Clinical and translational results from a phase 1 trial of gemcitabine/nab-paclitaxel with nivolumab/ipilimumab or hydroxychloroquine/ipilimumab in untreated metastatic pancreatic adenocarcinoma

Background Patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) often respond to cytotoxic therapy, but early disease progression is typical. Responses to immunotherapy alone are rare. Recent advances in chemoimmunotherapy combinations offer promise. We report results from cohorts A and B of REVOLUTION, an adaptive platform trial designed to evaluate the safety and antitumor activity of chemoimmunotherapy combinations in untreated mPDAC. Methods REVOLUTION ( NCT04787991 ) is an open-label, exploratory platform trial. Patients were assigned to enrolling cohorts in a non-randomized fashion. All patients received gemcitabine (1,000 mg/m 2 ), nab-paclitaxel (125 mg/m 2 ), and two doses of ipilimumab (1 mg/kg), administered intravenously. In addition, cohort A received nivolumab (360 mg intravenously every 3 weeks) and cohort B received hydroxychloroquine (600 mg orally two times a day). The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response, progression-free survival, and overall survival (OS). Exploratory endpoints included pharmacodynamic changes and associations between biomarkers and clinical outcomes. Results Both cohorts enrolled 15 patients. Grade 3–4 treatment-related adverse events occurred in 60% and 53% of patients in cohorts A and B, respectively. One grade 5 event occurred in cohort B, which exhibited more frequent dose modifications and non-compliance. Cohort A demonstrated an ORR of 33% (5/15) and a 12-month OS rate of 65.5% (95% CI 35.7% to 84.0%), with higher baseline levels of programmed cell death protein-1 (PD-1) + CD39 + central memory CD4 + T cells associated with prolonged survival. Cohort B demonstrated an ORR of 40% (6/15) and a 12-month OS rate of 53.9% (95% CI 24.3% to 76.3%). Cohort A showed increases in activated and proliferating CD4 + and CD8 + T cells, regulatory T cells, and circulating soluble PD-1 and Th1-associated cytokines. Cohort B exhibited delayed but sustained increases in activated CD4 + T cells and pharmacodynamic evidence of autophagy inhibition. Conclusions REVOLUTION cohorts A and B demonstrated encouraging antitumor activity in patients with mPDAC. In cohort B, hydroxychloroquine-related tolerability issues contributed to early discontinuations and reduced drug exposure. These findings highlight the potential and limitations of current chemoimmunotherapy approaches. Although neither cohort will be expanded, the results reinforce the continued promise of chemoimmunotherapy in mPDAC and the importance of refining these strategies.