FDA Approves Pembrolizumab Plus Gemcitabine, Cisplatin for Locally Advanced Unresectable or Metastatic Biliary Tract Cancer

The FDA has approved pembrolizumab (Keytruda; Merck) in combination with gemcitabine and cisplatin for the treatment of locally advanced unresectable or metastatic biliary tract cancer, Merck announced in a news release today.¹ This approval adds a sixth indication for pembrolizumab-based regimens in gastrointestinal cancers.

FDA Approved | Image credit: chrisdorney - stock.adobe.com.jpg

The approval was supported by findings from the phase 3 KEYNOTE-966 trial (NCT04003636), in which pembrolizumab plus chemotherapy statistically significantly improved overall survival (OS), the primary end point in the study. At the time of a pre-specified OS analysis, the risk of death was reduced by 17% with the pembrolizumab combination compared with chemotherapy alone (HR, 0.83; 95% CI, 0.72-0.95; one-sided P = .0034).² Patients treated with pembrolizumab plus chemotherapy showed a median OS of 12.7 months (95% CI, 11.5-13.6), compared with 10.9 months (95% CI, 9.9-11.6) among those receiving chemotherapy alone.

“Many patients with biliary tract cancer are diagnosed with locally advanced or metastatic disease, at which point they are not eligible for surgery and face poor survival outcomes with limited treatment options,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, said in a statement.¹ “With this approval, Merck is proud to offer a new treatment option to certain patients with locally advanced unresectable or metastatic biliary tract cancer, and their healthcare providers, that has shown an overall survival benefit compared to chemotherapy alone.”

KEYNOTE-966

The multicenter, double-blind, randomized, placebo-controlled, phase 3 KEYNOTE-966 trial assessed pembrolizumab in combination with gemcitabine and cisplatin for locally advanced unresectable or metastatic biliary tract cancer in 1069 patients who had not received prior systemic therapy in the advanced disease setting.

Patients were randomized in a 1:1 fashion to receive either intravenous pembrolizumab at 200 mg on day 1 plus gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8 every 3 weeks (n = 533) or intravenous placebo and the same chemotherapy regimen (n = 536). Treatment continued until disease progression or unacceptable toxicity. Tumors were assessed at baseline and every 6 weeks for 54 weeks, then every 12 weeks.

OS was the main end point, with progression-free survival (PFS), objective response rate and duration of response serving as additional measures of efficacy. Outcomes were assessed by blinded independent central review based on RECIST v1.1 criteria, with modifications to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The risk of disease progression or death was 14% lower in the pembrolizumab group vs the chemotherapy alone group (HR, 0.86; 95% CI, 0.75-1.00). While not statistically significant, median PFS was 6.5 months in the pembrolizumab group (95% CI, 5.7-6.9) vs 5.6 months with chemotherapy alone (95% CI, 5.1-6.6).

Adverse reactions disrupting pembrolizumab treatment occurred in 55% of patients. Decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased alanine aminotransferase (2.6%), increased aspartate aminotransferase (2.5%), and biliary obstruction (2.3%) were the most common adverse events or laboratory abnormalities leading to pembrolizumab discontinuation.

“Cancers of the biliary tract can be highly aggressive tumors, underscoring the need for additional treatment options for the growing number of patients facing this challenging disease,” said Robin Kate Kelley, MD, professor of clinical medicine in the division of hematology/oncology, University of California, San Francisco, in a statement.¹ “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.”

References

1. FDA approves 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://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-plus-gemcitabine-and-cisplatin-as-treatment-for-patients-with-locally-advanced-unresectable-or-metastatic-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. Published correction appears in Lancet. 2023;402(10406):964.