The KRAS G12C battlefield just got more crowded. Bristol Myers Squibb unveiled Phase 1/2 data for BMS-986369 at ASCO 2024, showing a 38% objective response rate (ORR) and median progression-free survival (PFS) of 8.2 months in previously treated KRAS G12C-mutant non-small cell lung cancer (NSCLC) patients. These numbers sit squarely in line with Amgen's Lumakras (sotorasib) and Mirati's Krazati (adagrasib), but the mechanism of action tells a different story.
BMS-986369 is a covalent, reversible inhibitor that locks KRAS G12C in its inactive GDP-bound state. Unlike the irreversible binding of sotorasib and adagrasib, BMS' compound forms a reversible covalent bond, potentially allowing for reduced off-target toxicity and a higher barrier to resistance. Preclinical models suggest BMS-986369 retains activity against common acquired resistance mutations like G12C/Y96D, a key advantage over existing therapies.
Safety Profile and Dosing
The safety profile appears manageable: Grade 3+ treatment-related adverse events occurred in 22% of patients, predominantly transaminase elevations (ALT/AST increase in 12%). No Grade 5 events were reported. Notably, diarrhea and nausea rates were lower than those seen with Lumakras (15% vs 31% for any-grade diarrhea). BMS is advancing a 600 mg twice-daily dose into Phase 3.
The competitive landscape is shifting. Amgen's Lumakras generated $2.6B in 2023 sales but is under pressure from the FDA's accelerated approval withdrawal risk (confirmatory trial CodeBreaK 200 missed PFS endpoint). Mirati's Krazati, now part of BMS after the $5.8B acquisition, adds a second KRAS G12C asset. BMS-986369, discovered internally, could cannibalize Krazati but offers a differentiated profile for patients who progress on prior KRAS therapy.
What to watch: BMS plans to initiate a Phase 3 trial in 2L+ KRAS G12C NSCLC by Q4 2024, with potential FDA filing in 2025. Key questions remain: (1) Can BMS-986369 show superiority over Lumakras in a head-to-head? (2) Will the reversible binding translate to better durability? (3) How will it perform in combination with checkpoint inhibitors? The KRAS G12C market is projected to reach $10B by 2030, but only the best-in-class molecule will capture share.
