KRAS G12C-Targeted Therapy in Non-Small Cell Lung Cancer: From Resistant Salvage to Potential First-Line Backbone

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• KRAS G12C mutations are key drivers in non-small cell lung cancer (NSCLC).
• Covalent inhibitors like sotorasib and adagrasib are approved for previously treated KRAS G12C-mutant NSCLC.
• These approved therapies demonstrate improved progression-free survival (PFS) and overall survival (OS) compared to docetaxel.

Purpose of the Study:

• To review the structural, signaling, and clinical biology of KRAS G12C.
• To examine the evidence for first-line KRAS G12C inhibition in specific NSCLC subsets.
• To discuss emerging therapeutic strategies and combination therapies.

Main Methods:

• Integration of structural and signaling biology data.
• Analysis of contemporary clinical trial data (e.g., CodeBreaK 200, KRYSTAL-12).
• Review of real-world evidence on KRAS G12C targeted therapies.

Main Results:

• Approved covalent inhibitors show efficacy but face challenges in response durability.
• Resistance mechanisms include on-target mutations, bypass signaling, and co-occurring alterations (STK11, KEAP1, TP53).
• Next-generation inhibitors and combination strategies are being developed to overcome resistance and enable earlier treatment.

Conclusions:

• First-line KRAS G12C inhibition is an emerging strategy for select NSCLC patients.
• Randomized phase III trials are necessary to confirm the efficacy of frontline KRAS G12C inhibition.
• Platinum-based chemoimmunotherapy remains the standard of care outside of clinical trials.