FDA OKs Pembrolizumab/Chemo in Advanced Biliary Tract Cancer

The FDA has approved pembrolizumab (Keytruda) plus gemcitabine and cisplatin for patients with locally advanced unresectable or metastatic biliary tract cancer, according to a press release from Merck.¹

The approval is based on results from the phase 3 KEYNOTE-966 trial (NCT04003636).² A statistically significant improvement in overall survival (OS), the primary end point, was observed by investigators. A reduction in the risk of death by 17% (HR, 0.83; 95% CI, 0.72-0.95; one-sided P = .0034) was reported in the combination arm vs the chemotherapy alone arm.

Additionally, the median OS was 12.7 months (95% CI, 11.5-13.6) in the pembrolizumab arm vs 10.9 months (95% CI, 9.9-11.6) in the chemotherapy arm.

“Today's approval of pembrolizumab in combination with chemotherapy offers patients with locally advanced unresectable or metastatic biliary tract cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer,” lead study author Robin Kate Kelly, MD, professor of Clinical Medicine in the division of Hematology/Oncology at the University of California, San Francisco, said in the press release.

A total of 1069 patients enrolled on the study and were randomly assigned 1:1 to either the pembrolizumab arm (n = 533) or the chemotherapy alone arm (n = 536). Patients were given intravenous (IV) pembrolizumab at 200 mg on day 1 plus 1000 mg/m² of IV gemcitabine and 25 mg/m² of IV cisplatin on days 1 and 8 every 3 weeks.

Patients continued treatment until toxicity or disease progression occurred. Pembrolizumab was continued for up to 35 cycles while gemcitabine and cisplatin were administered for up to 8 cycles. If patients were clinically stable and deriving benefit from treatment, they could receive the investigative combination beyond the RECIST-defined disease progression. Investigators assessed tumor progression at baseline, every 6 weeks up to 54 weeks, and then every 12 weeks thereafter.

The primary end point was OS. Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) assessed by blinded independent central review vi RECIST v1.1.

The prespecified final analysis identified a median PFS of 6.5 months (95% CI, 5.7-6.9) in the pembrolizumab arm and 5.6 months (95% CI, 5.1-6.6) in the chemotherapy arm; investigators noted that statistical significance was not reached.1 The median ORR in the pembrolizumab arm was 29.0% (95% CI, 25%-33%), which included a complete response (CR) rate of 2.1% and a partial response (PR) of 27.0%. The ORR for the chemotherapy arm was 29.0% (95% CI, 25%-33%) with a CR of 1.3% and a PR of 27.0%. Additionally, the DOR was 8.3 months (95% CI, 6.9-10.2) in the pembrolizumab arm and 6.8 months (95% CI, 5.7-7.1) in the chemotherapy-alone arm.

Pembrolizumab was discontinued in 15% of patients. The most common adverse effect (AE) resulting in discontinuation was pneumonitis in 1.3% of patients. Interruption of pembrolizumab treatment due to AEs necessary in 55% of patients, with the most common being decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), and decreased white blood cell count (4%).

AEs between both arms included pyrexia (26.0% vs. 20.0%), rash (21.0% vs. 13.0%), pruritus (15.0% vs. 10,0%) and hypothyroidism (9.0% vs. 2.6%), respectively. There were no clinically meaningful differences in grade 3/4 AEs between arms.

References

1. FDA approved Merck’s Keytruda (pembrolizumab) plus gemcitabine and cisplatin as treatment for patients with locally advanced unresectable or metastatic biliary tract cancer. News release. Merck. November 1, 2023. Accessed November 1, 2023. https://bit.ly/3tXMx3D
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. Published correction appears in Lancet. 2023;402(10406):964.