KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/ Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation

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Conference Proceeding

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European Journal of Cancer


Background: KRAS is a key mediator of a signaling cascade that promotes cellular growth and proliferation and is the most frequently mutated oncogene in cancers, including lung adenocarcinoma. Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS G12C that irreversibly and selectively binds to and locks KRAS G12C in its inactive state. Adagrasib was optimized to exhibit a long half-life in order to achieve durable and continuous KRAS inhibition, which is postulated to prevent feedback loops and lead to deep and durable antitumor activity. Adagrasib has demonstrated objective responses and favorable tolerability in the Phase 1/1b setting. Methods: Adagrasib is being evaluated in KRYSTAL-1, a multi-cohort Phase 1/2 study in patients with advanced or metastatic solid tumors harboring a KRAS G12C mutation previously treated with chemotherapy and anti-PD-1/PD-L1 therapy. A dose of 600 mg twice daily (BID) was evaluated in dose expansion and established as the recommended Phase 2 dose (RP2D). The study endpoints include safety, pharmacokinetics (PK), and clinical activity and efficacy. Exploratory objectives include evaluation of pharmacodynamic biomarkers and correlation of molecular markers with antitumor activity. Results: As of 30 August 2020, 79 patients (57% female; median age, 65 years [range 25–85]; 22%/78% ECOG PS 0/1) with pretreated NSCLC were treated with adagrasib 600 mg BID in Phase 1/1b (n = 18) or a Phase 2 (n = 61) cohort. The most commonly reported (>20%) treatment-related adverse events (TRAEs) include: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). The only commonly reported (>2%) grade 3/4 treatment-related serious adverse event was hyponatremia (3%, 2/ 79). Among the 51 patients evaluable for clinical activity (14 from Phase 1/1b; 37 from Phase 2), 45% of patients had an objective response (23/51 which includes 5 patients who had an unconfirmed partial response and remain on treatment). Disease control rate was 96% (49/51) of patients. Among the 14 patients evaluable for clinical activity from Phase 1/1b with longer follow-up, the confirmed Objective Response Rate (ORR) was 43% (6/14); and the majority of patients with responses (4/6) have had treatment ongoing >11 months. The median time on treatment was 8.2 months (range:1.4, 13.1+). Additional data including pharmacodynamic and mechanistic biomarker analyses will be presented. Conclusions: Adagrasib is tolerable and demonstrates durable clinical activity in patients with previously treated KRAS G12C-mutant NSCLC.


Clinical trial information: NCT03785249.




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