FDA Grants Pembrolizumab New Biliary Tract Cancer Indication

FDA Grants Pembrolizumab New Biliary Tract Cancer Indication

The FDA has approved pembrolizumab (Keytruda) in combination with gemcitabine and cisplatin to treat locally advanced unresectable or metastatic biliary tract cancer.¹

KEYNOTE-966 Efficacy Data

The regulatory decision is supported by findings from the phase 3 KEYNOTE-966 trial (NCT04003636), in which the combination significantly improved overall survival (OS) compared to chemotherapy alone. The median OS with and without immunotherapy was 12.7 months (95% CI, 11.5-13.6) vs 10.9 months (95% CI, 9.9-11.6), respectively, yielding a 17% reduction in the risk of death (HR, 0.83; 95% CI, 0.72-0.95).²

The KEYNOTE-966 trial enrolled 1,069 patients and was multicenter, double-blind, randomized, and placebo controlled. Participants could not have received prior systemic therapy in the advanced setting.

At a prespecified final analysis for progression-free survival (PFS) and overall response rate (ORR), PFS was also approved in the pembrolizumab arm, although it did not reach statistical significance (HR, 0.86; 95% CI, 0.75-1.00). The median PFS with and without immunotherapy was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 5.1-6.6).

Also at this time point, the ORR was 29% (95% CI, 25%-33%) with pembrolizumab, and included 11 complete responses (2.1%) and 142 partial responses (27%). In the chemotherapy alone arm, the ORR was 29% (95% CI, 25%-33%), and included 7 complete responses (1.3%) and 146 partial responses (27%).

Among those included in the OS analysis, the median duration of response was 8.3 months (95% CI, 6.9-10.2) in the combination arm vs 6.8 months (95% CI, 5.7-7.1) with chemotherapy alone.

Significance of the Approval

Biliary tract cancer is both a rare and highly aggressive form of cancer. Each year, about 20,00 patients in the U.S. receive a biliary tract cancer diagnosis, and approximately 70% are diagnosed at an advanced stage. The current 5-year survival rate with standard-of-care therapies is about 2% to 3% for these patients with advanced disease and is about 9% to 11% for those with any-stage disease.¹

“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,” Robin Kate Kelley, MD, professor of clinical medicine in the Division of Hematology/Oncology, University of California, San Francisco, stated in a press release. “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.”

Of note, this approval marks the sixth gastrointestinal cancer indication that pembrolizumab has received.

Safety Data From the Trial

In the trial, the most common adverse event (AE) leading to treatment discontinuation was pneumonitis (1.3%). The most common AEs resulting in treatment interruptions included 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 (ALT) (2.6%), increased aspartate aminotransferase (AST) (2.5%) and biliary obstruction (2.3%).

There was more than a 5% difference in the incidence of pyrexia, rash, pruritis, and hypothyroidism between the 2 arms. Between the pembrolizumab and the chemotherapy-alone arm, the incidence rates were 26% vs 20%, respectively; 21% vs 13%; 15% vs 10%; and 9% vs 2.6%. However, there were no clinically meaningful differences in the rate of grade 3 and 4 toxicities between the 2 arms.

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. 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, Yoo C, Finn RS, et al. Pembrolizumab (pembro) in combination with gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC): phase 3 KEYNOTE-966 study. Presented at: 2023 AACR Annual Meeting. April 14-19, 2023; Orlando, FL. Abstract CT008.