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/m2) and gemcitabine (1000 mg/m2). 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.
['Tempero|M|M|', 'Oh|D-Y|DY|', 'Tabernero|J|J|', 'Reni|M|M|', 'Van Cutsem|E|E|', 'Hendifar|A|A|', 'Waldschmidt|D-T|DT|', 'Starling|N|N|', 'Bachet|J-B|JB|', 'Chang|H-M|HM|', 'Maurel|J|J|', 'Garcia-Carbonero|R|R|', 'Lonardi|S|S|', 'Coussens|L M|LM|', 'Fong|L|L|', 'Tsao|L C|LC|', 'Cole|G|G|', 'James|D|D|', 'Macarulla|T|T|']
D000225:Adenine D000230:Adenocarcinoma D000418:Albumins D000971:Antineoplastic Combined Chemotherapy Protocols D003841:Deoxycytidine D006801:Humans D017239:Paclitaxel D010190:Pancreatic Neoplasms D010880:Piperidines D016896:Treatment Outcome D059016:Tumor Microenvironment
ibrutinib metastatic pancreatic adenocarcinoma phase III