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Duvelisib extends PFS in relapsed or refractory chronic lymphocytic leukemia
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ATLANTA — Duvelisib significantly prolonged PFS compared with ofatumumab among patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, according to results of the DUO trial presented at ASH Annual Meeting and Exposition.
Researchers observed PFS advantages in all analyzed subgroups, including patients with 17p deletion, a genotype often associated with poor prognosis.
Duvelisib (Verastem) — a first-in-class oral dual inhibitor of PI3K-delta and PI3K-gamma in development for advanced B-cell malignancies — also exhibited a manageable safety profile.
“The results support duvelisib oral monotherapy as a potential new and convenient treatment option for previously treated patients with CLL and small lymphocytic lymphoma,” Ian W. Flinn, MD, PhD, director of the blood cancer research program at Sarah Cannon Research Institute, said during his presentation.
Novel targeted therapies have greatly improved outcomes for patients with CLL or small lymphocytic leukemia; however, the disease remains incurable and many patients relapse. Effective therapies that target novel pathways are needed for patients with relapsed or refractory disease.
Results of a phase 1 study of duvelisib monotherapy for 55 patients with relapsed/refractory CLL or small lymphocytic lymphoma showed a 56% overall response rate, with one patient achieving complete response.
The randomized phase 3 DUO trial included 319 patients (median age, 69 years; range, 39-90; 60% men; 92% white) with relapsed or refractory CLL or small lymphocytic lymphoma treated at one of 59 sites around the world.
Patients had undergone a median two prior therapies (range, 1-10), and 33% had received three or more prior therapy. Nearly all patients (94%) had received prior alkylator therapy (cyclophosphamide, 65%; bendamustine, 38%; chlorambucil, 36%). Most had received rituximab (Genentech, Biogen; 80%) and purine analogue therapy (66%).
A median 20 months (range, 0.5-149) had elapsed since their last anticancer therapy; 36% completed their last therapy within the prior 12 months.
All patients had ECOG scores of 0 to 2, and had baseline platelet counts of at least 10 G/L.
Researchers randomly assigned 160 patients to duvelisib 25 mg twice daily. The other 159 patients received ofatumumab (Arzerra, Novartis), administered at a 300-mg IV infusion on day 1, followed by 2,000 mg via IV once weekly for 7 weeks, and then monthly for 4 months.
A comparable number of patients in each group (31 for duvelisib, 33 for ofatumumab) had 17p deletion and/or TP53 mutation.
The majority of patients in the duvelisib (n = 97) and ofatumumab (n = 99) groups had CLL.
Upon disease progression, patients were allowed to participate in an optional crossover study. Eight patients initially assigned duvelisib crossed over to ofatumumab, administered on the same dosing schedule followed in DUO. Eighty-nine patients initially assigned ofatumumab crossed over to duvelisib 25 mg twice daily.
PFS as assessed by blinded independent review committee served as the primary endpoint. Key secondary endpoints included ORR, duration of response, OS and safety.
Duvelisib-treated patients achieved significantly longer median PFS as assessed by independent review committee (13.3 months vs. 9.9 months; HR = 0.52; P < .0001) and investigator assessment (17.6 months vs. 9.7 months; HR = 0.4; P < .0001).
The median PFS benefit persisted in an independent review committee assessment of patients with 17p deletion (12.7 months vs. 9 months; HR = 0.41; P = .0011).
Independent review committee assessment also showed a higher ORR among duvelisib-treated patients in the entire cohort (73.8% vs. 45.3%; P < .0001) and in the subset of patients with 17p deletion (70% vs. 43%; P = .0182). A higher percentage of duvelisib-treated patients achieved 50% or greater decrease in sum of the products of diameters of target lymph nodes from baseline (85% vs. 15.7%).
Median OS did not differ significantly between the duvelisib and ofatumumab groups (not estimable vs. not estimable; HR = 0.99). However, Flinn emphasized many patients received a subsequent anticancer therapy. Also, among the 89 patients who were initially assigned ofatumumab and crossed over to duvelisib, researchers reported a 73% ORR and median PFS of 15 months.
An adverse event analysis was performed after a median observation period of 50 weeks for the duvelisib group and 23 weeks for the ofatumumab group. The adverse event profile of duvelisib appeared consistent with that observed in prior studies, Flinn said.
Duvelisib-treated patients experienced higher rates of neutropenia (all grade, 33% vs. 20%; grade 3 or higher, 30% vs. 17%), anemia (all grade, 23% vs. 10%; grade 3 or higher, 13% vs. 5%) and thrombocytopenia (all grade, 15% vs. 6%; grade 3 or higher, 8% vs. 2%).
They also experienced higher rates of grade 3 or higher diarrhea (15% vs. 1%), pneumonia (14% vs. 1%) and colitis (12% vs. 1%).
Six percent of duvelisib-treated patients experienced severe opportunistic infections. These included four cases of bronchopulmonary aspergillosis, two cases each of fungal infection and pneumocystis jiroveci pneumonia, and one case of cytomegalovirus colitis. No severe Herpes zoster infections occurred.
A higher percentage of duvelisib-treated patients discontinued treatment due to adverse events (35% vs. 4%), disease progression (22% vs. 20%), subject withdrawal (8% vs. 5%) and death (8% vs. 2%). However, adverse events of interest — neutropenia, diarrhea, colitis, pneumonia, transaminase elevations, rash and pneumonitis — infrequently led to discontinuation, Flinn said.
Thirty-four patients (22%) assigned duvelisib remained on treatment at data cutoff. – by Mark Leiser
For more information:
Flinn IW, et al. Abstract 493. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Flinn reports research funding from AbbVie, Acerta, Agios, Celgene, Curis, Genentech, Gilead, Incyte, Infinity, Janssen, Kite Pharma, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium, Verastem and other pharmaceutical companies. Please see the abstract for all other authors’ relevant financial disclosures.