Pembrolizumab Added to Gemcitabine/Cisplatin Improves OS in Biliary Tract Cancer

Richard S. Finn, MD

The addition of pembrolizumab (Keytruda) to gemcitabine and cisplatin elicited a significant improvement in overall survival (OS) vs gemcitabine and cisplatin alone in the first-line for patients with advanced or unresectable biliary tract cancer.¹

These data come from the phase 3 KEYNOTE-966 trial (NCT04003636) of the PD-1 inhibitor pembrolizumab in combination with gemcitabine and cisplatin compared with placebo plus gemcitabine and cisplatin for this patient population.

Topline findings revealed the safety profile of pembrolizumab to be similar to that reported in previous trials.

"The results of KEYNOTE-966 represents another breakthrough in the treatment of our patients with biliary tract tumors. After more than 10 years of being 'stuck' with chemotherapy as the only treatment option for patients in the front-line setting, this study provides level 1 evidence that adding pembrolizumab to standard chemotherapy improves outcomes for our patients," Richard S. Finn, MD, professor of medicine in the division of hematology/oncology, department of medicine at the Geffen School of Medicine at UCLA, and lead accruer on the KEYNOTE-966 study, told Targeted Oncology.

Previously at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2022, experts presented a positive data from the phase 3 TOPAZ trial (NCT03875235).² In the study, patients with biliary tract cancer had an improvement in median overall survival (OS) when given the frontline combination of durvalumab (Imfinzi), gemcitabine, and cisplatin vs treatment with gemcitabine and cisplatin alone (12.8 vs 11.5 months, respectively; HR, 0.80; 95% CI, 0.66-0.97; P = .021).

Then on September 2, 2022, the FDA granted approval for the combination of durvalumab, gemcitabine, and cisplatin for adult patients with locally advanced or metastatic biliary tract cancers.

“We've made tremendous progress in biliary tract cancers, especially as we start to understand the genomic landscape. We have been able to see a couple of drugs FDA approved, specifically for certain biomarkers,” Rachna T. Shroff, MD, MS, University of Arizona Cancer Center, interim chief of the Division of Hematology and Oncology, told Targeted Oncology^TM. "[An] exciting space is immunotherapy and with gemcitabine, cisplatin, and durvalumab as our new standard of care based on TOPAZ [NCT03875235], and [this] KEYNOTE-966 study suggesting that pembrolizumab can also be beneficial in when given in combination with gemcitabine and cisplatin. Clearly there's a role for immunotherapy in biliary tract cancers."

Now in the randomized, double-blind phase 3 KEYNOTE-966 trial (NCT04003636), investigators are evaluating the addition of pembrolizumab to gemcitabine and cisplatin vs gemcitabine and cisplatin alone for the first-line treatment of advanced and/or unresectable biliary tract cancer.³

A total of 1069 patients were enrolled and randomly assigned to receive pembrolizumab at a dose of 200 mg intravenously (IV) every 3 weeks for up to approximately 2 years plus 1000 mg/m² of IV gemcitabine and 25 mg/m² of cisplatin on days 1 and 8 of every 3-week cycle. In the control group, patients were given a placebo in addition to gemcitabine and cisplatin following the same schedule.

Patients continued treatment with pembrolizumab for 35 cycles or until progression, unacceptable toxicity, or withdrawal. For gemcitabine, patients continued until progression, unacceptable toxicity, or withdrawal, and for cisplatin, treatment was given for a maximum of 8 cycles.

Enrollment in the trial was open to adult patients with histologically confirmed metastatic or unresectable biliary tract cancer who have measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and no prior systemic therapy for advanced disease. If patients have past or ongoing hepatitis C or controlled hepatitis B virus infection, they were also eligible for enrollment per protocol-defined criteria.³

Investigators evaluated the primary end point of OS with the secondary end points of progression-free survival, objective response rate, duration of response, and safety. Additional exploratory end points of the trial consisted of disease control rate and health-related quality of life.

Full results of the trial are anticipated to be presented at an upcoming medical meeting. Additionally, findings will be submitted to regulatory agencies.

“Biliary tract cancer is typically diagnosed at an advanced stage, and these patients face a poor prognosis, with 5-year survival rates estimated to be approximately 5% to 15%,” said Eliav Barr, MD, senior vice president, head of global clinical development, and chief medical officer with Merck Research Laboratories, in a press release. “We are very encouraged by these OS results that show the potential benefit of pembrolizumab in addition to chemotherapy for biliary cancer patients who are in urgent need of new treatment options.”

"These data provide a new benchmark for studies in the front-line setting and provide a backbone to build on for new drug development for these diseases. It will also raise the question if using these drugs in the neo-adjuvant or adjuvant setting will continue to improve outcomes for our patients," Finn told Targeted Oncology.

References

1. Merck’s KEYTRUDA® (pembrolizumab) plus chemotherapy significantly improved overall survival versus chemotherapy in first-line advanced or unresectable biliary tract cancer in KEYNOTE-966 trial. News release. Merck. January 25, 2023. Accessed January 25, 2023. https://bit.ly/3wssRTi

2. Valle JW, Kelly RK, Furuse J, et al. KEYNOTE-966 trial in progress: pembrolizumab plus gemcitabine and cisplatin for advanced biliary tract cancer. Ann Oncol. 2020;31(suppl 4):S260-S273. doi:10.1016/annonc/annonc259

3. Pembrolizumab (MK-3475) plus gemcitabine/cisplatin versus placebo plus gemcitabine/cisplatin for first-line advanced and/or unresectable biliary tract carcinoma (BTC) (MK-3475-966/KEYNOTE-966) (KEYNOTE-966). ClinicalTrials.gov. Updated January 12, 2023. Accessed January 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04003636