Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study

Background: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. Patients and methods: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis >6 weeks of randomization; Karnofsky performance score >70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m(2)) and gemcitabine (1000 mg/m(2)). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. Results: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade >3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. Conclusions: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.

Automated summary

This study evaluated the safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC. Results showed that although there were differences in overall response rates, ibrutinib plus nab-paclitaxel/gemcitabine did not improve overall survival or progression-free survival for patients with PDAC. Additionally, patients in the ibrutinib arm received lower cumulative drug doses.