Expert Point of View: Nilofer Azad, MD

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Nilofer Azad, MD, Professor of Oncology at Johns Hopkins University School of Medicine and Co-Director of Cancer Genetics and Epigenetics at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, was invited to discuss the results of the phase III TOPAZ-1 study, which found an overall survival benefit for durvalumab plus gemcitabine/cisplatin vs gemcitabine/cisplatin alone as first-line treatment of advanced biliary tract cancer. “We have some open questions about this positive study, but overall, we absolutely have a trial that could change the standard of care,” Dr. Azad commented.

The current first-line standard of care is gemcitabine plus cisplatin, which yielded a median overall survival of less than 12 months in the landmark trial.1 Single-agent immunotherapy has produced modest results in this cancer. In KEYNOTE-158, the response rate to single-agent pembrolizumab was 6%, and median overall survival was 9 months.2 Although other studies of PD-1 inhibitors have yielded similar modest response rates, response rates with durvalumab plus chemotherapy have edged upward in earlier trials. Preliminary clinical data for durvalumab plus chemotherapy are “moderately strong,” she said, and there is a biologic rationale for the combination evaluated in TOPAZ-1. Moreover, Dr. Oh and her team previously conducted a phase II study of durvalumab with or without the CTLA-4 inhibitor tremelimumab and gemcitabine/cisplatin,3 in which response rates reached 50% to 73%, Dr. Azad noted. “This is the backdrop and the rationale for testing durvalumab in combination with gemcitabine/cisplatin.”

Nilofer Azad, MD

Nilofer Azad, MD

Deciphering Outcomes in TOPAZ-1

In TOPAZ-1, patients were randomly assigned to durvalumab plus gemcitabine/cisplatin or gemcitabine/cisplatin alone for eight cycles; in the experimental arm, patients received maintenance with durvalumab until disease progression, whereas the placebo arm received no further therapy. The use of active maintenance therapy in the experimental arm may have been a factor in the outcomes, Dr. Azad suggested.

“I don’t want to undercut how meaningful it is for us to finally have a phase III trial in the first line showing a statistically significant benefit—1.3 months—in overall survival. The separation of the curves persists even as we get further into follow up.... But if you look at when that curve separates, at the 6-month mark, patients in the control arm were no longer receiving any treatment. This definitely opens up the question as to whether durvalumab may be having its maximum impact as a maintenance regimen,” she said.

Addressing this question, Dr. Oh explained that a separation of curves was seen earlier than 6 months for progression-free survival and earlier than 3 months for duration of response, and the time to response was shorter in the durvalumab arm. She also explained that these trends are consistent with clinical trials in other tumor types where a delayed separation in overall survival is observed with immunotherapy plus chemotherapy.

Questions Remain

One unanswered question pertains to the greater benefit seen in Asian (hazard ratio [HR] = 0.72) than in Western patients (HR = 0.89), said Dr. Azad. Since Asians constituted about half the population, could their outcomes be driving the overall study result? Also, there appears to be a relative benefit by primary tumor location and presence of metastases; intrahepatic cholangiocarcinoma had a somewhat greater benefit, as did patients with nonmetastatic disease at diagnosis. Additionally, PD-L1 expression ≥ 1% narrowly missed statistical significance as a potential biomarker, which is another issue for future research. 

DISCLOSURE: Dr. Azad has served as a consultant or advisor for AMAG Pharmaceuticals, Helsinn Therapeutics/QED Therapeutics, Incyte, Merck, and Taiho Pharmaceuticals.


1. Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273-1281, 2010.

2. Piha-Paul SA, Oh DY, Ueno M, et al: Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer 147:2190-2198, 2020.

3. O’Reilly EM, Oh DY, Dhani N, et al: Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma. JAMA Oncol 5:1431-1438, 2019.


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