Potential New Standard of Care for Biliary Tract Cancer

SAN FRANCISCO ― Adding the checkpoint inhibitor durvalumab (Imfinzi) to chemotherapy significantly improved overall survival in patients with advanced biliary tract cancer, as compared to chemotherapy alone, according to interim results from the TOPAZ-1 trial.

The risk of death for those taking durvalumab plus chemotherapy was 20% lower than for patients on chemotherapy alone. At 18 months, overall survival was 35.1% in the durvalumab group vs 25.6% for chemotherapy alone. By 2 years, overall survival was 24.9% vs 10.4%.

"TOPAZ-1 is the first phase 3 trial to show that adding immunotherapy to standard chemotherapy can increase survival in biliary tract cancer, and importantly, does so without inducing any new serious side effects," said lead author Do-Youn Oh, MD, PhD, professor in the Division of Medical Oncology at Seoul National University Hospital and Seoul National University College of Medicine, Korea.

"The study met its primary endpoint at a prespecified interim analysis, and durvalumab plus gemcitabine and cisplatin demonstrated statistically significant and clinically meaningful prolonged overall survival compared with placebo plus chemotherapy," she said.

"This is an effective first-line therapy and could become a new standard of care for patients with advanced biliary tract cancer," she added.

Oh presented the results here at the at the Gastrointestinal Cancers Symposium (GICS) 2022.

In a discussion of the paper, Nilofer Saba Azad, MD, from the Department of Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, Maryland, noted that overall, "we are seeing enticing benefit in survival and response rate.

"There is moderately strong preliminary clinical data and biological rationale that immune checkpoint may have some activity in biliary tract cancer," she said. "The trial was adequately powered and accounted for important known clinical subsets, and was placebo controlled. The results suggest a meaningful benefit for patients."

However, she pointed out that there are still open questions, mostly having to do with the subgroup analysis.

Biliary Tract Cancer: Incidence Is Rising

Biliary tract cancers are a relatively rare and heterogeneous group of cancers, and global incidence is rising. "Advanced unresectable biliary tract cancer is an area of high unmet need due to its aggressive nature, limited treatment options, and poor prognosis," explained Oh. "The first-line standard of care for advanced biliary tract cancers, gemcitabine and cisplatin, has remained unchanged for over a decade."

Previous research has suggested that checkpoint inhibition may result in antitumor immune responses, she commented. A previous phase 2 trial showed that durvalumab combined with gemcitabine and cisplatin showed promising antitumor activity in advanced biliary tract cancer. This latest study is a larger phase 3 trial to investigate this effect further.

The study involved 365 patients with unresectable locally advanced, recurrent, or metastatic biliary tract cancers. Patients had one of three types of biliary tract cancer: 55% had intrahepatic cancers; 19 % had extrahepatic cancers; and 25% had gallbladder cancer.

The trial was conducted in the US and 17 countries in Europe, South America, and Asia. Nearly 55% of the cohort was from Asia, including South Korea, Thailand, Japan, and China.

All patients received chemotherapy with gemcitabine (1000 mg/m²) and cisplatin (25 mg/m² on days 1 and 8 every 3 weeks) for up to eight cycles.

Patients were randomized to receive either durvalumab (1500 mg every 3 weeks or placebo before chemotherapy, and also to receive durvalumab (1500 mg every 4 weeks) or placebo after chemotherapy until disease progression or unacceptable toxicity.

At approximately 1 year, the authors found that adding durvalumab significantly improved overall survival (hazard ratio [HR], 0.80; P = .021).

Progression-free survival was also significantly better with durvalumab compared to placebo: 7.2 months vs 5.7 months (HR, 0.75; P = .001).

The overall response rate (ORR) was 26.7% with durvalumab and 18.7% with placebo.

The most common adverse events were anemia (experienced by 48.2% of patients), neutropenia (31.7%), and nausea (40.2%). Grade 3/4 adverse events occurred in 75.7% of patients receiving durvalumab vs 77.8% for placebo, indicating that the majority of side effects in both arms were from chemotherapy, Oh commented. Discontinuation of any study medication because of toxicity occurred in 8.9% and 11.4% of patients, respectively.

Enticing Benefit, but Questions Remain

In her discussion of the paper, Azad pointed out that Asian patients comprised more than half of the cohort and appeared to derive more benefit from the investigational treatment compared to other groups. "So the question is if that is driving the benefit or just an increased benefit," she said. "That is going to be an open question for our research community."

Azad also noted that patients with nonmetastatic disease at enrollment did a little better, so more data are needed on how that affected the outcomes.

"PDL-1 just missed statistical significance, but that is something that will be further explored," she said. "And we still have open questions about viral hepatitis, liver fluke infection, and cirrhosis, and I do hope that these will be included in the final analysis of the study."

The GICS meeting is organized by the American Society of Clinical Oncology (ASCO), and the society highlighted these data in a press release. Cathy Eng, MD, FACP, ASCO expert in gastrointestinal cancers, commented in the statement: "TOPAZ-1 is the first phase 3 trial to demonstrate the benefit of immunotherapy for improved overall survival, in combination with chemotherapy, creating a new standard of care."

The study received funding from AstraZeneca, marker of durvalumab. Oh reported relationships with ASLAN Pharmaceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Celgene, Genentech/Roche, Halozyme, Handock, Lilly, MSD, Merck Serono, Novartis, Servier, Taiho,, Turning Point Therapeutics, and Zymeworks. Azad reported relationships with Agios, Array, Astex, AtlasMedx, Bayer, Bristol-Myers Squibb, Celgene, Debiopharm, EMD Serono, Genentech, Incyte, Intensity, Loxo/Lilly, Merck and Syndax.

Gastrointestinal Cancers Symposium (GICS) 2022: Abstract 378. Presented January 21, 2022.

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