KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced solid tumors harboring a KRASG12C mutation

Background: KRAS, a mediator of signalling pathways essential for cellular growth, proliferation, and survival, is the most frequently mutated oncogene in cancer. Notably, KRAS mutations occur in similar to 90% of pancreatic cancers, of which similar to 2% are KRAS(G12C) mutations. Other gastrointestinal (GI) tumors also harbor KRAS(G12C) mutations, such as biliary tract cancer (BTC; 1%) and appendiceal cancer (3-4%), and they are also seen in non-GI tumors, such as endometrial and ovarian cancer (1-2%). Adagrasib, a covalent KRAS(G12C) inhibitor that irreversibly and selectively binds KRAS(G12C) in its inactive state, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. Methods: KRYSTAL-1 is a multicohort phase 1/2 study (NCT03785249) evaluating adagrasib in patients (pts) with advanced solid tumors harboring a KRAS(G12C) mutation. Here we report data from a phase 2 cohort evaluating adagrasib monotherapy administered orally at 600 mg BID in pts with unresectable or metastatic KRAS(G12C)-mutated solid tumors (excluding non-small cell lung cancer and colorectal cancer), including pancreatic ductal adenocarcinoma (PDAC), BTC, other GI, and non-GI tumors. Study objectives include evaluation of clinical activity (ORR, DCR, DOR, PFS, OS) and safety. Results: As of October 1, 2022, 64 pts with KRAS(G12C)-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of these, 21 pts had PDAC, 12 BTC, 16 other GI tumors (9 appendiceal, 4 gastro-esophageal junction/esophageal, 3 small bowel), and 14 non-GI tumors (5 ovarian, 4 unknown primary, 3 endometrial, 1 breast, 1 glioblastoma). Overall, median age was 65 years, 61% had ECOG PS 1, and median prior lines of systemic therapy was 2. Among 57 pts with measurable disease (blinded independent central review), ORR was 35.1% (20/57; all partial responses); DCR was 86.0% (49/57); median DOR was 5.3 months (n=20; 95% CI 2.8-7.3); median PFS was 7.4 months (95% CI 5.3-8.6); and median OS was 14.0 months (n=64; 95% CI 8.5-18.6). Among 21 pts with PDAC, ORR was 33.3% (7/21); DCR was 81.0% (17/21); median PFS was 5.4 months (95% CI 3.9-8.2); and median OS was 8.0 months (95% CI 5.2-11.8). Among 12 pts with BTC, ORR was 41.7% (5/12); DCR was 91.7% (11/12); median PFS was 8.6 months (95% CI 2.7-11.3); and median OS was 15.1 months (95% CI 8.6-not estimable). Overall (n=63), treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of pts (most commonly [>= 20%] nausea [49.2%], diarrhea [47.6%], fatigue [41.3%], vomiting [39.7%]), grade 3 TRAEs in 25.4%, and grade 4 TRAEs in 1.6%. No grade 5 TRAE occurred. Conclusions: Adagrasib is well tolerated and demonstrates promising clinical activity in pretreated pts with PDAC, BTC, and other solid tumors harboring a KRAS(G12C) mutation. Clinical trial information: NCT03785249.