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SAN FRANCISCO -- The KRAS inhibitor adagrasib showed encouraging activity in patients with previously treated unresectable or metastatic pancreatic cancer and other gastrointestinal (GI) cancers with KRAS G12C mutations, according to a preliminary analysis of the .

With a median follow-up of 6.3 months, the objective response rate among 27 evaluable patients treated with adagrasib was 41%, while the disease control rate was 100%, reported Tanios Bekaii-Saab, MD, of the Mayo Clinic in Phoenix, during a presentation at the Gastrointestinal Cancers Symposium.

KRAS mutations are found in most pancreatic cancer patients, with about 2% having KRAS G12C mutations, Bekaii-Saab noted.

"The KRAS protein cycles between GTP-on and GDP-off states and has a protein resynthesis half-life of 24 hours. Adagrasib is a covalent inhibitor of KRAS G12C. What it does is irreversibly and selectively binds to KRAS G12C in its inactive form. So, it keeps it in that GDP-bound state and shuts down its activity," he explained.

"Maintaining the continuous exposure of adagrasib above a target threshold enables this inhibition at the complete dose interval and maximizes the depth and duration of antitumor response," he added.

During a discussion following the presentation, session moderator Sepideh Gholami, MD, of the University of California Davis, asked Bekaii-Saab about the prospect of a phase III study of adagrasib in this small population of patients.

"I think a phase III trial would be incredibly challenging with that small subset of patients," Bekaii-Saab said. "We face that quite a bit in all of these low-yield alterations. For now, as long we can continue with the enrollment and we continue to see these signals, there are certainly multiple paths to get this to the clinic -- at least initially."

The results from KRYSTAL-1 have been encouraging, Bekaii-Saab emphasized. "The initial data with other KRAS G12C inhibitors did not look as promising, so it was really very exciting to see that happening with adagrasib," he noted.

The study included 30 patients with KRAS G12C-mutant GI tumors -- 12 with pancreatic ductal adenocarcinoma (PDAC), eight with biliary tract cancer, five with appendiceal cancer, two with gastroesophageal junction cancer, two with small bowel cancer, and one with esophageal cancer.

Twenty-seven patients were evaluable for clinical activity, 10 with PDAC and 17 with other GI cancers. Median age was 65.5 years, 40% were women, 80% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1, and all had at least one prior line of systemic therapy.

Of the 10 PDAC patients, five had a partial response, and five had stable disease. Median time to response was 2.8 months, with a median duration of response of 6.97 months. Median progression-free survival (PFS) was 6.6 months (95% CI 1.0-9.7 months), with treatment ongoing in five patients.

Six of the 17 patients with other GI cancers had a partial response, while the remaining 11 had stable disease. Median time to response was 1.3 months, with a median duration of response of 7.85 months. Median PFS was 7.85 months (95% CI 6.90-11.30), with treatment ongoing in 11 patients.

"The response rate was about 35% for this subgroup," Bekaii-Saab noted. "But, when you look at biliary tract cancers, 50% of patients actually had a response. They are small numbers, but these are solid responses."

The most common treatment-related adverse events (TRAEs) included nausea, diarrhea, vomiting, and fatigue. There were no grade 4 or 5 TRAEs, and no TRAEs led to treatment discontinuation, Bekaii-Saab reported.

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