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

This phase 2 randomized clinical trial assesses the safety and efficacy of durvalumabwith and without tremelimumab for the treatment of patients with metastatic pancreatic ductal adenocarcinoma. Key PointsQuestionDoes 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? FindingsIn 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. MeaningThe 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. ImportanceNew therapeutic options for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are needed. This study evaluated dual checkpoint combination therapy in patients with mPDAC. ObjectiveTo 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 ParticipantsPart 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. InterventionsPatients 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 MeasuresSafety 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. ResultsAmong 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 RelevanceTreatment 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 RegistrationClinicalTrials.gov identifier: NCT02558894