According to the KEYNOTE-966 study results announced at the 2023 American Association for Cancer Research (AACR) annual meeting, adding pembrolizumab on the basis of gemcitabine and cisplatin brings statistically and clinically significant survival benefits to patients with advanced biliary tract cancer. These results validate the outcomes of the randomized phase III TOPAZ-1 study. Encouragingly, this approach demonstrated consistent survival benefits across geographical regions and PD-L1 expression subgroups. The KEYNOTE-966 study results were concurrently published in “The Lancet.”

During the AACR meeting held in Orlando from April 14th to 19th, 2023, Professor Robin Kate Kelley of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, presented the randomized phase III KEYNOTE-966 study data.

Biliary tract cancers (BTC) have a low response rate to single-agent immune checkpoint inhibitors. The standard treatment for advanced biliary tract tumors — gemcitabine and cisplatin — aids the immune response against cancer cells, providing a theoretical basis for combining PD-1 inhibitor pembrolizumab with chemotherapy.

The KEYNOTE-966 study included 1,069 patients with metastatic or unresectable biliary tract tumors who had not previously received systemic treatment. The patients, with an ECOG performance status of 0 or 1 and a life expectancy of more than 3 months, were randomly assigned to receive either 200 mg of pembrolizumab (n=533) or placebo (n=536) (intravenous injection, once every three weeks for up to 35 cycles). All patients also received gemcitabine and cisplatin.

Stratification factors included geographical region (Asia vs. non-Asia), disease stage (locally advanced vs. metastatic), and site of origin (extrahepatic bile duct cancer vs. gallbladder vs. intrahepatic bile duct cancer).

The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), duration of response based on blind independent center evaluation per RECIST 1.1, and safety.

At the time of final analysis, the median follow-up was 25.6 months (range 18.3-38.4).

Results

The KEYNOTE-966 study results were published in “The Lancet” journal.

Both the pembrolizumab and placebo groups had similar baseline characteristics. Median ages were 64 and 63 years, respectively; 48% vs. 50% were white, and 46% vs. 47% were Asian.

In terms of disease origin, intrahepatic bile duct cancer was 60% in the trial group and 58% in the control group, extrahepatic bile duct cancer was 18% and 20%, and gallbladder cancer was 22% in both groups. 89% of patients in the pembrolizumab group and 88% in the placebo group had metastatic disease.

OS Data

The final analysis showed that compared to the placebo regimen, the pembrolizumab regimen significantly prolonged patients’ OS (median OS, 12.7 months vs. 10.9 months; HR=0.83; 95%CI: 0.72~0.95). The 12-month OS rate for the pembrolizumab combined with chemotherapy group and the placebo combined with chemotherapy group were 52% and 44%, respectively, and the 24-month OS rates were 25% and 18%.

Descriptive subgroup analysis showed that the pembrolizumab group benefited in most pre-specified subgroups, including those with a combined positive score (CPS) of less than 1 and a CPS of ≥1.

PFS Data

In the first interim analysis with a median follow-up of 13.6 months, the median PFS duration was longer in the pembrolizumab group (6.5 months vs. 5.6 months), but the difference was not statistically significant. The 6-month and 12-month PFS rates for the pembrolizumab group were 52% and 25% respectively, while for the placebo group, they were 46% and 20%.

The final analysis for PFS was similar to the results of the first interim analysis. The median PFS for the pembrolizumab combined with cisplatin and gemcitabine group was 6.5 months (95% CI: 5.7~6.9), while for the placebo combined with cisplatin and gemcitabine group, it was 5.6 months (95% CI: 4.9~6.5) (HR=0.87; 95%CI: 0.76~0.99). In the pembrolizumab group, the 12-month and 24-month PFS rates were 24% and 9% respectively; in the placebo group, the 12-month and 24-month PFS rates were 19% and 5%.

Response Rate

In the first interim analysis, the objective response rate (ORR) was 29% for both the pembrolizumab combined with chemotherapy group and the placebo combined with chemotherapy group. Within the pembrolizumab combined with chemotherapy group, the complete response rate was 2%, and the partial response rate was 27%. In contrast, within the placebo combined with chemotherapy group, the complete response rate was 1%, and the partial response rate was 27%.

Compared to the placebo group (6.9 months; 95% CI: 5.7~8.2), the median duration of response was longer in the pembrolizumab group (9.7 months; 95% CI: 6.9~12.2).

Safety

The incidence rate of grade 3-5 adverse events was similar between the two groups (85.3% in the Paboli Pearl monotherapy group vs. 84.1% in the placebo group). The Paboli Pearl monotherapy group had a lower rate of fatal adverse events (6% vs. 9%), a higher rate of drug-related grade 5 adverse events (1.5% vs. 0.6%), and a higher incidence rate of any grade of immune-mediated adverse events (22% vs. 13%). For a detailed breakdown of any grade of adverse events in the Paboli Pearl monotherapy group and the placebo group in the final analysis, see Table 2.

Professor Kelley noted that the addition of Paboli Pearl monotherapy did not substantially change the toxicity profile.

Professor Kelley reported that the KEYNOTE-966 study reinforces and validates the results of the randomized Phase III TOPAZ-1 study. The TOPAZ-1 study was the basis for the FDA’s approval of the PD-L1 checkpoint inhibitor, Duvally’s monotherapy, combined with gemcitabine and cisplatin for adult patients with locally advanced or metastatic biliary cancer. The results of the TOPAZ-1 study showed that the addition of Duvally’s monotherapy to the combination chemotherapy regimen of gemcitabine and cisplatin resulted in statistically significant improvements in OS and PFS, with a median OS of 12.8 months vs. 11.5 months; HR=0.8; 95%CI: 0.66~0.97; and median PFS of 7.2 months vs. 5.7 months; HR=0.75; 95%CI: 0.64~0.89.

The KEYNOTE-966 study confirmed the benefits of immunotherapy combined with chemotherapy in a larger patient population and is representative across different regions. The study also considered variations in practice patterns and individualized patient management, allowing the continued use of gemcitabine for more than 6 months when clinically indicated.

Impact and Significance of the KEYNOTE-966 Study

Professor Susanna Slater from the Royal Marsden NHS Foundation Trust published a concurrent review in The Lancet.

The KEYNOTE-966 study is the second significant global Phase III study assessing first-line chemotherapy immunotherapy in advanced biliary tumor patients and the first to use an anti-PD-1 antibody in such a global Phase III trial. The results show that the chemotherapy combined with the Paboli Pearl monotherapy scheme provides statistically and clinically meaningful improvements in OS for treated patients, with manageable toxicity.

The results of the KEYNOTE-966 study mark a significant advancement in the management of patients with biliary tumors. Adding Paboli Pearl monotherapy to chemotherapy represents a new standard for first-line treatment of patients with advanced biliary tumors, significantly extending patient survival, regardless of PD-L1 combined positive scores.

In the future, efforts are needed to identify predictive biomarkers and patient subgroups more likely to benefit from this chemotherapy-immunotherapy combination. The KEYNOTE-966 study team plans to observe biomarkers and clinical subgroups to find any correlations related to treatment response.

Researchers hope that these ongoing analyses can guide new combinations and the next generation of immunotherapies to further improve patient outcomes.