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

M Tempero; D-Y Oh; J Tabernero; M Reni; E Van Cutsem; A Hendifar; D-T Waldschmidt; N Starling; J-B Bachet; H-M Chang; J Maurel; R Garcia-Carbonero; S Lonardi; L M Coussens; L Fong; L C Tsao; G Cole Jr; D James; T Macarulla

doi:10.1016/j.annonc.2021.01.070

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

Ann Oncol. 2021 May;32(5):600-608. doi: 10.1016/j.annonc.2021.01.070. Epub 2021 Feb 1.

Authors

M Tempero¹, D-Y Oh², J Tabernero³, M Reni⁴, E Van Cutsem⁵, A Hendifar⁶, D-T Waldschmidt⁷, N Starling⁸, J-B Bachet⁹, H-M Chang¹⁰, J Maurel¹¹, R Garcia-Carbonero¹², S Lonardi¹³, L M Coussens¹⁴, L Fong¹⁵, L C Tsao¹⁶, G Cole Jr¹⁷, D James¹⁸, T Macarulla³

Affiliations

¹ Department of Medicine, University of California San Francisco, San Francisco, USA. Electronic address: Margaret.Tempero@ucsf.edu.
² Department of Internal Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
³ Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), IOB-Quiron, UVic-UICC, CIBERONC, Barcelona, Spain.
⁴ Department of Radiochemotherapy, San Raffaele Hospital Scientific Institute, Milan, Italy.
⁵ Department of Digestive Oncology, University Hospitals Gasthuisberg/Leuven & KU Leuven, Leuven, Belgium.
⁶ Department of Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, USA.
⁷ Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany.
⁸ Section of GI and Lymphoma Units, Department of Medicine, The Royal Marsden, London, UK.
⁹ Department of Hepatogastroenterology, UPMC, Sorbonne University, Pitié Salpêtrière Hospital, APHP, Paris, France.
¹⁰ Division of Oncology, Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, South Korea.
¹¹ Department of Medical Oncology, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Hospital Clinic Barcelona, University of Barcelona, Barcelona, Spain.
¹² Department of Medical Oncology, Hospital Universitario Doce de Octubre, Imas12, UCM, CNIO, CIBERONC, Madrid, Spain.
¹³ Dipartimento di Oncologia Clinical e Sperimentale, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
¹⁴ Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA.
¹⁵ Department of Medicine, University of California San Francisco, San Francisco, USA.
¹⁶ Department of Statistics, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, USA.
¹⁷ Department of Oncology Development, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, USA.
¹⁸ Department of Clinical Science, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, USA.

PMID: 33539945
DOI: 10.1016/j.annonc.2021.01.070

Abstract

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.

Keywords: ibrutinib; metastatic pancreatic adenocarcinoma; phase III.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives
Adenocarcinoma* / drug therapy
Albumins / adverse effects
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Deoxycytidine / analogs & derivatives
Gemcitabine
Humans
Paclitaxel / adverse effects
Pancreatic Neoplasms* / drug therapy
Piperidines
Treatment Outcome
Tumor Microenvironment

Substances

130-nm albumin-bound paclitaxel
Albumins
Piperidines
Deoxycytidine
ibrutinib
Adenine
Paclitaxel
Gemcitabine