Metastatic NSCLC — KRAS G12C-mutant

Sequencing for KRAS G12C-mutant metastatic non-small cell lung cancer: PD-L1-guided first-line immunotherapy, followed by a KRAS G12C inhibitor (sotorasib or adagrasib) at progression.

PD-L1 tumor proportion score?

• PD-L1 ≥ 50% → Pembrolizumab monotherapy (± platinum-doublet chemotherapy)
• PD-L1 < 50% → Pembrolizumab + carboplatin/pemetrexed

1L: Pembrolizumab monotherapy (± platinum-doublet chemotherapy)

PD-L1 ≥50%: single-agent pembrolizumab is standard; add chemotherapy for high disease burden. No approved 1L KRAS G12C inhibitor — reserve targeted therapy for progression.

Evidence: KEYNOTE-024

• Progression → KRAS G12C inhibitor at progression?

1L: Pembrolizumab + carboplatin/pemetrexed

PD-L1 <50%: chemoimmunotherapy is the frontline standard for non-squamous NSCLC.

Evidence: KEYNOTE-189

• Progression → KRAS G12C inhibitor at progression?

KRAS G12C inhibitor at progression?

• Sotorasib → Sotorasib
• Adagrasib (CNS disease) → Adagrasib

2L: Sotorasib

Superior PFS vs docetaxel. Monitor LFTs (hepatotoxicity) and rare ILD/pneumonitis.

Evidence: CodeBreaK 200

• Progression → Docetaxel ± ramucirumab

2L: Adagrasib

CNS-penetrant option with documented intracranial activity; monitor GI toxicity, QTc, and LFTs.

Evidence: KRYSTAL-1

• Progression → Docetaxel ± ramucirumab

3L+: Docetaxel ± ramucirumab

After failure of immunotherapy and a KRAS G12C inhibitor; consider a biomarker-matched clinical trial.