KEYNOTE-966: Pembrolizumab Combined With GemCis Versus GemCis Alone in Patients With BTC

In the KEYNOTE-966 study, pembrolizumab was added to gemcitabine/cisplatin to assess outcomes in patients with advanced biliary tract cancer.

Patients with biliary tract cancer (BTC) often have a poor prognosis.¹ The standard of care for first-line therapy for pa- tients with advanced BTC has historically been a chemother- apy-based regimen with gemcitabine/cisplatin (GemCis). This therapy was established more than 10 years ago based on the results of the phase 3 ABC-02 study.² In this study, median overall survival (OS) was 11.7 months for GemCis versus 8.1 months for gemcitabine alone.² In the phase 3 TOPAZ-1 study, the PD-L1 inhibitor durvalumab was added to GemCis and significantly improved OS compared with GemCis alone (12.8 months vs 11.5 months; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66-0.97; two-sided P=.021).³ Results from the KEYNOTE-966 (NCT04003636) study, which investigated the addition of the anti-PD-1 monoclonal antibody pembrolizumab to GemCis as first-line therapy for patients with BTC, were published this year and reaffirmed the results of the TOPAZ-1 study.

KEYNOTE-966 was a randomized, double-blind, placebo-controlled, phase 3 trial that assessed the efficacy of the addition of pembrolizumab to GemCis in patients with advanced BTC.⁴

KEYNOTE-966 was a randomized, double-blind, place- bo-controlled, phase 3 trial that assessed the efficacy of the ad- dition of pembrolizumab to GemCis in patients with advanced BTC.⁴ Between October 4, 2019, and June 8, 2021, 1564 pa- tients were screened for study eligibility.⁴ Eligible patients were

≥18 years of age; had histologically confirmed unresectable lo- cally advanced or metastatic extrahepatic cholangiocarcinoma (CCA), gallbladder cancer, or intrahepatic CCA; had disease measurable per Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1.⁴ The primary end point was OS, which was evaluated in the intention-to-treat population.

A total of 1069 patients were randomly assigned to receive either pembrolizumab with GemCis (n=533) or placebo plus GemCis (n=536).⁴ Baseline demographics were generally bal- anced between treatment groups. Median follow-up at final analysis was 25.6 months.⁴ Median OS in the pembrolizumab group was 12.7 months versus 10.9 months in the placebo

group (HR, 0.83; 95% CI, 0.72-0.95; one-sided P=.0034).⁴

Median progression-free survival was 6.5 months in the pem- brolizumab group and 5.6 months in the placebo group.⁴ Treatment-related adverse events (TRAEs) occurred in 493 (93%) of 529 patients in the pembrolizumab group and 500 (94%) patients in the placebo group.⁴ TRAEs that occurred in ≥50% of participants in either treatment group were decreased neutrophil count (pembrolizumab group, 321 [61%]; placebo group, 320 [60%]) and anemia (pembrolizumab group, 278 [53%]; placebo group, 269 [50%]).⁴

Pembrolizumab in combination with GemCis improved OS compared with GemCis alone without any new safety signals, adding to the evidence first described in TOPAZ-1 that the addition of immunotherapy to chemotherapy in patients with advanced BTC provides a clinical benefit over chemotherapy alone.

References

1. Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428-444.
2. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362: 1273-1281.
3. Oh D-Y, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1:1-11.
4. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cis- platin 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.