Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study

Abstract

Background. Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC. Materials and Methods. This was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS).Results. Twenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m 2 . The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months). Conclusion. Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study. The Oncologist 2020;25:e808-e815 Implications for Practice: Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.

An Immunological Glance on Pancreatic Ductal Adenocarcinoma

“…Thus, patients displaying high diversity of TCR clonality before treatment followed by high proliferation of specific clones after ipilimumab therapy were associated with better survival than patients having a more unfavorable TCR repertoire at baseline (median survival 8.66 months vs. 4.28 months) [84]. Another phase 1b study involving the combination of ipilimumab and gemcitabine concluded an overall survival of 6.9 months for 21 patients with an advanced (previously pretreated) disease with a tolerable toxicity profile [85]. Furthermore, patients benefited from combined therapeutic approaches as the additive effect of GVAX, PD-1 inhibitors, or chemotherapeutic drugs became evident.…”

The Immune Microenvironment in Pancreatic Cancer

“…Multiple clinical trials have tested the combination of checkpoint inhibition and chemotherapy in PDAC patients [ 175 ]. Published studies have reported on the anti-CTLA-4 antibodies tremelimumab and ipilimumab, respectively [ 227 , 228 ], as well as the anti-PD-1 antibody pembrolizumab [ 229 ]. However, most of these trials are phase I studies, and no conclusive beneficial evidence has been reported [ 176 ].…”

Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma

“…When PD-1/CTL4 inhibitors combined with commonly used chemotherapeutic agents such as Nab-paclitaxel, gemcitabine, carboplatin, and FOLFOX improved overall survival [47]. Remarkably, therapeutic procedures using a combination of immune checkpoint inhibitors with radiotherapy or chemotherapy have shown significant outcomes [185,186].…”