Dr Veluswamy on the Emergence of KRAS G12C Inhibitors in NSCLC

We've gone from what was considered an undruggable mutation to now having almost an embarrassment of riches as far as RAS therapeutics. We can now target multiple different variants, and we have 2 FDA-approved drugs for G12C. With that said, everyone should be getting KRAS tested.

Rajwanth R. Veluswamy, MD, MSCR, associate professor of medicine, Hematology and Medical Oncology, Perlmutter Cancer Center, NYU Langone Health; co-director, KRAS Excellence Initiative [editor: confirm affiliation — discussion guide lists Icahn School of Medicine at Mount Sinai], discussed testing, frontline immunotherapy, and the evolving inhibitor landscape in KRAS G12C–mutant NSCLC.

During the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, Veluswamy addressed an exploratory analysis of the phase 3 EMPOWER-Lung 1 trial (NCT03088540) in which 39 patients with KRAS G12C–mutant, PD-L1–high NSCLC showed extended long-term survival with first-line cemiplimab (Libtayo) monotherapy [editor: confirm abstract venue and citation].

A confirmatory trial, he said, would need to enroll that subgroup prospectively, randomize accordingly, and be powered for the comparison. The signal fits G12C biology: these are generally smoking-associated tumors in which immunotherapy performs well. G12C accounts for roughly 40% of KRAS mutations in lung cancer and about 13% of lung adenocarcinomas, he noted.

Testing, Veluswamy said, should be universal. KRAS is included on NGS panels, and liquid biopsy has shortened turnaround times, easing treatment decisions.

Sotorasib (Lumakras) and adagrasib (Krazati), which received accelerated approvals roughly 4 to 5 years ago, were the first targeted agents for KRAS G12C. Although each produced a modest progression-free survival (PFS) gain of about 5 to 6 weeks vs docetaxel, tolerability was markedly better, some patients had durable benefit, and both remain the standard of care in his practice, with clear room for improvement.

Divarasib, a next-generation KRAS G12C(OFF) inhibitor with the same mechanism but greater potency, improved response rates and duration of response in phase 1. In July 2026, the phase 3 Krascendo 1 trial (NCT06497556) comparing divarasib with sotorasib or adagrasib in previously treated KRAS G12C–mutant NSCLC met its primary PFS and key secondary overall survival end points, according to a press release.1,2 Veluswamy expects the full readout to establish a new standard of care.

Beyond G12C, the field now spans allele-specific, pan-KRAS, and multi-RAS inhibitors, as well as OFF-, ON/OFF-, and ON-state small molecules, a convergence he expects to benefit patients over the next several years.