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ORLANDO -- Adding pembrolizumab (Keytruda) to first-line chemotherapy resulted in a statistically significant and clinically meaningful overall survival (OS) improvement for patients with advanced biliary tract cancer, according to results from a phase III trial.

In the KEYNOTE-966 study involving 1,069 patients receiving standard gemcitabine plus cisplatin, the group randomized to the PD-1 checkpoint inhibitor had a median OS of 12.7 months compared with 10.9 months among patients assigned to placebo (HR 0.83, 95% CI 0.72-0.95), reported Robin Kate Kelley, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center.

Estimated 12-month OS rates were 52% in the pembrolizumab group and 44% in the placebo group, while 24-month OS rates were 25% and 18%, respectively, she said at the annual meeting of the American Association for Cancer Research (AACR).

KEYNOTE-966 "is the largest phase III trial to date in biliary tract cancer to our knowledge, and one of only very few positive phase III trials in this difficult-to-treat disease," said Kelley. Results were published simultaneously in .

The treatment of advanced and metastatic biliary tract cancer is "an area of high unmet need," and the addition of pembrolizumab to chemotherapy "represents a new standard of care first-line treatment option," according to Susanna Slater, MBChB, and David Cunningham, MD, both of the Royal Marsden Hospital NHS Trust in London, writing in an .

For more than a decade, gemcitabine and cisplatin has been the only accepted first-line treatment for patients with locally advanced and metastatic biliary tract cancer.

In , the PD-L1 inhibitor durvalumab (Imfinzi) gained a first-line indication in combination with the two chemotherapeutic agents in this setting, based on findings from the phase III TOPAZ-1 trial.

AACR discussant Rachna Shroff, MD, of the University of Arizona Cancer Center in Tucson, said that while gemcitabine-cisplatin plus durvalumab has "become the new gold standard, KEYNOTE-966 establishes gemcitabine-cisplatin plus pembrolizumab as another frontline option for newly diagnosed biliary tract cancers."

"I don't think there is any question there," she said. However, she noted that OS rates are still hovering around 12 to 13 months with these regimens, adding, "we have a lot of work to do."

Kelley noted that since most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy has not been effective in treating these cancers. However, gemcitabine and cisplatin does help promote an immune response against cancer cells, she said, "providing a strong rationale" for .

The study was conducted at 175 medical centers across North and South America, Europe, and Asia. Slightly more than half (52%) of patients were male and younger than 65 years (53%). About 45% were enrolled in Asia, 88% had metastatic disease at enrollment, and 59% had tumors of intrahepatic origin. OS was the primary endpoint, and the current analysis had a median follow-up of 25.6 months.

Patients were randomly assigned 1:1 to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with IV gemcitabine (1,000 mg/m² on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m² on days 1 and 8 every 3 weeks; maximum eight cycles).

Regarding the trial's secondary endpoint of progression-free survival (PFS), median PFS was 6.5 months in the pembrolizumab group versus 5.6 months in the placebo group (HR 0.86, 95% CI 0.75-1.00), missing the prespecified efficacy boundary for a statistically significant benefit.

While two arms shared the same 29% rate of complete or partial response to treatment, the median duration of response was 9.7 months in the pembrolizumab group and 6.9 months in the placebo group.

In the as-treated population, nearly everyone in the pembrolizumab and placebo groups experienced at least one adverse event (AE). Grade 3/4 AEs were reported in 79% and 75% of the two groups, respectively.

Grade 3/4 treatment-related AEs (TRAEs) were similar between groups (70% and 69%), and AEs of any cause leading to death occurred in 6% participants in the pembrolizumab group and 9% of those in the placebo group, with 2% and 1% deemed related to treatment.

AEs led to discontinuation of one or more study drugs in 26% of participants in the pembrolizumab group and in 23% of those in the placebo group, while discontinuation of all study drugs occurred in 7% of each group.