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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr O’Reilly reported holding a consulting or advisory role with Aduro Biotech, Agios, ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boston Scientific, Bristol-Myers Squibb, CASI Pharmaceuticals, Celgene, Celsion, Delcath Systems, Eisai, Gilead Sciences, Halozyme, IntegraGen, Ipsen, Janssen, MedImmune, Merck, Merrimack, New B Innovation, Newlink Genetics, Onxeo, Sanofi, Servier, Silenseed, Sillajen, Sirtex Medical, VAXIMM, Vicus Therapeutics, and Westhaven; receiving grants from AstraZeneca during the conduct of the study; receiving grants from MabVax Therapeutics, Genentech, Celgene, Bristol-Myers Squibb, Silenseed, Momenta Pharmaceuticals, OncoMed Pharmaceuticals, Halozyme, and Pfizer outside the submitted work; and receiving personal fees from Celgene, BioLine, Bayer, and Sobi outside the submitted work. Dr Oh reported holding a consulting or advisory role with Debiopharm Group, Lilly, MSD, and Roche; receiving research funding from AstraZeneca and from AstraZeneca and Array outside the submitted work; holding a consulting or advisory role with Halozyme, Merck, and Debio outside this work. Dr Dhani reported receiving honoraria from Celgene; receiving research funding from AstraZeneca, Celgene, and Halozyme; receiving funds for travel, accommodations, and expenses from Celgene; and receiving compensation for participation in the advisory boards of AstraZeneca, Celgene, and Shire Baxalta outside the submitted work. Dr Renouf reported holding a consulting or advisory role with Celgene and Shire receiving personal fees from Amgen, Celgene, Shire, Servier, Taiho Pharma, Bayer, and Ipsen outside the submitted work. Dr Sun reported receiving honoraria from Genentech/Roche and Taiho Pharmaceutical, holding a consulting or advisory role with Bayer, and receiving research funding from Bayer and Merck. Dr Fisher reported having stock and other ownership interests in Seattle Genetics; receiving honoraria from Merck, Genentech, and Ipsen; hold a consulting or advisory role with Celgene and Ipsen; receiving research funding from Aduro Biotech, Bristol-Myers Squibb, EpicentRx, Forty seven, Genentech/Roche, Ipsen, Merck, Newlink Genetics, Pharmaceutical Research Associates, Polaris, Sun Pharma, and XBiotech; and receiving funding for travel, accommodations, and expenses from Genentech/Roche and Merck. Dr Hezel reported receiving personal fees from Novartis, Merck, BioTelemetry, Eisai, and Bayer outside the submitted work. Dr Chang reported having stock and other ownership interests in AstraZeneca and receiving funding for travel, accommodations, and expenses from MedImmune. Dr Vlahovic reported having stock and other ownership interests in AstraZeneca. Dr Takahashi reported receiving stock grants as long-term incentives from AstraZeneca in 2017 and 2018, with vesting complete in March 2020. Dr Yang reported having stock and other ownership interests in AstraZeneca. Dr Philip reported receiving honoraria from Amgen, Bayer, Bristol-Myers Squibbm, Celgene, Halozyme, Ipsen, Merrimack, Novartis, Roche, and Sanofi; holding a consulting or advisory role with Celgene, Gilead Sciences, Halozyme, Ipsen, Merrimack, and Novartis; being a member of the speakers bureau for Amgen, Bayer, Celgene, Roche, and Sanofi; and receiving research funding from Bayer, Genentech, Immunomedics, Incyte, Karyopharm Therapeutics, Merck, Momenta Pharmaceuticals, Novartis, Plexxikon, Regeneron, and Taiho Pharmaceutical; receiving grants from AstraZeneca during the conduct of the study; and having a relationship with Celgene, EMD Serono, Halozyme, Roche, and Sanofi. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Percentage of Change in Target Lesion Size

Percentage of change was assessed by the investigator at each study site. Dotted reference lines at −30% and 20% denote thresholds for partial response (PR) and progressive disease (PD), respectively. The censored case was of a patient treated with durvalumab plus tremelimumab therapy who maintained stable disease until week 43 (PD on day 302). This patient was re-treated with tremelimumab therapy after PD and survived without appearance of new lesions until data cutoff (day 467).

Figure 3.. Progression-Free Survival (PFS) and Overall Survival (OS) in Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Durvalumab Plus Tremelimumab (D + T) Therapy vs Durvalumab Monotherapy (D)