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Original Investigation
July 18, 2019

Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial

Author Affiliations
  • 1Gastrointestinal Medical Oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
  • 2Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
  • 3Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 4Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
  • 5Department of Oncology, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea
  • 6Division of Medical Oncology, University of Kansas Medical Center, Kansas City
  • 7Department of Medicine–Medical Oncology, Stanford University, Stanford, California
  • 8Division of Hematology and Oncology, University of Rochester, Rochester, New York
  • 9AstraZeneca, Gaithersburg, Maryland
  • 10Independent Biostatistician, Durham, North Carolina
  • 11Department of Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan
JAMA Oncol. Published online July 18, 2019. doi:10.1001/jamaoncol.2019.1588
Key Points

Question  Does combination immuno-oncology therapy (anti–programmed death–ligand 1 and anticytotoxic T-lymphocyte–associated antigen 4) provide clinical benefit for patients with metastatic pancreatic ductal adenocarcinoma?

Findings  In part A of this phase 2 randomized clinical trial of 65 patients, durvalumab plus tremelimumab therapy was tolerated in patients with metastatic pancreatic ductal adenocarcinoma and had an objective response rate of 3.1%, and no patients responded to durvalumab monotherapy. The threshold for continuation to part B of the study was an objective response rate of 10% for either arm (durvalumab plus tremelimumab therapy or durvalumab monotherapy), so part B was not conducted based on the findings of part A.

Meaning  The efficacy of immunotherapy in part A of this trial was reflective of a population of patients with metastatic pancreatic ductal adenocarcinoma who had poor prognoses and rapidly progressing disease.


Importance  New therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC.

Objective  To evaluate the safety and efficacy of the anti–PD-L1 (programmed death-ligand 1) antibody using either durvalumab monotherapy or in combination with the anticytotoxic T-lymphocyte antigen 4 antibody using durvalumab plus tremelimumab therapy in patients with mPDAC.

Design, Setting, and Participants  Part A of this multicenter, 2-part, phase 2 randomized clinical trial was a lead-in safety, open-label study with planned expansion to part B pending an efficacy signal from part A. Between November 26, 2015, and March 23, 2017, 65 patients with mPDAC who had previously received only 1 first-line fluorouracil–based or gemcitabine-based treatment were enrolled at 21 sites in 6 countries. Efficacy analysis included the intent-to-treat population; safety analysis included patients who received at least 1 dose of study treatment and for whom any postdose data were available.

Interventions  Patients received durvalumab (1500 mg every 4 weeks) plus tremelimumab (75 mg every 4 weeks) combination therapy for 4 cycles followed by durvalumab therapy (1500 mg every 4 weeks) or durvalumab monotherapy (1500 mg every 4 weeks) for up to 12 months or until the onset of progressive disease or unacceptable toxic effects.

Main Outcomes and Measures  Safety and efficacy were measured by objective response rate, which was used to determine study expansion to part B. The threshold for expansion was an objective response rate of 10% for either treatment arm.

Results  Among 65 randomized patients, 34 (52%) were men and median age was 61 (95% CI, 37-81) years. Grade 3 or higher treatment-related adverse events occurred in 7 of 32 patients (22%) receiving combination therapy and in 2 of 32 patients (6%) receiving monotherapy; 1 patient randomized to the monotherapy arm did not receive treatment owing to worsened disease. Fatigue, diarrhea, and pruritus were the most common adverse events in both arms. Overall, 4 of 64 patients (6%) discontinued treatment owing to treatment-related adverse events. Objective response rate was 3.1% (95% CI, 0.08-16.22) for patients receiving combination therapy and 0% (95% CI, 0.00-10.58) for patients receiving monotherapy. Low patient numbers limited observation of the associations between treatment response and PD-L1 expression or microsatellite instability status.

Conclusion and Relevance  Treatment was well tolerated, and the efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy reflected a population of patients with mPDAC who had poor prognoses and rapidly progressing disease. Patients were not enrolled in part B because the threshold for efficacy was not met in part A.

Trial Registration  ClinicalTrials.gov identifier: NCT02558894