistance mechanism explains why sotorasib monotherapy produced only ~10% ORR in colorectal cancer — a stark contrast to its 36% ORR in NSCLC.

The solution, validated by adagrasib + cetuximab (anti-EGFR antibody) in KRYSTAL-1, is to simultaneously block both KRAS G12C and EGFR. This vertical pathway blockade prevents the feedback loop from reactivating downstream signaling. The 35% ORR for adagrasib + cetuximab in CRC represented a major improvement and supported regulatory approval.

The next step is testing this combination approach with more potent or differentiated agents. NCT06662786 (Janssen) tests amivantamab — a bispecific antibody targeting both EGFR and MET — combined with mFOLFOX6 chemotherapy versus cetuximab plus chemotherapy in KRAS G12C CRC patients. Amivantamab's dual EGFR/MET targeting addresses not only the primary EGFR bypass but also MET-driven resistance that emerges with EGFR inhibitor therapy. Phase 3 data from this trial are expected to reshape the colorectal KRAS G12C treatment algorithm. See our colorectal cancer clinical trials tracker for the full CRC pipeline.

Pancreatic Cancer: The Hardest KRAS Problem

Pancreatic ductal adenocarcinoma (PDAC) harbors KRAS mutations in approximately 90% of cases, but KRAS G12C specifically accounts for only ~2% — a small subgroup within an already rare disease. Despite this low frequency, pancreatic KRAS G12C has attracted significant research attention because it represents the first potentially targetable KRAS mutation in a cancer type with nearly no effective targeted therapy.

Sotorasib monotherapy showed limited activity in pancreatic KRAS G12C in early cohorts, consistent with the broad resistance biology of pancreatic cancer (dense stroma, immunosuppressive microenvironment, rapid acquisition of secondary mutations). The combination rationale being tested is sotorasib plus panitumumab (anti-EGFR antibody), applying the same KRAS + EGFR dual-blockade logic validated in colorectal cancer. Early Phase 1/2 data from this combination in pancreatic G12C are pending and will determine whether meaningful clinical activity is achievable in this indication.

Resistance Mechanisms: Why KRAS G12C Inhibitors Stop Working

Acquired resistance to KRAS G12C inhibitors is an active area of investigation and a major driver of next-generation compound development. Mechanisms identified from patient biopsies at progression include:

• KRAS amplification: Increased copy number of the mutant KRAS allele overwhelms the covalent inhibitor, effectively diluting the drug effect.
• Secondary KRAS mutations: Mutations at Y96, R68S, and other positions alter the switch-II pocket geometry, impairing covalent inhibitor binding.
• Bypass RTK activation: Upregulation of EGFR, MET, FGFR, or other receptor tyrosine kinases re-engages the RAS/MAPK pathway independent of KRAS G12C — analogous to the colorectal resistance biology seen at baseline.
• KRAS switch-II pocket (S-IIP) mutations: Structural alterations in the S-IIP that prevent covalent drug docking without affecting KRAS catalytic function.
• RAS/MAPK pathway reactivation: NF1 loss, RAF mutations, or MEK mutations that activate the pathway downstream of KRAS, bypassing the inhibited oncoprotein entirely.

These resistance patterns explain why combination strategies (KRAS G12C + SHP2 inhibitor, KRAS G12C + MEK inhibitor, KRAS G12C + EGFR antibody) are being tested — each combination attempts to preempt or address a specific resistance mechanism. They also motivate the development of non-covalent and pan-RAS inhibitors that can potentially re-sensitize tumors that have acquired switch-II pocket resistance mutations.

Pan-KRAS Inhibitors: The Next Frontier

First- and next-generation KRAS G12C inhibitors all work via the same mechanism: covalent binding to Cys12 in the switch-II pocket of the GDP-bound inactive state. This restricts their utility to KRAS G12C specifically. A new class of pan-KRAS inhibitors — targeting ALL KRAS mutations, including G12D (the most common), G12V, G12R, and others — is now entering early clinical development.

Three notable pan-KRAS programs in Phase 1 as of 2026:

• BGB-53038 (BeOne Medicines): A non-covalent pan-KRAS inhibitor targeting the GDP-bound state across multiple KRAS mutant alleles. Phase 1 dose escalation underway in solid tumors.
• BBO-11818 (TheRas): A RAS-targeting compound with activity across multiple RAS family members; designed to address resistance mechanisms that emerge after KRAS G12C-specific inhibitor failure.
• KST-6051 (Kestrel Therapeutics): Pan-KRAS inhibitor with early Phase 1 data in solid tumors harboring any KRAS mutation variant.

Pan-KRAS inhibitors face a significant challenge that covalent G12C-specific inhibitors avoided: selectivity for mutant over wild-type KRAS. Normal KRAS is essential for cellular homeostasis, particularly in the gut and hematopoietic system. Inhibiting wild-type KRAS is expected to produce dose-limiting toxicity. The therapeutic window for pan-KRAS inhibition will depend on achieving sufficient selectivity or identifying tumor-selective delivery strategies — still an open question at this stage of development.

Combination Strategies Under Investigation

Beyond the pivotal Phase 3 programs, the KRAS G12C field is generating extensive Phase 1 and Phase 2 combination data across three major hypotheses:

KRAS G12C Inhibitor + Anti-PD-1 Immunotherapy

The mechanistic rationale: KRAS G12C inhibition suppresses tumor-derived VEGF and immunosuppressive cytokines, potentially converting cold tumors to hot. Early data from adagrasib + pembrolizumab (KRYSTAL-7) and calderasib + pembrolizumab suggest synergy is achievable without prohibitive additive toxicity. The 1L setting (before chemotherapy) is the primary battleground — establishing a KRAS-targeted first-line option would represent a major paradigm shift.

KRAS G12C Inhibitor + MEK Inhibitor

Targeting both KRAS and MEK simultaneously addresses multiple points of RAS/MAPK pathway activation and preempts feedback reactivation via MEK. However, the toxicity profile of this combination has proven challenging — overlapping GI and cutaneous toxicities have limited tolerability in early trials. Improved scheduling and dose optimization strategies are being tested.

KRAS G12C Inhibitor + SHP2 Inhibitor

SHP2 is a phosphatase that functions upstream of RAS and is required for RTK-driven RAS activation. SHP2 inhibitors block the feedback reactivation of KRAS through upstream RTKs (EGFR, MET, FGFR), theoretically suppressing both primary signaling and acquired resistance mechanisms simultaneously. Multiple KRAS G12C + SHP2 inhibitor combinations are in Phase 1/2, including combinations using RMC-4630 (Revolution Medicines) and TNO155 (Novartis).

Related Clinical Trial Trackers

• NSCLC Clinical Trials — Full Pipeline Tracker — all non-small cell lung cancer trials, including KRAS, EGFR, ALK, RET, MET programs
• Colorectal Cancer Clinical Trials Tracker — KRAS G12C CRC, BRAF V600E, microsatellite instability, and antibody-drug conjugate programs
• EGFR-Mutant Lung Cancer Clinical Trials — exon 19 deletions, L858R, exon 20 insertions, and osimertinib resistance landscape

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