Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL

Abstract

The outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is poor, particularly in patients ineligible for stem cell transplantation or who fail induction therapy or salvage therapy. The phase 1b portion of this open-label, dose-escalation (3+3+3 design) study examined the maximum tolerated dose (MTD) and preliminary safety and activity of the regimen in transplant-ineligible adults with histologically confirmed relapsed/refractory DLBCL after at least 1 prior therapy. Patients received once-daily 560 mg ibrutinib, 375 mg/m2 intravenous rituximab day 1 of cycles 1 to 6, and 10, 15, 20, or 25 mg lenalidomide days 1 to 21 of each 28-day cycle. Forty-five patients were treated; median time since diagnosis was 14.1 months, and 51% of the patients had non-germinal center B-cell-like (non-GCB) DLBCL, 33% had transformed DLBCL, 60% were refractory, and 27% were primary refractory. Because of dose-limiting toxicities, a de-escalation cohort (10 mg lenalidomide) was initiated, and with subsequent re-escalation up to 25 mg lenalidomide, the MTD was not reached. In response-evaluable patients, the overall response rate (ORR) was 44% (complete response [CR], 28%); among them, the ORR was 65% (CR, 41%) in non-GCB and 69% and 56% in relapsed (n = 16) and secondary refractory (n = 27) disease, respectively. Overall and for non-GCB, median response duration was 15.9 months, with 2 patients receiving therapy beyond 3 years. Phase 2 was initiated with 20 mg lenalidomide in relapsed/refractory non-GCB, whereas the phase 1b 25-mg lenalidomide cohort was being completed; an additional 25-mg cohort in phase 2 is currently ongoing. This study was registered at www.clinicaltrials.gov as #NCT02077166.

Conflict of interest statement

Conflict-of-interest disclosure: A.G. received research funding through institutional clinical studies and received research funding, consulting fees, speaker’s fees, and other honoraria from Acerta, Genentech, Gilead, Janssen, Kite Pharma, Takeda, and Pharmacyclics LLC, an AbbVie Company, and has stock ownership and a leadership role in Clinical Outcome Tracking Analysis. R.R. received consulting fees from Pharmacyclics LLC, an AbbVie Company, and received research funding from Janssen and Pharmacyclics LLC, an AbbVie Company. N.G. received research funding from Celgene, Genentech, Janssen, SGN, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; consulting fees from Celgene, Gilead, Janssen, SGN, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company; speaker’s fees from AstraZeneca, BMS, Gilead, Janssen, SGN, and Pharmacyclics LLC, an AbbVie Company; and honoraria from AstraZeneca, BMS, Gilead, Janssen, SGN, TG Therapeutics, and Pharmacyclics LLC, an AbbVie Company. J.M. received consulting fees from Gilead, Celgene, Kyowa, Seattle Genetics, Alexion, Bayer, Bristol-Myers Squibb, Janssen, Juno, Kite Pharma, Pfizer, and Pharmacyclics LLC, an AbbVie Company; honoraria from Kyowa and Seattle Genetics; and speaker’s fees from AstraZeneca, Bayer, Gilead, Janssen, Kite Pharma, and Pharmacyclics LLC, an AbbVie Company. D.S.M. has stock ownership in Biogen, Eli Lilly, Gilead, Johnson & Johnson, Merck, Novo Nordisk, Pfizer, Vertex, and Zoetis. N.H.D. received research funding from Eisai and Pharmacyclics LLC, an AbbVie Company. M.K. received research funding from Genentech, Merck, and Pharmacyclics LLC, an AbbVie Company, and consulting fees from Kite Pharma and Incyte. E.K. is employed by Comprehensive Cancer Centers of Nevada. J.P. and J.K.N. are employed by Pharmacyclics LLC, an AbbVie Company; J.P. additionally has stock ownership in AbbVie. D.M.B. has employment and leadership roles with, research funding from, stock ownership in, and travel/accommodation expenses from AbbVie and Pfizer, and has patents/royalties with AbbVie. J.R. received research funding from Celgene, Seattle Genetics, and Pharmacyclics LLC, an AbbVie Company; and received honoraria and consulting fees from AstraZeneca, Celgene, Janssen, and Seattle Genetics. M.D. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Phase 1b schema and treatment duration. The phase 1b treatment schema is presented in panel A. Data on treatment duration are presented in panel B for patients in the all-treated population, with each bar representing an individual patient. Patients are ordered by the study initial dose date and color-coded by DLBCL subtype. The indicated lenalidomide dose was given in combination with 560 mg/day ibrutinib and 375 mg/m2 IV rituximab. PO, per os.

Figure 2.

Best response. Data are presented for patients in the response-evaluable population by dose cohort (A) and by DLBCL subtype/category (B). Five patients with non-GCB DLBCL treated with 15 mg lenalidomide (cohort 1, n = 3; cohort 1+, n = 2) were nonevaluable for response, and a sixth patient (20 mg lenalidomide) died of DLBCL after 5 days of treatment. The response-evaluable population included patients who had measurable disease at baseline and at least 1 posttreatment disease assessment by the investigator. LEN, lenalidomide; RTX, rituximab.

Figure 3.

Maximum percentage reduction in tumor size. Data are presented for patients in the all-treated population who had a baseline and at least 1 postbaseline tumor assessment. The number next to each bar indicates the dose cohort (ie, lenalidomide dose) for that patient. // indicates values greater than 100% (112%, 153%, and 414%). SPD, sum of the product of the diameters.