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Durvalumab fails to advance in pancreatic cancer

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New strategies must focus on the microenvironment

“This study clearly and soberly demonstrates that despite the observed clinical benefits of dual ICI [immune check-point inhibition] therapy appreciated in other tumor types, PDAC remains refractory to standalone dual ICI therapy,” Dan A. Laheru, MD, and colleagues wrote in an invited commentary. “The priming of antitumor T-cell responses in the draining lymph nodes by anti-CTLA-4 therapy, tremelimumab, appears to be insufficient in priming T cells in PDAC for the addition of PD-L1 therapy.”

Current evidence suggests two main challenges will have to be overcome to pave the way for effective ICI therapy in PDAC and similarly nonimmunogenic cancers, they proposed. One will be inducing high-quality effector T cells into the tumor microenvironment (TME); the other will be reprogramming this “extremely immunosuppressive” milieu.

“Although there remains a rationale for testing dual checkpoint blockade therapy in patients with PDAC, this strategy will likely need to include agents that will first trigger the trafficking of T cells into the otherwise T-cell-poor tumor so that T cells are available for activation by ICIs. Furthermore, other agents need to be further tested in combination that would effectively reprogram the otherwise immunosuppressive PDAC TME to optimize T-cell function by turning off inhibitory signals,” Dr. Laheru and colleagues noted. “This study also strongly suggests that we should no longer test stand-alone ICI monotherapy or dual ICI in patients with PDAC without a T-cell inducing agent, whether that is a personalized vaccine-based therapy, small-molecule/antibody immunomodulator, or another immunotherapy agent altogether.

“The road to developing improved immunotherapy for patients with PDAC remains challenging,” they concluded. “Through the results of such work presented by the authors along with a greater understanding of the immune microenvironment, it is our hope that subsequent trials will allow future patients with PDAC to realize the benefits of immunotherapy that have helped so many in other cancer types.”

Arsen Osipov, MD, Neeha Zaidi, MD, and Dan A. Laheru, MD, are with the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.



The immune checkpoint inhibitor durvalumab, whether used as monotherapy or in combination immunotherapy, does not have sufficient efficacy in advanced pancreatic ductal adenocarcinoma (PDAC) to warrant further investigation, 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.

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