According to results of an open-label, multicenter phase 2 study published in JAMA Oncology, the overall response rates (ORRs) of adult patients with metastatic pancreatic ductal adenocarcinoma (PDAC) receiving second-line therapy with either single-agent or combination immune checkpoint inhibitor therapy did not meet efficacy criteria for study expansion.1
The prognosis for most patients diagnosed with PDAC is poor, with a 5-year overall survival rate for all stage-PDAC in the single digits. Furthermore, treatment options for patients with metastatic disease are very limited following progression on first-line chemotherapy.
In this phase 2 study (ClinicalTrials.gov Identifier: NCT02558894), patients with metastatic PDAC that had progressed following first-line fluoropyrimidine- or gemcitabine-based chemotherapy were randomly assigned in a 1:1 ratio to receive a maximum of 12 months of either monotherapy with the programmed cell death-ligand 1 (PD-L1) inhibitor, durvalumab (1500 mg every 4 weeks), or 4 cycles of combination immune checkpoint inhibitor therapy with durvalumab (1500 mg every 4 weeks) plus the anticytotoxic T-lymphocyte–associated antigen 4 antibody, tremelimumab (75 mg every 4 weeks) followed by durvalumab monotherapy (1500 mg every 4 weeks).
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Rationales for evaluating immune checkpoint inhibitor therapy in the setting of advanced PDAC included its known immunosuppressive tumor microenvironment, as well as the potential for an additive or synergistic effect when combining immunotherapies targeting different T-cell immune checkpoints. In addition, preliminary results from a phase 1 study of single-agent durvalumab in this patient population showed a manageable adverse event profile and an ORR of approximately 7% in the subgroup of evaluable patients.2
Part A of this phase 2 study was designed as a safety-lead in, with the potential for expansion of patient enrollment (Part B) in the event that the adverse effects of treatment were manageable and a predetermined efficacy signal, an ORR of at least 10%, was met in either study arm.
The median age of the 65 patients who underwent study randomization was 61 years, and median study follow-up was 3.1 months.
For the 64 patients who received at least 1 dose of study drug, approximately 14% (ie, 6% and 22% single-agent and combination immune checkpoint inhibitor therapy, respectively) experienced at least 1 grade 3 or higher treatment-related adverse event. Six percent of patients discontinued treatment as the result of a treatment-related adverse event. No treatment-related deaths occurred.
In the intent-to-treat population, the ORR was 0% for patients receiving single-agent durvalumab and 3.1% for those treated with combination therapy.
“The absence of significant activity of durvalumab with or without tremelimumab in patients with PDAC indicates that combining modes of action in this small study did not sufficiently overcome the immune inhibitory environment known to be a key contributor to poor response in patients with metastatic PDAC,” the study authors noted.
Study limitations noted by the study authors included the absence of a control arm, such as combination chemotherapy, as well the low response rates to therapy. As a result of the latter, it was not possible to perform a meaningful assessment of the impact of specific biomarkers, such as the level of PD-L1 expression in tumor, tumor mutational burden, and the presence of germline BRCA1/2 mutations, on ORR.
The authors of an invited accompanying editorial commented that
“immunology-focused studies in metastatic PDAC remain very challenging in many respects given that, even in the best of circumstances, it may take months for an effective immune response to develop. It is likely that the current immunotherapies take too long to induce an effective response in metastatic patients with PDAC who progress quickly, measured in weeks rather than months.”3
They further concluded that ”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 immune checkpoint inhibitors.”3
References
- O’Reilly EM, Oh DY, Dhani N, et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: A phase 2 randomized clinical trial [published online July 18, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.1588
- Segal NH, Hamid O, Hwu WJ, et al. A phase 1 multi-arm dose-expansion study of the anti-programmed cell death-ligand-1 (PD-L1) antibody MEDI4736: preliminary data. Ann Oncol. 2014; 25(suppl 4):iv361-iv372.
- Osipov A, Zaidi N, Laheru DA. Dual checkpoint inhibition in pancreatic cancer revealing the limitations of synergy and the potential of novel combinations. JAMA Oncol. doi: 10.1001/jamaoncol.2019.1583
