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Sotorasib (Lumakras) was active and well tolerated in patients with metastatic pancreatic cancer with a KRAS G12C mutation, a phase I/II study found.

Of 38 patients treated with sotorasib, most of whom had been previously treated with two or more lines of therapy, eight patients had a confirmed partial response, resulting in an objective response rate of 21.1% (95% CI 9.55-37.32) over a median follow-up of 16.8 months, reported John H. Strickler, MD, of Duke University Medical Center in Durham, North Carolina, and colleagues.

Among the secondary endpoints, the median duration of response was 5.7 months (95% CI 1.6 to not evaluable), median progression-free survival was 4.0 months (95% CI 2.8-5.6), median overall survival was 6.9 months (95% CI 5.0-9.1), and the disease control rate was 84.2%.

Most treatment-related adverse events (TRAEs) were grade 2 or lower, and no TRAEs were fatal or led to treatment discontinuation.

"These data support the further exploration of sotorasib in this patient population with high unmet medical need," said Strickler during an .

"The efficacy we see in pancreatic cancer is remarkable in the refractory setting," said discussant E. Gabriela Chiorean, MD, of the Fred Hutchinson Cancer Research Center in Seattle. "The response rate of 20%, with a duration of response of 6 months, and encouraging survival rates of 7 months in the third line and beyond is unheard of."

"The data presented today are a stepping stone for future combinatorial approaches with sotorasib," she noted. "We also need to bring these approaches earlier in the disease treatment stage. Earlier lines of therapy will enable more patients to have access to treatment because very few patients reach a third line of therapy."

Sotorasib was granted accelerated approval by the FDA for the second-line treatment of non-small cell lung cancer harboring KRAS G12C mutations in 2021.

These study results follow on the heels of those from KRYSTAL-1, which were presented last month at the Gastrointestinal Cancers Symposium, showing that five of 10 evaluable patients with KRAS G12C-mutated pancreatic ductal adenocarcinoma had a partial response with the KRAS inhibitor adagrasib.

When asked about the differences between the two KRAS inhibitors, Chiorean noted that while the response rate of 50% in KRYSTAL-1 was "very encouraging," that study only included 10 patients. "There are so many variables when you talk about a small patient population," she said. "And one cannot assume that these data will pan out if we have 40 patients or 100 patients."

"I think the good news for both molecules is clearly there is substantial activity for a patient population that desperately needs breakthroughs," Strickler said. "So, I'm excited both as an investigator and a clinician that we are hopefully going to have some real options for patients who desperately need them."

This study was conducted in two phases -- a dose-escalation and expansion phase that included 12 patients, and an efficacy and safety phase that included 26 patients. All 38 patients received sotorasib 960 mg orally once daily.

Stage IV disease was present in 55.3% of patients at diagnosis, and in all patients at enrollment. Baseline Eastern Cooperative Oncology Group (ECOG) scores were 0, 1, and 2 in 31.6%, 57.9%, and 10.5% of patients, respectively, and 79% of patients had received two or more prior lines of therapy.

TRAEs of any grade occurred in 16 patients. Grade ≥3 TRAEs occurred in just six patients, and included diarrhea, fatigue, abdominal pain, ALT and AST increases, pleural effusion, and pulmonary embolism.

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