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.
NCT03785249, NCT04613596.
Medical writing support for the development of this abstract, under the direction of the authors, was provided by Victoria Eyre-Brook, PhD, and Charlotte Kennerley, PhD, of Ashfield MedComms, an Inizio company, and funded by Mirati Therapeutics, Inc.
Mirati Therapeutics, Inc.
Mirati Therapeutics, Inc.
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