KRYSTAL-1: Adagrasib in Previously Treated Patients with Unresectable or Metastatic Pancreatic Cancer and Other Gastrointestinal Tumors with a KRAS G12C Mutation

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KRAS mutations occur in approximately 90% of pancreatic cancers; of these, approximately 2% are KRAS G12C mutations. Adagrasib is a selective KRAS G12C inhibitor that was evaluated as monotherapy or in combination with other treatments in the multicohort phase 1/2 KRYSTAL-1 study in patients with advanced solid tumors harboring a KRAS G12C mutation. Preliminary data from patients enrolled in a phase 2 cohort that evaluated single-agent adagrasib in patients with unresectable or metastatic solid tumors, including pancreatic and other gastrointestinal (GI) cancers, were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The study enrolled patients with previously treated unresectable or metastatic solid tumors harboring a KRAS G12C mutation with treated and/or stable brain metastases. Eligible patients received oral adagrasib 600 mg twice a day. Study end points included clinical activity, safety, and pharmacokinetics. Data cutoff date was September 10, 2021.

A total of 42 patients were enrolled in the phase 2 cohort; of these, 30 patients had KRAS G12C–mutant GI tumors (12 pancreatic ductal adenocarcinoma [PDAC], 8 biliary tract, 5 appendiceal, 2 gastroesophageal junction, 2 small bowel, and 1 esophageal). The median age of the GI cancer cohort (n = 30) was 63.5 years, 52% were female, and 71% had Eastern Cooperative Oncology Group performance status 1. In the overall cohort (n = 30), patients had received a median of 2 prior lines of therapy with a median follow-up of 6.3 months. In the PDAC cohort (n = 12), patients received a median of 2.5 prior lines of therapy with a median follow-up of 8.1 months. In the other GI cohort (n = 17), patients received a median of 2 prior lines of therapy with a median follow-up of 6.3 months.

Of the 27 patients with GI tumors who were evaluable for clinical activity, overall response rate was achieved by 11 patients (all partial responses [PRs]); the disease control rate (DCR) was 100%. In the PDAC cohort of evaluable patients (n = 10), PRs were achieved by 5 patients (50%); DCR was 100%. Among the 17 evaluable patients with other GI tumors, 6 achieved PRs (35%) with a DCR of 100%.

In the overall GI cohort (n = 30), treatment-related adverse events (TRAEs) of any grade occurred in 87% of patients and grade 3 TRAEs in 27% of patients. The most common any-grade TRAEs included nausea (50%), vomiting (40%), diarrhea (37%), and fatigue (33%). The most common grade 3 TRAEs that occurred in ≥5% of patients included fatigue (10%) and QT prolongation (7%).

Based on these results, it was concluded that adagrasib monotherapy was well-tolerated and demonstrated encouraging clinical activity in previously treated patients with GI tumors harboring a KRAS G12C mutation.


Bekaii-Saab TS, Spira AI, Yager R, et al. KRYSTAL-1: updated activity and safety of adagrasib (MRTX849) in patients (pts) with unresectable or metastatic pancreatic cancer (PDAC) and other gastrointestinal (GI) tumors harboring a KRASG12C mutation. Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 20-22, 2022. Abstract 519.

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