Background

KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS^G12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS^G12C that irreversibly and selectively binds to KRAS^G12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (~24 h), and extensive tissue distribution.

Methods

KRYSTAL-1 (NCT03785249) is a multi-cohort Phase 1/2 study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRAS^G12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.

Results

As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (Phase 1/1b and Phase 2). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14).

Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n=3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.

Conclusions

Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRAS^G12C-mutant NSCLC. Additional PD and mechanistic data will be presented.

Clinical trial identification

NCT03785249

Editorial acknowledgement

Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.