KRAS G12C resistance patterns are reshaping second-line NSCLC sequencing

Reading the signal

Sotorasib and adagrasib opened the door on KRAS G12C as a directly drugged target in non-small-cell lung cancer. The resistance picture from post-progression sampling has been accumulating for the past two years and is now coherent enough to shape practice.

Three resistance buckets are doing most of the work in the published series:

• Secondary KRAS mutations that compromise the binding pocket, enabling continued KRAS-driven signalling
• Bypass-track activation, particularly through MET, FGFR and EGFR, which restores downstream signalling without going through KRAS at all
• Lineage-state shifts, including squamous transformation, which change the disease the regimen is treating

Each bucket implies a different second-line decision. Bypass-driven resistance positions a combination strategy. Secondary KRAS mutations argue for a structurally different KRAS inhibitor or for a non-KRAS chemistry-based regimen. Lineage shifts mean the regimen needs to address the new histology, not the old molecular driver.

Commercial implications

For sponsors with KRAS G12C assets, second-generation pan-KRAS programs, or combination partners:

1. Post-progression biopsy infrastructure is the practical commercial bottleneck. Plasma ctDNA at progression is more accessible than tissue rebiopsy and is already being used to read out the resistance pattern. The community oncology setting is more variable on this than the academic centres.
2. The combination story is now indication-specific within NSCLC. First-line G12C plus checkpoint inhibitor combinations have different commercial logic from second-line G12C plus targeted bypass-track combinations. Trial designs and label aspirations need to track that.
3. The window for a second-line single-agent KRAS asset is narrowing. Without a clear differentiation on resistance coverage or toxicity, a sequential single-agent approach faces the combination class on one side and chemotherapy on the other.

What we are watching

• Sequential single-agent versus combination first-line G12C trial readouts and how they reframe second-line eligibility.
• ctDNA-guided resistance assays moving toward routine reimbursement and the speed at which they reach community oncology.
• Pan-KRAS and KRAS-on (active-state) programs as they enter pivotal trials and how they handle the resistance bucket landscape mapped here.