, according to results of a phase 2 randomized controlled trial.
“Immune checkpoint blockade in PDAC as a single-agent therapy was not currently indicated beyond the subgroup of patients with microsatellite instability or mismatch repair deficiency ... however, a precedent existed for evaluating a combination of 2 immune checkpoint antagonists in this setting,” noted the investigators, led by Eileen M. O’Reilly, MD, gastrointestinal medical oncology, David M. Rubenstein Center for Pancreatic Cancer, Memorial Sloan Kettering Cancer Center and Cornell University, New York. In particular, a combination of agents that inhibit programmed cell death-1 ligand 1 (PD-L1) and the human T-cell receptor protein cytotoxic T-lymphocyte-associated protein 4 (CTLA4), nonredundant mechanisms, has shown promise.
Dr. O’Reilly and coinvestigators treated 65 patients in the trial’s initial cohort who had received only a single first-line fluorouracil- or gemcitabine-based chemotherapy regimen for recurrent or metastatic PDAC. Patients were randomized to combination therapy with durvalumab (Imfinzi), an anti-PD-L1 antibody, and tremelimumab, an investigational anti-CTLA4 antibody, followed by durvalumab alone, or to durvalumab monotherapy.
The objective response rate was just 3.1% with combination therapy and 0% with monotherapy—values that fell far short of the predefined 10% rate needed to initiate a planned expansion cohort. Both groups had a median progression-free survival of 1.5 months, Dr. O’Reilly and associates wrote. Their report is in JAMA Oncology.
The rate of grade 3 or higher treatment-related adverse events was 22% in the combination therapy group and 6% in the monotherapy group. In both groups, the most common events were fatigue and diarrhea. Some 6% and 3% of patients, respectively, stopped treatment because of a treatment-related adverse event.
The small trial population precluded detailed analyses of associations between treatment response and PD-L1 expression or microsatellite instability status.
“The observed efficacy of durvalumab plus tremelimumab therapy and durvalumab monotherapy was reflective of a population of patients with [metastatic PDAC] who had poor prognoses and rapidly progressing disease; however, treatment was well tolerated,” Dr. O’Reilly and coinvestigators wrote.
“Future studies are needed to evaluate how to best combine immune checkpoint blockade with other agents, including cytotoxic and targeted therapies, with the intention of overcoming the unique immunosuppressive, hypoxic, and fibrotic tumor microenvironment of PDAC. Such studies should evaluate biomarker expression to identify patients most likely to benefit from immune checkpoint blockade,” they recommended.
Dr. O’Reilly disclosed holding a consulting or advisory role or receiving grants from numerous pharmaceutical companies, including AstraZeneca, which funded the study.
SOURCE: O’Reilly EM et al. JAMA Oncol. 2019 July 18. doi:10.1001/jamaoncol.2019.1588.