LBA4 Preliminary safety and efficacy of adagrasib with pembrolizumab in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) harboring a KRASG12C mutation

The combination of adagrasib (ada), a KRASG12C inhibitor, with an immune checkpoint inhibitor (CPI) has demonstrated enhanced preclinical anti-tumor activity. We report safety and efficacy of ada + pembrolizumab (pembro) in patients (pts) enrolled in the KRYSTAL-1 (NCT03785249) and KRYSTAL-7 (NCT04613596) trials. In a Ph 1b cohort of KRYSTAL-1 and Ph 2 KRYSTAL-7, pts with treatment-naïve, KRASG12C-mutated, advanced NSCLC received concurrent ada 400 mg BID + pembro 200 mg Q3W. Pts were enrolled across all PD-L1 levels. Endpoints were safety and efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]). As of 30 Aug 2022, 75 pts (median follow-up 3.5 mo) had received ada + pembro in KRYSTAL-7 and were safety evaluable. Median age was 66 yrs, 51% were female, 35%/65% were ECOG PS 0/1. Any grade treatment-related adverse events (TRAEs) occurred in 83% of pts; most common were nausea (48%), diarrhea (43%) and vomiting (24%). Grade 3–4 TRAEs occurred in 44% of pts; most common were increased lipase (11%) and increased ALT/AST (8%/9%), all Grade 3. There were no Grade 5 TRAEs. TRAEs led to both ada and pembro discontinuation in 3% of pts. In a preliminary analysis of tumor response among 53 pts with at least 1 on-study scan (median treatment duration 2 mo), ORR was 49% (26/53 [5 uPR]) and disease control rate (DCR) was 89%; 6 pts had responses on the second on-study scan or later and ORR was 56% in pts enrolled ≥6 mo before data cut-off. DOR, PFS, and OS were not mature, with most pts still on treatment. In KRYSTAL-1, 7 pts (median follow-up 19.3 mo) were clinically evaluable. ORR was 57% (4/7), DCR was 100%; treatment was ongoing >18 months in 2 responders. Safety was consistent with KRYSTAL-7. Additional analyses will be presented. In the largest dataset evaluating a KRASG12C inhibitor combined with a CPI as first-line treatment for NSCLC presented to date, concurrent ada 400 mg BID in combination with pembro had manageable toxicity and demonstrated encouraging preliminary efficacy.