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 Cole17, D James18, T Macarulla3. 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.
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.
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.
Authors: Lacey J Padrón; Deena M Maurer; Mark H O'Hara; Eileen M O'Reilly; Robert A Wolff; Zev A Wainberg; Andrew H Ko; George Fisher; Osama Rahma; Jaclyn P Lyman; Christopher R Cabanski; Jia Xin Yu; Shannon M Pfeiffer; Marko Spasic; Jingying Xu; Pier Federico Gherardini; Joyson Karakunnel; Rosemarie Mick; Cécile Alanio; Katelyn T Byrne; Travis J Hollmann; Jonni S Moore; Derek D Jones; Marco Tognetti; Richard O Chen; Xiaodong Yang; Lisa Salvador; E John Wherry; Ute Dugan; Jill O'Donnell-Tormey; Lisa H Butterfield; Vanessa M Hubbard-Lucey; Ramy Ibrahim; Justin Fairchild; Samantha Bucktrout; Theresa M LaVallee; Robert H Vonderheide Journal: Nat Med Date: 2022-06-03 Impact factor: 87.241
Authors: Stergios J Moschos; Zeynep Eroglu; Nikhil I Khushalani; Kari L Kendra; George Ansstas; Gino K In; Peng Wang; Glenn Liu; Frances A Collichio; Paul B Googe; Craig C Carson; Karen McKinnon; Hsing-Hui Wang; Nana Nikolaishvilli-Feinberg; Anastasia Ivanova; Christy C Arrowood; Nancy Garrett-Mead; Kathleen C Conway; Sharon N Edmiston; David W Ollila; Jonathan S Serody; Nancy E Thomas; S Percy Ivy; Lokesh Agrawal; Elizabeth C Dees; James L Abbruzzese Journal: Melanoma Res Date: 2021-04-01 Impact factor: 3.199