Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma

Author(s): Michael L. Wang, M.D., Wojciech Jurczak, M.D., Ph.D., Mats Jerkeman, M.D., Ph.D., Judith Trotman, F.R.A.C.P., Pier L. Zinzani, M.D., Ph.D., David Belada, M.D., Ph.D., Carola Boccomini, M.D., Ian W. Flinn, M.D., Ph.D., Pratyush Giri, F.R.A.C.P., Andre Goy, M.D., Paul A. Hamlin, M.D., Olivier Hermine, M.D., Ph.D., José-Ángel Hernández-Rivas, M.D., Ph.D., Xiaonan Hong, M.D., Seok Jin Kim, M.D., Ph.D., David Lewis, F.R.C.Path., Ph.D., Yuko Mishima, M.D., Ph.D., Muhit Özcan, M.D., Guilherme F. Perini, M.D., Christopher Pocock, M.D., Ph.D., Yuqin Song, M.D., Ph.D., Stephen E. Spurgeon, M.D., John M. Storring, M.D., Jan Walewski, M.D., Jun Zhu, M.D., Ph.D., Rui Qin, Ph.D., Todd Henninger, Ph.D., Sanjay Deshpande, M.D., Angela Howes, Ph.D., Steven Le Gouill, M.D., Ph.D., and Martin Dreyling, M.D. for the SHINE Investigators*
Source: N Engl J Med 2022; 386:2482-2494 DOI: 10.1056/NEJMoa2201817
Lucio Gordan MD

Dr. Gordan's Thoughts

While an interesting study, and likely will be accepted as a standard of care, OS is of critical importance, as the addition of Ibrutinib adds expected toxicity and significant cost to therapy.

ABSTRACT

BACKGROUND

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.

METHODS

We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.

RESULTS

Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P=0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P=0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.

CONCLUSIONS

Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number,

Author Affiliations

From the University of Texas M.D. Anderson Cancer Center, Houston (M.L.W.); Maria Sklodowska-Curie National Research Institute of Oncology, Kraków (W.J.), and Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw (J.W.) — both in Poland; Skane University Hospital and Lund University, Lund, Sweden (M.J.); Concord Repatriation General Hospital, University of Sydney, Sydney (J.T.), and Royal Adelaide Hospital, Adelaide, SA (P.G.) — both in Australia; IRCCS Azienda Ospedaliero–Universitaria di Bologna, Istituto di Ematologia “Seràgnoli,” Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna (P.L.Z.), and SC Ematologia, Azienda Ospedaliero–Universitaria Città della Salute e della Scienza di Torino, Turin (C.B.) — both in Italy; the Fourth Department of Internal Medicine–Hematology, Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic (D.B.); Sarah Cannon Research Institute and Tennessee Oncology, Nashville (I.W.F.); John Theurer Cancer Center, Hackensack (A.G.), and Janssen Research and Development, Raritan (R.Q., T.H., S.D., A.H.) — both in New Jersey; Memorial Sloan Kettering Cancer Center, New York (P.A.H.); the Department of Hematology, Hôpital Necker, Assistance Publique–Hôpitaux de Paris and Institut Imagine, Université de Paris, INSERM Unité Mixte de Recherche 1183 (O.H.), and Institut Curie Comprehensive Cancer Center (S.L.G.), Paris, and Hospitalier Universitaire de Nantes, Centre de Recherche en Cancérologie et Immunologie Nantes Angers, INSERM, Université de Nantes, Nantes (S.L.G.) — all in France; the Department of Hematology, Hospital Universitario Infanta Leonor, Universidad Complutense, Madrid (J.-Á.H.-R.); Fudan University Shanghai Cancer Center, Shanghai (X.H.), and Key Laboratory of Carcinogenesis and Translational Research, Department of Lymphoma, Peking University Cancer Hospital and Institute, Beijing (Y.S., J.Z.) — both in China; the Division of Hematology–Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.J.K.); University Hospitals Plymouth NHS Trust, Plymouth (D.L.), and Kent and Canterbury Hospital, Canterbury (C.P.) — both in the United Kingdom; the Department of Hematology–Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo (Y.M.); Ankara University School of Medicine, Ankara, Turkey (M.Ö.); Hospital Israelita Albert Einstein, São Paulo (G.F.P.); the Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland (S.E.S.); the Research Institute of the McGill University Health Centre, McGill University, Montreal (J.M.S.); and Klinikum der Universität München, Ludwig Maximilian University of Munich, Munich, Germany (M.D.).

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