68O - Frequency of clinical acquired RAS-MAPK pathway resistance alterations in patients treated with KRASG12C inhibitors: An individual patient meta-analysis

Background

Mutant-selective covalent inhibitors of KRAS^G12C (G12Ci) have demonstrated efficacy in KRAS G12C-mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and pancreatic cancer. However, resistance invariably develops, resulting in short-lived response. To elucidate patterns and putative mechanisms of acquired resistance, we present the first individual patient data meta-analysis (IPDMA) of paired genomic sequencing in patients (pts) treated with G12Ci and provide supporting mechanistic data from in-vitro experiments.

Methods

This IPDMA integrates sequencing data from five published studies alongside data collected from 21 pts at the Massachusetts General Hospital. All pts included were treated with a mutant-selective G12Ci, had a progression-free survival of at least three months and had paired genomic sequencing results at baseline and disease progression. Cell-based experiments were conducted using engineered cell models.

Results

A total of 122 pts were analyzed. The majority of pts had NSCLC (n=67) or CRC (n=49) and were treated with Adagrasib (n=61), Sotorasib (n=30) or Divarasib (n=28), either as single agent (n=97) or combined with an anti-EGFR antibody (n=25). Overall, RAS-MAPK pathway alterations emerged in 49% of pts (n=61), with 44% developing at least one new KRAS alteration (n=54) and 27% (n=33) showing multiple concurrent resistance mechanisms affecting the RAS/MAPK pathway. The most prevalent alterations were KRAS activating mut (26% of pts), KRAS amplifications (21%), RAF/MAPK mut/fusions (21%) and KRAS switch-II pocket mut (20%). Notably, the proportion of pts with at least one acquired RAS-MAPK alteration was significantly higher in CRC compared to NSCLC (78% vs. 28%, p<0.001). Engineered KRAS^G12C cell lines expressing various RAS-MAPK pathway alterations demonstrated resistance to mutant-selective G12Ci yet were largely susceptible to targeting by panKRASi and panRASi.

Conclusions

Acquired genomic alterations in the RAS-MAPK pathway are major drivers of resistance to G12Ci in CRC and less prevalently in NSCLC. PanKRASi and panRASi may represent novel strategies to overcome acquired resistance in a majority of pts.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Entertainment Industry Foundation.

Disclosure

J.M. Riedl: Financial Interests, Personal, Advisory Board: Amgen. R. Heist: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Biohaven, Claim Therapeutics, Daiichi Sankyo, Lilly, Merck, Novartis, Regeneron, Sanofi; Financial Interests, Institutional, Research Grant: AbbVie, Daiichi Sankyo, Lilly, Mirati, Mythic, Novartis, Turning Point. All other authors have declared no conflicts of interest.