Key clinical point: Durvalumab, whether used alone or in combination with tremelimumab, has little to no activity against advanced pancreatic cancer.
Major finding: The objective response rate was 3.1% with combination therapy and 0% with monotherapy, falling short of the 10% needed to proceed to an expansion cohort.
Study details: Multicenter, open-label phase 2 randomized controlled trial of durvalumab with or without tremelimumab in 65 patients with previously treated recurrent or metastatic pancreatic ductal adenocarcinoma.
Disclosures: Dr. O’Reilly disclosed holding a consulting or advisory role or receiving grants from numerous pharmaceutical companies, including AstraZeneca, which funded the study.
O’Reilly EM et al. JAMA Oncol. 2019 July 18. doi: 10.1001/jamaoncol.2019.1588.
“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.