Adagrasib Confers High Response Rates in Several Gastrointestinal, Pancreatic Tumors

Patients with previously treated pancreatic ductal adenocarcinoma, which is the most common type of cancer that forms in the pancreas, and other non-colorectal gastrointestinal tumors harboring KRAS G12C mutations derived encouraging responses after receiving treatment with adagrasib, according to recent study findings.

The study results also showed that at a median follow-up of 6.3 months, treatment with the study drug resulted in a disease control rate (percentage of patients who achieve complete response, partial response or stable disease while receiving treatment) of 100%. Moreover, the data demonstrated that 41% of the 27 evaluable patients enrolled in a cohort of the phase 2 KRYSTAL-1 trial achieved a partial response to treatment.

“Adagrasib is (a) KRAS G12C selective, covalent inhibitor with a long half-life that enables exposure above a target threshold throughout the dosing interval (with) monotherapy demonstrating promising clinical activity with 100% disease control rate for those patients with pancreas cancer and other (gastrointestinal) non–colorectal cancers harboring G12C mutations,” Dr. Tanios S. Bekaii-Saab, medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, said during a presentation of the data at the 2022 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Previous reports have indicated that the frequency of KRAS mutations in pancreatic cancer is about 90%, with 2% of those being KRAS G12C. Adagrasib, a covalent inhibitor of KRAS G12C, irreversibly attaches to the protein in its inactive form and shuts down its activity. Continuous exposure to the agent above a target threshold leads to KRAS-dependent signaling inhibition and maximizes depth and duration of antitumor activity.

Forty-two patients (median age, 65.5 years; 60% male; 67% White) were enrolled into this cohort, of which, 30 had other gastrointestinal tumors that harbored a KRAS G12C mutation. Of those patients with that mutation, there were 12 cases of pancreatic ductal adenocarcinoma, eight biliary tract cancers, five appendiceal cancers, two gastro-esophageal junction cancers, two small bowel cancers and one esophageal cancer.

Previously reported data from the phase 1/2 trial established clinical activity with adagrasib in various solid tumors including gastrointestinal malignancies as well as lung and gynecologic cancers. Patients analyzed herein were treated with the recommended phase 2 dose of 600 mg twice per day administered orally.

Measuring the objective response rate (percentage of patients with partial and complete responses to treatment) served as the main goal of the study. Additional goals included assessing overall survival, progression-free survival (the time during and after treatment when the patient lives without disease progression) and safety.

Ten out of 12 patients with pancreatic ductal adenocarcinoma were evaluable for clinical activity, in whom median follow-up was 8.1 months and median number of prior therapies was 2.5 (range, 1-4). Five partial responses were noted, which included one unconfirmed partial response. Median time to treatment response was 2.8 months and the median duration of response was 6.97 months.

The results demonstrated that the median progression-free survival in this group was 6.6 months and treatment was ongoing in 50% of patients.

In 17 patients with other gastrointestinal tumors who were evaluable for response, there were six partial responses, which included two that were unconfirmed. Responses were noted in five patients with biliary tract cancer and one patient each with gastro-esophageal junction and small bowel cancer. Median time to treatment response was 1.3 months and median duration of response was 7.85 months in this patient group. Median progression-free survival was 7.85 months, and 11 patients were still receiving treatment at the time of data cutoff in September.

“When you look at biliary tract cancer, 50% of the patients had the response. These are small numbers, but these are solid responses,” Bekaii-Saab said.

There were no serious or fatal treatment-related toxicities and there were minimal non-gastrointestinal side effects among this patient population. The most common side effects of any severity included but were not limited to nausea (48%), vomiting (43%), diarrhea (43%) and fatigue (29%).

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