Adagrasib has clinical activity across a broad range of KRAS G12C-mutated tumors, including pancreatic and biliary tract cancers, with a manageable safety profile, according to updated data from the Phase II KRYSTAL-1 study presented at a 2023 ASCO Plenary Series.
In the Phase I/II KRYSTAL-1 study, 63 patients with KRAS G12C-mutated solid tumors, including pancreatic ductal adenocarcinoma, biliary tract cancers, other gastrointestinal (GI), and non-GI tumors, were treated with adagrasib. Among 57 patients with measurable disease, overall response rate (ORR) was 35.1 percent, disease control rate was 86 percent, median duration of response was 5.3 months, median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 14 months.
"Tumor reductions were observed across multiple tumor types, and deep responses were seen for pancreatic, small bowel, ovarian, esophagus, unknown primary, and breast cancer," said lead author Shubham Pant, MD, MBBS, Associate Professor in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center.
KRAS G12C mutations act as oncogenic drivers in a range of solid tumors, including 14 percent of patients with non-small cell lung cancer (NSCLC) and 3-4 percent with colorectal cancer, as well as in 1-3 percent with small bowel cancer, 1-3 percent with biliary tract cancer, and 1 percent with ovarian and endometrial cancer.
Adagrasib is a covalent inhibitor of KRAS G12C that has been granted accelerated approval by the FDA for the treatment of KRAS G12C-mutated NSCLC, and has also been granted breakthrough therapy designation in combination with cetuximab for the treatment of patients with KRAS G12C-mutated colorectal cancer.
Preliminary data from the Phase II cohort of KRYSTAL-1 evaluated adagrasib 600 mg twice daily in patients with previously treated GI tumors, and it demonstrated clinical activity and manageable safety with a median follow-up of 6.3 months. Pant reported updated data from this Phase II cohort of patients with KRAS G12C-mutated solid tumors, other than non-small cell lung cancer and colorectal cancer, with a median follow-up of 16.8 months.
The median age of patients was 65; about 60 percent had ECOG 1 status. Tumor types included pancreatic adenocarcinoma (21 patients), biliary tract cancers (12 patients), appendiceal (10 patients), ovarian (5 patients), unknown primary (4 patients), gastroesophageal junction esophagus (4 patients), endometrial (3 patients), small bowel (3 patients), and breast and glioblastoma (1 patient each).
Patients received a median of two lines of prior systemic anticancer therapy, but "it is also important to note that about one-third of the patients received three or more prior lines of treatment," Pant clarified.
Among 63 patients treated with adagrasib, 57 had measurable disease at baseline for the blinded independent central review. At the time of data cutoff, the confirmed ORR, the primary endpoint, was 35 percent and disease control rate was 86 percent.
In pancreatic cancers, the confirmed ORR was 33.3 percent and the disease control rate was 81 percent. In patients with biliary tract cancers, 41.7 percent of patients had a confirmed ORR with the disease control rate of 91.7 percent. "In gynecological cancers, we had a robust response rate of 57.1 percent," Pant stated.
No responses were seen in patients with appendiceal cancers. This lack of response is fairly consistent with recent reports that RAS-mutated mucinous appendiceal cancers are relatively indolent tumors, he said. Most responses were seen by the first scan, with a median time to response of only 1.4 months and 12 patients still remain on treatment.
The overall median PFS was 7.4 months and the median OS was 14 months. For pancreatic cancer, the median PFS was 5.4 months and the median OS was 8 months. For biliary tract cancers, the median PFS was 8.6 months and the median OS was 15.1 months.
The most common treatment-related adverse events (TRAE) were nausea, diarrhea, fatigue, and vomiting, which were mostly Grade 1 and 2. There was one Grade 4 TRAE, which was febrile neutropenia, and no Grade 5 TRAEs. TRAEs led to a dose reduction in 39.7 percent of patients and dose interruptions in 44.4 percent of patients, but no TRAEs led to treatment discontinuation.
"The KRYSTAL-1 cohort is the largest Phase II tumor-agnostic data set to evaluate KRAS G12C-mutated solid tumors, excluding NSCLC and colorectal cancer," Pant noted. "Adagrasib monotherapy demonstrated clinically meaningful activity in a variety of KRAS G12C-mutated solid tumors for which no standard-of-care treatment option is available. The clinical activity of adagrasib in patients with pancreatic cancer and biliary tract cancer is noteworthy, as chemotherapy, as we know, has limited clinical activities in this patient population in the second-line setting.
"Adagrasib monotherapy is well-tolerated and has a manageable safety profile. Most adverse events are Grade 1 and 2, and KRAS G12C-targeted agents may represent a novel tumor-agnostic treatment option for patients with solid tumors harboring a KRAS G12C mutation," Pant concluded.
Mark L. Fuerst is a contributing writer.