Frontline Ibrutinib Plus R-CHOP Misses Primary Endpoint in Phase III DLBCL Trial

Thorsten Graef, MD, PhD

Combining ibrutinib (Imbruvica) with standard R-CHOP did not improve event-free survival versus R-CHOP alone in the first-line setting for patients with diffuse large B-cell lymphoma (DLBCL), missing the primary endpoint of the phase III DBL3001 study.

AbbVie (Pharmacyclics), which codevelops ibrutinib with Janssen Biotech, noted in a press release that, “clinically meaningful improvements were observed in a patient subpopulation that warrant further analysis.” No data from the study were provided, but Abbie reported its intent to share the results at an upcoming medical conference and publish them in a peer-reviewed journal.

"Since its first US FDA approval in 2013, Imbruvica has redefined standard of care in many different blood cancers—several of which had little to no treatment options available to patients before," Thorsten Graef, MD, PhD, Head of Clinical Development at Pharmacyclics LLC, an AbbVie company, said in a statement.

"These medical achievements reflect our objective of focusing research where there is great unmet patient need and understanding that the nature of research is such that some studies succeed and others do not. We continue to believe that ibrutinib has great untapped potential as a cancer treatment alone or in combination. Together with our global partner Janssen, we are advancing our robust ibrutinib scientific development program and anticipate results from several studies in the future."

The phase III Janssen-sponsored DLB-3001 study included 838 patients with newly diagnosed DLBCL who had the non-germinal center B cell (GCB) or activated B-cell (ABC) subtypes of the disease. Patients were randomized to ibrutinib or placebo plus R-CHOP for 6 to 8 twenty-one-day cycles.

Early-stage findings had shown promise that ibrutinib could improve outcomes with standard R-CHOP in patients with non-Hodgkin lymphoma (NHL). Findings from a phase Ib study presented at the 2013 ASCO Annual Meeting showed that the frontline combination of ibrutinib and R-CHOP induced an objective response rate of 100% in patients with NHL.

In the study, the combination led to complete responses in 10 of 15 patients, and the remaining 5 patients had partial responses. Complete responses occurred in all 3 ibrutinib dosages evaluated. The maximum-tolerated dose of ibrutinib was not reached, and no pharmacokinetic interaction occurred between ibrutinib and the individual drugs that constitute R-CHOP.

The primary objective of the phase Ib study was determining the dose for phase II evaluation and identifying dose-limiting toxicities with ibrutinib when used in combination with R-CHOP in patients with previously untreated NHL. Secondarily, investigators wanted to assess the adverse-event profile of the combination, evaluate ibrutinib pharmacokinetics in combination with R-CHOP, and determine overall response rate with the combination.

The study comprised 2 stages of clinical evaluation. During the first stage, which was reported at the ASCO meeting, investigators evaluated dose escalation of ibrutinib in combination with R-CHOP, beginning with 280 mg and increasing to 420 mg and 560 mg in separate cohorts. The stage included patients with mantle cell lymphoma, follicular lymphoma, and DLBCL.

Investigators entered 17 patients into the first stage, and 15 completed the planned six cycles of therapy. One patient discontinued prematurely because of nonadherence and one because of grade 2 gastritis.

Three patients developed dose-limiting toxicity, two in the 280-mg cohort. One patient had a brief episode of syncope and another developed periorbital cellulitis. The third patient was in the 560-mg cohort and discontinued treatment because of gastritis.

The most common adverse events (all grades) were neutropenia (n = 14), thrombocytopenia (n = 14), nausea (n = 13), vomiting (n = 11), anemia (n = 8), headache (n = 7), diarrhea (n = 6), constipation (n = 4), fatigue (n = 7), and infusion-related reaction (n = 6).

The most frequent grade 3/4 adverse events were neutropenia (15), thrombocytopenia (7), anemia (5), and syncope (3). Two patients (both in the 280-mg cohort) developed febrile neutropenia during a cumulative total of 91 cycles of therapy among the 17 patients entered into the dose-finding stage.

Younes A, Flinn I, Berdeja JG, et al. Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL). J Clin Oncol. 2013;31(suppl; abstr 8502).