FDA OKs Pembrolizumab Plus Standard Chemotherapy for Advanced BTC

• Pembrolizumab (Keytruda) plus gemcitabine and cisplatin has been granted FDA approval for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).
• Findings from the phase 3 KEYNOTE-966 trial (NCT04003636) support this approval.
• For those given the immunotherapy combination, the median overall survival was 12.7 months (95% CI, 11.5-13.6) vs 10.9 months (95% CI, 9.9-11.6) with chemotherapy alone.

The FDA has granted approval to pembrolizumab combined with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic BTC.¹

Results from the phase 3 KEYNOTE-966 trial support the regulatory decision as patients treated with the combination had significantly improved overall survival (OS) rates compared with patients given chemotherapy alone.

The median OS was 12.7 months (95% CI, 11.5-13.6) among patients given pembrolizumab plus chemotherapy vs 10.9 months (95% CI, 9.9-11.6) for those treated with chemotherapy alone.

"The results of KEYNOTE-966 represent 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 frontline 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, previously told Targeted Oncology.

3d illustration human body stomach: © pic4u - stock.adobe.com

About KEYNOTE-966

KEYNOTE-966 is a multicenter, double-blind, randomized, placebo-controlled trial which enrolled 1069 patients with locally advanced unresectable or metastatic BTC. Patients included were those who had not previously received systemic treatment for advanced disease.

Once enrolled, patients were randomized in a 1:1 fashion to receive intravenous placebo (n = 536) or pembrolizumab (n = 533) at 200 mg on day 1 with gemcitabine at 1000 mg/m² and cisplatin at 25 mg/m² on days 1 and 8 every 3 weeks (n = 533). Patients continued to receive treatment until intolerable toxicity or disease progression. Immunotherapy was continued for up to 35 cycles or approximately 24 months, and while gemcitabine could be continued beyond 8 cycles, cisplatin could only be given for a maximum of 8 cycles.

The primary end point of the study was OS, and other key end points were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) by blinded independent central review (BICR) assessment and in accordance with RECIST v1.1 criteria, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

According to previous data reported from the prespecified final analysis for PFS and ORR, pembrolizumab added to chemotherapy led to a numerical, but not statistically significant, improvement in PFS compared with chemotherapy alone in these patients with BTC.²

In the pembrolizumab arm, the median PFS was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 5.1-6.6) with chemotherapy alone (HR, 0.86; 95% CI, 0.75-1.00). The ORR in the pembrolizumab plus chemotherapy arm was 29% (95% CI, 25%-33%) vs 29% (95% CI, 25%-33%) with chemotherapy alone. Of the patients who responded to pembrolizumab with chemotherapy, 2.1% achieved a complete response (CR) and 27% experienced a partial response (PR). With chemotherapy alone, the rates of CR and PR were 1.3% and 27%, respectively. Patients received pembrolizumab for a median duration of 6 months (range, 1 day-28 months).

Looking at safety, adverse events (AEs) were the cause of dose interruptions of pembrolizumab in 55% of patients. These AEs were made up of reduced neutrophil count (18%), reduced 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%). Additionally, 15% of patients discontinued immunotherapy because of toxicity. The most commonly observed AE was pneumonitis (1.3%).

Results also showed that 7% of patients in the pembrolizumab plus chemotherapy arm experienced grade 3 or 4 immune-mediated AEs vs 4% of those who received chemotherapy alone. There were immune-mediated AEs leading to death in 1 patient treated with the combination of pembrolizumab, gemcitabine, and cisplatin.

“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 press release.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. November 1, 2023. Accessed November 1, 2023. https://tinyurl.com/55xswd8f

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