The iR2 regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: A multicentre, non-randomised, open-label phase 2 study

Radhakrishnan Ramchandren; Peter Johnson; Nilanjan Ghosh; Jia Ruan; Kirit M Ardeshna; Roderick Johnson; Gregor Verhoef; David Cunningham; Sven de Vos; Shireen Kassam; Luis Fayad; John Radford; Sarah Bailly; Fritz Offner; David Morgan; Javier Munoz; Jerry Ping; Edith Szafer-Glusman; Karl Eckert; Jutta K Neuenburg; Andre Goy

doi:10.1016/j.eclinm.2022.101779

The iR² regimen (ibrutinib plus lenalidomide and rituximab) for relapsed/refractory DLBCL: A multicentre, non-randomised, open-label phase 2 study

EClinicalMedicine. 2022 Dec 26:56:101779. doi: 10.1016/j.eclinm.2022.101779. eCollection 2023 Feb.

Authors

Radhakrishnan Ramchandren¹, Peter Johnson², Nilanjan Ghosh³, Jia Ruan⁴, Kirit M Ardeshna⁵, Roderick Johnson⁶, Gregor Verhoef⁷, David Cunningham⁸, Sven de Vos⁹, Shireen Kassam¹⁰, Luis Fayad¹¹, John Radford¹², Sarah Bailly¹³, Fritz Offner¹⁴, David Morgan¹⁵, Javier Munoz¹⁶, Jerry Ping¹⁷, Edith Szafer-Glusman¹⁷, Karl Eckert¹⁷, Jutta K Neuenburg¹⁷, Andre Goy¹⁸

Affiliations

¹ Division of Hematology/Oncology, University of Tennessee Health Science Center, Knoxville, TN, USA.
² Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton, UK.
³ Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.
⁴ Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
⁵ University College London/UCL Hospitals, Biomedical Research Centre, London, UK.
⁶ Leeds Cancer Centre at St. James's University Hospital, Leeds, UK.
⁷ Department of Haematology, UZ Leuven - Campus Gasthuisberg, Leuven, Belgium.
⁸ Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust - Royal Marsden Hospital, London, UK.
⁹ Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹⁰ Haematology Department, King's College Hospital, London, UK.
¹¹ Department of Lymphoma-Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹² Division of Cancer Sciences, The University of Manchester and the Christie NHS Foundation Trust, Manchester, UK.
¹³ Cliniques Universitaires Saint-Luc, Université Catholique de Louvain Brussels, Brussels, Belgium.
¹⁴ Department of Clinical Hematology, Universitair Ziekenhuis Gent, Ghent, Belgium.
¹⁵ Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹⁶ Department of Hematology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.
¹⁷ Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA, USA.
¹⁸ Department of Hematology & Oncology, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.

Abstract

Background: This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR² regimen) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for stem cell transplantation.

Methods: In phase 2, patients with relapsed/refractory non-germinal centre B-cell-like DLBCL received oral ibrutinib 560 mg once daily and oral lenalidomide 20 mg or 25 mg once daily on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity and intravenous rituximab 375 mg/m² on Day 1 of Cycles 1-6. The primary endpoint was overall response rate (ORR) in the response-evaluable population (received any study treatment and had ≥1 post-baseline disease assessment). The study was done at 24 academic and community hospitals in Belgium, Germany, United Kingdom, and USA. This study was registered with ClinicalTrials.gov, NCT02077166.

Findings: Between March 13, 2014 and October 2, 2018, 89 patients were enrolled with a median time on study of 35.0 months. Best ORR in the response-evaluable population (n = 85) was 49% (95% confidence interval [CI], 38-61) across dose cohorts and 53% (95% CI, 39-67) and 44% (95% CI, 26-62) in the 20 mg and 25 mg lenalidomide cohorts, respectively, with complete responses in 24/85 (28%), 17/53 (32%), and 7/32 (22%) patients, respectively. Grade 3/4 adverse events (AEs) occurred in 81/89 patients (91%), most frequently neutropenia (36/89; 40%), maculopapular rash (16/89; 18%), anaemia (12/89; 13%), and diarrhoea (9/89; 10%). Serious adverse events occurred in 57/89 patients (64%). Fatal AEs occurred in 12/89 patients (13%); causes of death were worsening of DLBCL (n = 7), pneumonia (n = 3), sepsis (n = 1), and cardiac arrest (n = 1).

Interpretation: The most frequent AEs (diarrhoea, neutropenia, fatigue, cough, anaemia, peripheral oedema, and maculopapular rash) were consistent with known safety profiles of the individual drugs. The iR² regimen demonstrated antitumour activity with durable responses in patients with relapsed/refractory DLBCL.

Funding: Pharmacyclics LLC, an AbbVie Company.

Keywords: Diffuse large B-cell lymphoma; Ibrutinib; Lenalidomide; Rituximab.

Associated data

ClinicalTrials.gov/NCT02077166