A disease control rate of 100% was achieved in gastrointestinal cancers treated with the KRAS G12C inhibitor adagrasib in the phase II KRYSTAL-1 trial, presented at the 2022 ASCO Gastrointestinal Cancers Symposium.1 The population included primarily those with pancreatic cancer; other noncolorectal gastrointestinal malignancies were also included.
“Adagrasib has now demonstrated responses across multiple tumor types,” said lead investigator Tanios S. Bekaii-Saab, MD, Medical Director of the Cancer Clinical Research Office and Vice Chair and Section Chief for Medical Oncology at the Mayo Clinic, Phoenix. Activity has been seen in non–small cell lung, colorectal, pancreatic, biliary tract, gastroesophageal junction, small bowel, ovarian, and endometrial cancers.
Tanios S. Bekaii-Saab, MD
After a median follow-up of 6.3 months, in 27 evaluable patients, the objective response rate was 41%, and the disease control rate was 100% in KRYSTAL-1. Seeing such outcomes with adagrasib is “very exciting,” said Dr. Bekaii-Saab, especially since the only drug approved in this class, sotorasib—active in lung and colorectal cancers—has not shown activity in pancreatic cancer.
KRAS mutations occur in up to 90% of pancreatic cancers, but about 2% are KRAS G12C mutations. Adagrasib is a KRAS G12C–selective, covalent inhibitor with a long half-life that enables exposure above a target threshold throughout the dosing interval. Continuous exposure at this level can inhibit KRAS-dependent signaling and maximize the depth and duration of the drug’s antitumor activity, Dr. Bekaii-Saab explained.
About the Phase II KRYSTAL-1 Cohort
At the time of data cutoff, KRYSTAL-1 had enrolled 42 patients with solid tumors, of whom 30 had gastrointestinal tumors harboring a KRAS G12C mutation. This group included 12 patients with pancreatic adenocarcinoma, 8 with biliary tract cancers, 5 with appendiceal cancers, 2 with gastroesophageal junction cancers, 2 with small bowel cancers, and 1 with esophageal cancer. Patients had received a median of two prior lines of therapy. Previously treated patients received adagrasib at the recommended dose of 600 mg twice daily. The primary endpoint was objective response rate.
Activity Observed Across Subtypes
Of 12 patients with pancreatic cancer, 10 were evaluable for clinical activity after a median follow-up of 8.1 months. Within this subgroup, five partial responses were observed, and five additional patients achieved stable disease, yielding a disease control rate of 100%. Median duration of response was 7 months, and median progression-free survival was 6.6 months. Treatment was ongoing in 50% of patients at the time of analysis.
In the 17 patients with other gastrointestinal tumors who were evaluable for response, there were 6 partial responses (35%), including in 4 of 8 patients with biliary tract cancer. The one patient with gastroesophageal cancer responded, as did one of the two patients with small bowel cancer. Median duration of response was 7.9 months, and median progression-free survival was 7.9 months. At the time of analysis, 11 patients were still receiving adagrasib.
KEY POINTS
- Preliminary findings of the phase II KRYSTAL-1 trial have shown that the KRAS G12C inhibitor adagrasib is active in gastrointestinal malignancies beyond colorectal cancer.
- The disease control rate was 100% in the overall cohort and 100% in the pancreatic cancer subset; objective responses were observed in 41% and 50%, respectively, and half the biliary tract cancer subset also responded.
- KRAS mutations are seen in approximately 90% of patients with pancreatic cancer, though KRAS G12C mutation is uncommon.
Dr. Bekaii-Saab emphasized the positive findings for patients with biliary tract cancers, for which treatment options are limited. A total of 50% of these patients had a response, he noted. “These numbers are small but solid responses.”
Gastrointestinal toxicities were the most common adverse events of any grade, with few nongastrointestinal toxicities observed and no grade 4 or greater adverse events. For grade 3 toxicities, fatigue was predominant (10%) followed by QTc prolongation (7%).
Enrollment continues to this study, and an early access program has initiated patient populations with KRAS G12C–mutant solid tumors (ClinicalTrials.gov identifier NCT05162443). In addition, other studies are evaluating drugs that target the other KRAS mutations in pancreatic cancer: KRAS G12D, which is the most common alteration, and KRAS G12V. “It’s an exciting time for KRAS targeting,” Dr. Bekaii-Saab concluded.
DISCLOSURE: Dr. Bekaii-Saab disclosed relationships with AbbVie, BeiGene, Boehringer Ingelheim, Cellularity, Daiichi Sankyo/UCB Japan, Eisai, Exact Sciences, Foundation Medicine, Immuneering, Natera, Sobi, Treos Bio, and Exelixis.
REFERENCE
1. Bekaii-Saab TS, Spira AI, Yaeger R, et al: KRYSTAL-1: Updated activity and safety of adagrasib (MRTX849) in patients with unresectable or metastatic pancreatic cancer and other gastrointestinal tumors harboring a KRAS G12C mutation. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 519. Presented January 21, 2022.
