Adagrasib Monotherapy Elicits High Rates of Disease Control in KRAS-Mutated PDAC and Other GI Malignancies

Tanios S. Bekaii-Saab, MD

Adagrasib monotherapy demonstrated encouraging clinical activity in patients with previously treated pancreatic ductal adenocarcinoma (PDAC) and other non–colorectal gastrointestinal tumors that harbor KRAS G12C mutations, according to results of a phase 2 KRYSTAL-1 trial (NCT03785249) that were presented at the 2022 Gastrointestinal Cancers Symposium.¹

With a median follow-up of 6.3 months, there was a disease control rate (DCR) of 100% in all evaluable patients (n = 27) with gastrointestinal tumors, of whom 41% achieved a partial response (PR) to therapy.

“Adagrasib is 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,” Tanios S. Bekaii-Saab, MD, medical director of the Cancer Clinical Research Office and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona, said in a presentation of the data.

The frequency of KRAS mutations in pancreatic cancer is about 90%, with 2% of those being KRAS G12C.² A covalent inhibitor of KRAS G12C, adagrasib, irreversibly attaches to the protein in its inactive, guanosine diphosphate–bound 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.

In total, 42 patients were enrolled to the cohort at the data cut-off of September 10, 2021, with 30 having other gastrointestinal tumors which harbored a KRAS G12C mutation. Of those, there were 12 cases of PDAC, 8 biliary tract cancers, 5 appendiceal cancers, 2 with gastro-esophageal junction cancers, 2 small bowel cancers, and 1 esophageal cancer. Median patient age was 65.5 years (range, 40-89) and most were male (60%) and White (67%). Most patients had an ECOG performance status of 1 (80%) and a median of 2.0 prior lines of therapy (range, 1-5).

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. The primary end point of the phase 2 portion included objective response rate, with duration of response (DOR), progression-free survival (PFS), overall survival, and safety as secondary end points.

Ten out of 12 patients with PDAC 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 PRs were noted (50%), which included 1 unconfirmed PR. Median time to response (TTR) was 2.8 months and the median DOR was 6.97 months. Median PFS in this group was 6.6 months (95% CI, 1.0-9.7) and treatment was ongoing in 50%, with 100% of patients having a disease control rate.

In patients with other gastrointestinal tumors who were evaluable for response (n = 17), there were 6 PRs (35%), which included 2 that were unconfirmed. Responses were noted in 5 patients with biliary tract cancer and 1 patient each with gastro-esophageal junction and small bowel cancer. Median TTR was 1.3 months and median DOR was 7.85 months. Median PFS was 7.85 months (95% CI, 6.9-11.3) and 11 patients were still receiving treatment at the time of data cutoff.

“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.

No grade 4 or greater toxicities were noted and there were few non-gastrointestinal adverse events (AEs) in the cohort. The most frequent any-grade AEs in the overall cohort were nausea (48%), vomiting (43%), diarrhea (43%), fatigue (29%), aspartate aminotransferase increase (19%), blood creatinine increase (19%), anemia (17%), and peripheral edema (17%). The most frequent grade 3 events were fatigue (7%) and QTc prolongation (5%).

A newly initiated early access program is available to this and other patient populations with KRAS G12C–mutant solid tumors (NCT05162443).

References

1. Bekaii-Saab TS, Spira AI, Yaeger 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. J Clin Oncol. 2022;40(suppl 4):519. doi:10.1200/JCO.2022.40.4_suppl.519
2. Nollmann FI, Ruess DA. Targeting mutant KRAS in pancreatic cancer: futile or promising? Biomedicines. 2020;8(8):281. doi:10.3390/biomedicines8080281