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Idelalisib, ibrutinib combination regimens beneficial in relapsed/refractory CLL
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NEW YORK — Two large randomized, phase 3 trials clearly demonstrated the benefit of using B-cell receptor pathway inhibitors as part of combination treatment for patients with relapsed/refractory chronic lymphocytic leukemia, according to a presenter at Lymphoma & Myeloma 2015.
“These trials are different from the studies the respective pharmaceutical companies embarked upon, which demonstrated that these drugs as single agents are uniquely effective,” Kanti R. Rai, MD, chief of the CLL research and treatment program at North Shore-LIJ Cancer Institute and a HemOnc Today Editorial Board member, said during a presentation. “The question became whether their use singly was less effective than when used in combination.”
Kanti R. Rai
The first study compared idelalisib (Zydelig, Gilead), a PI3 kinase inhibitor, plus ofatumumab (Arzerra, Novartis) — a human anti-CD20 monoclonal antibody — with ofatumumab alone in patients with relapsed/refractory CLL.
Jones and colleagues randomly assigned 174 patients to the combination and 87 patients to ofatumumab alone.
PFS served as the primary endpoint and overall response rate served as a secondary endpoint. The median observation periods were 11.1 months in the combination arm and 5.3 months in the ofatumumab monotherapy arm.
Results showed patients assigned the combination achieved significantly longer median PFS (16.3 months vs. 8 months; adjusted HR = 0.27; 95% CI, 0.19-0.39).
Researchers reported a considerably higher overall response rate (75% vs. 18%) in the combination arm (OR = 15.9; 95% CI, 7.8-32.6). This was driven almost entirely by partial responses. One patient assigned the combination achieved complete response, and no complete responses occurred in the ofatumumab monotherapy arm.
The combination also conferred a significant advantage in median PFS among patients with deletion 17p or TP53 mutations (13.7 months vs. 5.8 months; adjusted HR = 0.32; 95% CI, 0.18-0.57).
A higher percentage of patients assigned idelalisib plus ofatumumab experienced any-grade anemia (43% vs. 40%), grade 3 or higher anemia (17% vs. 12%), any-grade neutropenia (71% vs. 58%), grade 3 or higher neutropenia (47% vs. 33%) and any-grade thrombocytopenia (34% vs. 24%).
However, the overall safety profile of the combination was manageable, with a similar risk–benefit ratio observed in prior studies of patients with relapsed CLL, Rai said.
“There is clear-cut superiority for the combination,” Rai said. “There is hardly any complete remission, even with the combination, but that is not surprising because these are poor-prognosis patients. But to have such a sizable portion of patients with partial remission is, in itself, a major achievement. There is no question that idelalisib plus ofatumumab is a powerful salvage therapy for relapsed, refractory CLL.”
Rai also provided an overview of the HELIOS study, a phase 3 placebo-controlled trial that included 578 patients with previously treated CLL or small lymphocytic lymphoma.
In that study, Chanan-Khan and colleagues randomly assigned half of the patients to 420 mg daily ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton’s tyrosine kinase inhibitor, plus bendamustine (Treanda, Teva) and rituximab (Rituxan; Genentech, Biogen Idec). The other half received placebo plus bendamustine and rituximab.
Treatment continued for a maximum of six cycles, until progressive disease or unacceptable toxicity. Those assigned to bendamustine and rituximab alone were allowed to cross over to the ibrutinib regimen after confirmed progressive disease.
Results showed the combination was “impressively superior” to bendamustine and rituximab alone, Rai said.
PFS as assessed by independent review committee served as the primary endpoint. Secondary endpoints included overall response rate, OS, rate of minimal residual disease-negative response and safety.
The independent review committee analysis showed longer median PFS (not reached vs. 13.3 months; HR = 0.2; 95% CI, 0.15-0.27) in the ibrutinib arm. Overall response rates were higher with the ibrutinib combination as assessed by the independent review committee (82.7% vs. 67.8%; P < .0001) and by investigators (86.2% vs. 68.9%; P < .0001).
Results showed a trend toward improved OS in the ibrutinib arm (HR = 0.62; 95% CI, 0.38-1.02), but OS results were confounded because patients were allowed to cross over to single-agent ibrutinib.
A significantly higher percentage of patients assigned ibrutinib achieved minimal residual disease negativity (12.8% vs. 4.8%; P = .0011).
“This is quite extraordinary and gives us a great deal of encouragement about the combination of ibrutinib with chemoimmunotherapy in relapsed/refractory disease,” Rai said.
Researchers observed three cases of Richter’s transformation in the combination arm and none in the control arm.
No new safety signals emerged when ibrutinib was combined with bendamustine and rituximab.
Patients assigned ibrutinib experienced higher rates of any-grade neutropenia (58.2% vs. 54.7%), grade 3 or grade 4 neutropenia (53.7% vs. 50.5%) and any-grade thrombocytopenia (30.7% vs. 24.4%). Incidence of non-hematologic adverse events was comparable between treatment arms. – by Mark Leiser
References:
Rai KR, et al. Integration of new and old therapies in CLL. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York.
Jones AJ, et al. Abstract 7023. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Chanan-Khan AAA, et al. Abstract LBA7005. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Rai reports medical advisory board roles with Celgene, Genentech/Roche, Gilead and Pharmacyclics.