FDA Approval Sought for Pembrolizumab Plus Chemotherapy in Biliary Tract Cancer

The FDA has accepted for review a supplemental biologics license application (sBLA) seeking the approval of pembrolizumab (Keytruda) plus standard chemotherapy comprised of gemcitabine and cisplatin for use in patients with locally advanced unresectable or metastatic biliary tract cancer.¹

The application was supported by data from the phase 3 KEYNOTE-966 trial (NCT04003636), in which the addition of the immunotherapy to chemotherapy significantly improved overall survival (OS) compared with chemotherapy alone in this population.2 At a median follow-up of 25.6 months (interquartile range [IQR], 21.7-30.4), the median OS was 12.7 months (95% CI, 11.5-13.6) in the pembrolizumab arm (n = 533) vs 10.9 months (95% CI, 9.9-11.6) in the chemotherapy-alone arm (n = 536; HR, 0.83; 95% CI, 0.72-0.95; P = .0034).

The regulatory agency is slated to decide on the application by February 7, 2024, under the Prescription Drug User Fee Act.¹

“Most biliary tract cancers go undetected until an advanced stage, at which point many patients are ineligible for surgery and have few treatment options,” Scot Ebbinghaus, vice president of global clinical development at Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA to bring a new option to patients with advanced or unresectable biliary tract cancer that may help them live longer.”

A randomized, double-blind, placebo-controlled, phase 3 trial enrolled historically confirmed unresectable locally advanced or metastatic extrahepatic cholangiocarcinoma, gallbladder cancer, or intrahepatic cholangiocarcinoma.2 Patients needed to be at least 18 years of age, measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, acceptable organ function, and a life expectancy of over 3 months.

Study participants were randomly assigned 1:1 to receive intravenous (IV) pembrolizumab at 200 mg once every 3 weeks or placebo in combination with gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of 3-week cycles. Treatment continued until progressive disease, intolerable toxicity, investigator decision, withdrawn consent, or other reasons.

Patients were stratified based on geographical region (Asia vs not Asia), disease stage (locally advanced vs metastatic), and site of origin (extrahepatic vs gallbladder vs intrahepatic).

OS served as the primary end point, and secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety.

Overall, baseline demographic and patient characteristics were noted to be well balanced between the treatment arms. The median age across the investigative and control arms was 63.5 years (range, 55-71), with a little more than half of patients (53% vs 51%) being male. About half (46% vs 47%) of patients were Asian and the remaining half were White (48% vs 50%); 45.5% of patients were from Asia and 54.5% of patients were not.

Moreover, 45.5% of patients across the arms had an ECOG performance status of 0, 54% had a status of 1, and less than 1% had a status of 2 or higher. The site of disease origin for most patients was intrahepatic (60% vs 58%), followed by gallbladder (22% vs 22%), and extrahepatic (18% vs 20%). Most patients had metastatic disease (89% vs 88%) and the remainder (11% vs 12%) had locally advanced disease. Regarding PD-L1 status, most patients in the pembrolizumab (n = 363) and placebo (n = 365) arms had a status of 1 or higher (68%, both); 113 patients and 110 patients, respectively, had a status of less than 1.

The median treatment duration in the pembrolizumab and placebo arms was 6.37 months (IQR, 2.79-10.84) and 5.54 months (IQR, 2.53-9.69), respectively.

Additional data published in The Lancet showed that the estimated OS rate at 12 months with pembrolizumab was 52% (95% CI, 47%-56%) and 44% (95% CI, 40%-48%), respectively; the 24-month rates were 25% (95% CI, 21%-29%) and 18% (95% CI, 15%-22%), respectively.

Data from a subgroup analysis indicated that the survival benefit observed with the chemoimmunotherapy regimen was observed across most prespecified subsets, including those with a PD-L1 combined positive score of less than 1 (HR, 0.84; 95% CI, 0.62-1.14) and those with a score of 1 or higher (HR, 0.85; 95% CI, 0.72-1.00).

Data from the first interim analysis, which had a median follow-up of 13.6 months (IQR, 9.7-18.4), showed that the median PFS with pembrolizumab was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 5.1-6.6) with placebo. The estimated PFS rates at 6 months were 52% (95% CI, 48%-57%) and 46% (95% CI, 16%-24%), respectively. The efficacy boundary for statistical significance was not met (HR, 0.86; 95% CI, 0.75-1.00; P = .023). Findings from a post-hoc analysis showcased similar PFS outcomes at the time of the final analysis (HR, 0.87; 95% CI, 0.76-0.99).

Also, at the time of the first interim analysis, pembrolizumab plus chemotherapy resulted in an ORR of 29% (95% CI, 25%-33%) vs 29% (95% CI, 25%-33%) with chemotherapy alone, with 2% and 1% of patients, respectively, experiencing a complete response as their best overall response to treatment. Again, the efficacy boundary for statistically significant ORR benefit with the immunotherapy was not met (treatment difference, 0.2% points; 95% CI, 5.2-5.6; P = .47). The median DOR in the investigative arm was 9.7 months (95% CI, 6.9-12.2) vs 6.9 months (95% CI, 5.7-8.2) in the control arm.

Regarding the final safety analysis, treatment-related adverse effects (TRAEs) were reported in 93% of those in the pembrolizumab arm vs 94% of those in the placebo arm; grade 3 or 4 TRAEs occurred in 70% and 69% of patients, respectively. In the pembrolizumab arm, 15% of patients discontinued 1 or more study drugs and 3% discontinued all drugs; in the placebo arm, these rates were 15% and 3%, respectively. TRAEs resulted in death for 2% and 1% of patients, respectively.

The most common grade 3 or 4 AEs reported in at least 15% of patients in the investigative arm included decreased neutrophil count (32%; 17%), anemia (28%; <1%), nausea (2%; 0%), decreased platelet count (12%; 6%), fatigue (5%; <1%), constipation (<1%; 0%), decreased appetite (1%; <1%), decreased white blood cell count (11%; 1%), pyrexia (2%; 0%), vomiting (3%; 0%), diarrhea (2%; 0%), abdominal pain (2%; 0%), rash (1%; 0%), increased aspartate aminotransferase (3%; 0%), increased alanine aminotransferase (2%; 0%), hypomagnesemia (1%; 0%), and asthenia (2%; <1%).

References

1. FDA accepts application for Merck’s Keytruda (pembrolizumab) plus chemotherapy as treatment for advanced or unresectable biliary tract cancer. News release. Merck. June 8, 2023. Accessed June 8, 2023. https://www.merck.com/news/fda-accepts-application-for-mercks-keytruda-pembrolizumab-plus-chemotherapy-as-treatment-for-advanced-or-unresectable-biliary-tract-cancer/
2. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10391):1853-1865. doi:10.1016/S0140-6736(23)00727-4