In brief
- A narrative review by Akhil Kapoor and colleagues in Medical Oncology sets out the evidence on KRAS-targeted therapy in NSCLC, from the approved G12C inhibitors to combinations and mutant-specific agents.
- Sotorasib and adagrasib achieve objective response rates of 37% to 43% and a median progression-free survival of about 6 to 7 months in previously treated KRAS G12C NSCLC, with better tolerability than docetaxel.
- Next-generation G12C inhibitors (olomorasib, divarasib, glecirasib, D-1553 and IBI351) show response rates of 45% to 55%, and in some studies a longer progression-free survival than the first-generation agents.
- Resistance arises through on-target KRAS alterations, RTK-RAS bypass signalling, MAPK and PI3K pathway reactivation, and co-mutation-driven phenotypic remodelling.
- Combinations with PD-1 blockade, SHP2 or SOS1 inhibition, EGFR or MET inhibition, or platinum doublets are producing higher response rates in early trials.
Response rates of 37% to 43% with sotorasib and adagrasib
In previously treated KRAS G12C NSCLC, the two approved inhibitors reach a median progression-free survival of about 6 to 7 months, and the review reports better tolerability with both than with docetaxel. The review credits their approval with transforming the management of a driver historically deemed undruggable.
The figures are given as ranges covering both drugs, whose trials the authors list among their key sources from phase I to phase III.
Next-generation G12C inhibitors reach response rates of 45% to 55%
Olomorasib, divarasib, glecirasib, D-1553 and IBI351 form the second wave of G12C inhibitors the review assesses, and some of their studies report a progression-free survival longer than that seen with sotorasib or adagrasib. The abstract does not say whether any of these comparisons comes from a randomised head-to-head trial.
Among the non-G12C alleles, inhibitors specific to KRAS G12D show early proof-of-concept activity. The review also considers mutant-specific strategies for G12V, and names the expansion of treatment to non-G12C mutants as one of the conditions for further progress.
Resistance through four routes, on target and off
The review groups the ways KRAS-mutant tumours escape inhibition into on-target KRAS alterations, bypass signalling through the RTK-RAS axis, reactivation of the MAPK or PI3K pathways, and phenotypic remodelling driven by co-mutations. The authors tie future progress to combinations directed at these mechanisms.
Higher response rates with combinations in early trials
The review picks out four partners for KRAS inhibition: PD-1 blockade, SHP2 or SOS1 inhibition, EGFR or MET inhibition, and platinum doublets. In early trials these combinations are producing higher response rates and deeper, more durable suppression, according to the review.
“KRAS-mutant NSCLC is transitioning from historically untargetable disease to a therapeutically actionable subset.”Kapoor et al., Medical Oncology (2026)
Biomarkers and earlier disease settings set as the next steps
Alongside resistance-directed combinations and the move to non-G12C mutants, the authors name biomarker-guided personalisation and evaluation in earlier disease settings as the conditions on which further progress depends. The review draws on published clinical trials, translational studies, analyses of resistance mechanisms and real-world datasets.
As a narrative review, it summarises published studies and does not pool their results.
Sources
- Medical Oncology. KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms (2026-08-20). doi.org
Featuring Lung Summit faculty
This study was co-authored by Lung Summit faculty Vanita Noronha.
This article was produced independently by the Lung Summit editorial team, without industry funding or input.
