In the phase I/II KRYSTAL-1 trial, the KRAS inhibitor adagrasib demonstrated promising clinical activity in previously treated patients with pancreatic ductal adenocarcinoma, biliary tract cancer, and other solid tumors harboring KRAS G12C mutations, according to research presented at the April 2023 session of the ASCO Plenary Series by Shubham Pant, MD, and colleagues. The findings came from an updated analysis of one arm of the multicohort study after a median follow-up of 16.8 months.
Shubham Pant, MD
“Adagrasib monotherapy demonstrated clinically meaningful activity in a variety of KRAS G12C–mutated solid tumors, for which no standard-of-care treatment options are available,” said Dr. Pant, who is Professor in the Department of Gastrointestinal Medical Oncology, Director of Clinical Research, and Associate Director for Early-Phase Drug Development at The University of Texas MD Anderson Cancer Center in Houston.
The KRYSTAL-1 cohort is the largest phase II tumor-agnostic data set to evaluate KRAS G12C–mutated solid tumors, excluding non–small cell lung cancer (NSCLC) and colorectal cancer.
Long-Standing Need to Target KRAS G12C
KRAS, a mediator of signaling pathways essential for cellular growth, proliferation, and survival, is the most frequently mutated oncogene in cancer. The KRAS G12C mutation acts as an oncogenic driver in a range of solid tumors. KRAS G12C mutations occur in a wide range of gastrointestinal cancers, including colorectal cancer (3%–4%), appendiceal cancer (3%–4%), small bowel cancer (1%–3%), biliary tract cancer (1%), and pancreatic ductal adenocarcinoma (1%–3%). Outside the gastrointestinal tract, they are most common in NSCLC (14%), endometrial cancer (1.5%), and ovarian cancer (0.4%).
Adagrasib is a covalent KRAS G12C inhibitor that irreversibly and selectively binds KRAS G12C in its inactive state. It has a number of favorable properties, including a long half-life (23 hours), dose-dependent pharmacokinetics, and central nervous system penetration. The drug was granted accelerated approval by the U.S. Food and Drug Administration for the treatment of KRAS G12C–mutated NSCLC and received Breakthrough Therapy designation, in combination with cetuximab, for KRAS G12C–mutated colorectal cancer.
KRYSTAL-1 Details
KRYSTAL-1 is a multicohort phase I/II trial evaluating adagrasib in patients with advanced solid tumors harboring KRAS G12C mutations. There are multiple cohorts in the full population with a variety of tumors, which are treated with different doses (sometimes in combination with other agents). Dr. Pant’s presentation focused on a phase II cohort receiving adagrasib monotherapy administered orally at 600 mg twice daily to patients with unresectable or metastatic KRAS G12C–mutated solid tumors (excluding NSCLC and colorectal cancer).
As of October 1, 2022, 64 patients were enrolled in this arm, including 21 patients with pancreatic cancer, 12 with biliary tract cancer, 10 with appendiceal cancer, 5 with ovarian cancer, 4 with cancer of the esophagus or gastroesophageal junction, 4 with unknown primaries, 3 with small bowel cancer, 3 with endometrial cancer, and 1 each with breast cancer and glioblastoma. They had received a median of two prior lines of systemic therapy, but 34% had received at least three, and 8% had had no prior therapy.
Activity Observed
Efficacy outcomes were available for 57 patients with measurable disease who received at least one dose and had a median follow-up of 16.8 months. The objective response rate by blinded independent central review was 35.1%, all partial responses. The disease control rate was 86.0%, and the median duration of response was 5.3 months. Median progression-free survival was 7.4 months, and median overall survival was 14.0 months.
Activity varied according to tumor type. Adagrasib was particularly active in biliary tract cancer. At 1 year, 14.6% of this cohort were progression-free, and 87% were alive. Patients with pancreatic cancer also derived a benefit.
“The clinical activity of adagrasib in patients with pancreatic and biliary tract cancers is noteworthy, as chemotherapy has limited clinical activity in these patient populations in the second-line setting,” he said.
Safety Profile
Treatment-related adverse events of any grade were observed in 96.8% of patients, but these events were primarily grades 1 and 2, mostly nausea (49.2%), diarrhea (47.6%), fatigue (41.3%), and vomiting (39.7%). Grade 3 treatment-related adverse events occurred in 25.4% of patients; one patient (1.6%) experienced grade 4 febrile neutropenia. No patient died as a result of treatment.
Treatment-related adverse events led to dose reductions in 25 patients (39.7%) and dose interruptions, in 28 (44.4%). None led to treatment discontinuation, Dr. Pant said.
Disclosure: Dr. Pant has served as a consultant or advisor to Ipsen, Janssen, Novartis, and Zymeworks and has received institutional research funding from numerous entities.
