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 J. Johnson, Gregor Verhoef, David Cunningham, Sven de Vos, Shireen Kassam, Luis Fayad, John Radford, Sarah Bailly, Fritz Offner, David Morgan, Javier Muñoz, Jerry Ping, Edith Szafer‐Glusman, Karl Eckert, Jutta K. Neuenburg, André Goy
Abstract
Background This phase 1b/2 PCYC-1123-CA study evaluated efficacy and safety of the combination of ibrutinib, lenalidomide, and rituximab (iR 2 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/m 2 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 iR 2 regimen demonstrated antitumour activity with durable responses in patients with relapsed/refractory DLBCL. Funding Pharmacyclics LLC, an AbbVie Company.