Ibrutinib in combination with nab-paclitaxel and gemcitabine as first-line treatment for patients with metastatic pancreatic adenocarcinoma: results from the phase 3 RESOLVE study

Abstract

Introduction: Advanced pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies characterized by rapid disease progression and poor outcomes. First‐line treatment for PDAC includes Nab‐paclitaxel/gemcitabine (Nab‐P/ GCB) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin). Bruton's tyrosine kinase (BTK) inhibition may play a role in antitumor activity and the BTK inhibitor ibrutinib has been shown to do so through tumor microenvironment modulation. This phase 3 study evaluated the efficacy of ibrutinib plus Nab‐P/GCB in patients with PDAC. Methods: RESOLVE (NCT02436668; PCYC‐1137‐CA) was a phase 3, randomized, double‐blind, placebo‐controlled study evaluating ibrutinib+Nab‐P/GCB in patients with untreated metastatic PDAC. Key eligibility criteria included histologically‐confirmed PDAC; stage IV diagnosis within 6 weeks of randomization; Karnofsky performance score ≥70. Patients were randomized to once‐daily oral ibrutinib (560 mg) or placebo plus Nab‐P (125 mg/m 2) and GCB (1,000 mg/m 2) until disease progression or unacceptable toxicity. Primary endpoints were overall survival (OS) and progression‐ free survival (PFS); secondary endpoints included overall response rate (ORR) and safety. No multiplicity adjustments were made; all p‐values are nominal. Results: 424 patients were randomized to ibrutinib+Nab‐P/GCB (n=211) or placebo+Nab‐P/GCB (n=213). Baseline demographic and disease characteristics were generally well‐balanced between the two arms; across both arms, median age was 64 years (range, 32‐85), 55% were male, and 68% were white. Median c‐reactive protein (CRP) was 15 μg/mL for all patients. After median follow‐up of 25 months (range, 0.1+‐31+), the primary endpoint was not met. There was no significant difference in OS between ibrutinib+Nab‐P/GCB vs placebo+Nab‐P/GCB (median 9.7 vs 10.8 months; hazard ratio [HR] 1.109; P= .3225). No significant difference was observed among subgroups, though male sex, patients from US, and> median CRP numerically favored ibrutinib+Nab‐P/GCB (HRs 0.926, 0.908, 0.916, respectively). PFS was shorter for ibrutinib+Nab‐P/GCB compared with placebo+Nab‐P/GCB (median 5.3 vs 6.0 months; HR 1.525; P