Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial
Open accessAbstract
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.
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Immune checkpoint inhibitors have shown negligible activity in pancreatic adenocarcinoma.
“Consequently, immune checkpoint inhibitors (ICIs), thus far, have shown negligible activity in pancreatic adenocarcinoma (PDAC).”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [68]
In a phase II randomized study, durvalumab alone or in combination with tremelimumab showed an objective response rate of 0% and 3.1% in second or later-line treatment of PDAC.
“In a phase II randomized study, durvalumab alone or in combination with tremelimumab showed an objective response rate (ORR) of 0% and 3.1% in second or later-line treatment of PDAC [68].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [68]
There have been calls to reform PDAC drug development and to revise the criteria for advancing agents into larger trials.
“This has led to calls to revamp how drug development is furthered for this disease, and to redefine the thresholds needed for agents to move forward to larger phase trials281,282.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [282]
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- Authors
- O’Reilly, E. M., Oh, D.-Y., Dhani, N., Renouf, D. J., Lee, M. A., Sun, W., Fisher, G., Hezel, A., Chang, S.-C., Vlahovic, G., Takahashi, O., Yang, Y., Fitts, D., & Philip, P. A.
- Affiliations
- Gastrointestinal Medical Oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
- Seoul National University (KR)
- Princess Margaret Cancer Centre (CA)
- BC Cancer Agency (CA)
- The Catholic University of Korea Seoul St. Mary's Hospital (KR)
- University of Kansas Medical Center (US)
- Stanford Medicine (US)
- University of Rochester Medicine (US)
- AstraZeneca (United States) (US)
- Independent Biostatistician, Durham, North Carolina
- The Barbara Ann Karmanos Cancer Institute (US)
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-10-01
- Volume
- 5
- Issue
- 10
- Pages
- 1431
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6647002
- OpenAlex
- W2959096163
- Cited by
- 767
- References
- 45
- Citations by year
- 2026: 102 · 2025: 113 · 2024: 147 · 2023: 108 · 2022: 115 · 2021: 118 · 2020: 61 · 2019: 3
- FWCI
- 31.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- AstraZeneca
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Keywords
- metastatic pancreatic ductal adenocarcinoma, durvalumab, tremelimumab, PD-L1 inhibitors, CTLA-4 antibody, immune checkpoint inhibitors, dual checkpoint blockade, combination immunotherapy, objective response rate, treatment-related adverse events, first-line therapy, immunotherapy safety and efficacy, diarrhea, pruritus
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