Pembrolizumab plus chemotherapy prolongs survival in advanced biliary tract cancer
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Key takeaways:
- The addition of the PD-1 inhibitor to standard gemcitabine and cisplatin also produced longer-lasting responses.
- The results reinforce those of the randomized phase 3 TOPAZ-1 study, according to researchers.
The addition of pembrolizumab to gemcitabine and cisplatin conferred a statistically significant and clinically meaningful survival benefit for patients with advanced biliary tract cancer, according to results of the KEYNOTE-966 study.
“We were encouraged to see the consistency of benefit across geographic regions, including non-Asian regions, and across PD-L1 expression subgroups,” Robin “Katie” Kelley, MD, professor of clinical medicine at Helen Diller Family Comprehensive Cancer Center at University of California, San Francisco, told Healio.
Kelley presented the findings of the randomized, phase 3 study during a press conference at American Association for Cancer Research Annual Meeting.
Background and methods
Biliary tract cancers have low rates of response to immune checkpoint inhibitors as monotherapy, Kelley said. Gemcitabine and cisplatin — the standard treatment for advanced biliary tract cancer — help to promote an immune response against cancer cells, she said, thus providing a rationale for use of the PD-1 inhibitor pembrolizumab (Keytruda, Merck) with the chemotherapy combination.
KEYNOTE-966 included 1,069 patients with metastatic or unresectable biliary tract cancer who had not undergone prior systemic therapy. Researchers randomly assigned patients to 200 mg pembrolizumab via IV (n = 533) or placebo (n = 536) every 3 weeks for up to 35 cycles. All patients also received 1,000 mg/m2 gemcitabine via IV on days 1 and 8 every 3 weeks and 25 mg/m2 cisplatin via IV on days 1 and 8 every 3 weeks for eight cycles.
The pembrolizumab and placebo groups had similar baseline characteristics, including median age (64 years vs. 63 years), percentages of white (48% vs. 50%) and Asian (46% vs. 47%) participants, and site of origin (intrahepatic, 60% vs. 58%; gallbladder, 22% for both; extrahepatic, 18% vs. 20%).
OS served as the primary endpoint, with PFS, objective response rate, duration of response by blinded independent central review per RECIST version 1.1 and safety as secondary endpoints.
Median follow-up was 25.6 months (range, 18.3-38.4) at final analysis.
Results
Results, published simultaneously in The Lancet, showed significantly longer OS at final analysis with the pembrolizumab regimen compared with the placebo regimen (median, 12.7 months vs. 10.9 months; HR = 0.83; 95% CI, 0.72-0.95). Kelley reported 24 months OS rates of 25% with pembrolizumab and chemotherapy vs. 18% with placebo and chemotherapy.
At first interim analysis, with median follow-up of 13.6 months, the pembrolizumab group had numerically longer median PFS (6.5 months vs. 5.6 months) but the difference did not reach statistical significance. The pembrolizumab and placebo groups both had ORRs of 29% at first interim analysis, but the pembrolizumab group had longer median duration of response (9.7 months; 95% CI, 6.9-12.2) than the placebo group (6.9 months; 95% CI, 5.7-8.2).
The groups had similar rates of grade 3 to grade 5 adverse events (85.3% with pembrolizumab regimen vs. 84.1% with placebo regimen). The pembrolizumab group had a lower rate of adverse events that led to death (6% vs. 9%) and higher rates of drug-related grade 5 adverse events (1.5% vs. 0.6%) and immune-mediated adverse events of any grade (22% vs. 13%).
“The addition of pembrolizumab did not substantially change the toxicity profile,” Kelley told Healio.
Kelley added that the results reinforce those of the randomized phase 3 TOPAZ-1 study, which served as the basis for FDA approval of the PD-L1 checkpoint inhibitor durvalumab (Infinzi, AstraZeneca) with gemcitabine and cisplatin for adults with locally advanced or metastatic biliary tract cancer. The results of TOPAZ-1, which Healio previously reported, showed a statistically significant improvement in OS (median, 12.8 months vs. 11.5 months; HR = 0.8; 95% CI, 0.66-0.97) and PFS (median, 7.2 months vs. 5.7 months; HR = 0.75; 95% CI, 0.64-0.89) with the addition of durvalumab to the chemotherapy combination.
“KEYNOTE-966 substantiates the benefit across a larger patient cohort with a broad representation across regions,” Kelley said. “KEYNOTE-966 also incorporates the variability in practice patterns and individual patient management in allowing continuation of gemcitabine beyond 6 months when clinically indicated.”
Implications, next steps
In a commentary that accompanied the study in The Lancet, Susanna Slater, MBChB, MRCP, and medical oncologist David Cunningham, MD, FRCP, FMedSci, both of The Royal Marsden NHS Foundation Trust, wrote that the results mark a substantial advance in management of patients with biliary tract cancer.
“The addition of pembrolizumab to chemotherapy represents a new standard of care first-line treatment option for patients with advanced biliary tract cancer, with significant prolongation of survival regardless of PD-L1 combined positive score,” they wrote. “Further work is required to define predictive biomarkers and subgroups of patients more likely to benefit from treatment.”
Kelley told Healio that researchers plan to look at biomarkers and clinical subgroups for any associations with treatment response.
“We hope these ongoing analyses will guide the development of new combinations and next-generation immunotherapies to further improve outcomes,” she said. “Beyond clinical and translational biomarker analyses, patient-reported outcome data including quality-of-life analyses will be presented at an upcoming meeting.”
References:
- Kelley RK, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
- Kelley RK, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)00727-4.
- Slater S, et al. Lancet. 2023;doi: 10.1016/S0140-6736(23)00767-5.
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Kelley RK, et al. Abstract CT008. Presented at: American Association for Cancer Research Annual Meeting; April 14-19, 2023; Orlando.
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