Duvelisib Improves PFS in Phase III CLL Trial

Ian W. Flinn, MD, PhD

Duvelisib reduced the risk of disease progression or death by 48% versus ofatumumab (Arzerra) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in the phase III DUO trial.

In the overall population, the median progression-free survival (PFS) with the PI3K-delta and -gamma inhibitor was 3.4 months longer with duvelisib compared to ofatumumab. In patients with a 17p deletion, the median PFS benefit was 3.7 months.

“Although the treatment of CLL/SLL has advanced in recent years, there remains a substantial unmet need with many patients progressing or relapsing following the available therapies,” lead DUO investigator Ian Flinn, MD, PhD, Director of the Blood Cancer Research Program at Sarah Cannon Research Institute, said in a statement.

“These positive results from the randomized DUO study demonstrate that duvelisib prolongs PFS with a manageable safety profile in patients with relapsed or refractory CLL/SLL, including in high-risk patients with the 17p deletion. For our patients with CLL/SLL, and for the physicians who treat them, a convenient, oral monotherapy that is taken at home would be a valuable addition to the treatment landscape,” added Flinn.

The phase III DUO study randomized 319 patients with CLL/SLL in a 1:1 ratio to duvelisib at 25 mg twice daily until disease progression or unacceptable toxicity, or ofatumumab at 300 mg on day 1, followed by 7 weekly infusions and 4 monthly infusions of 2000 mg.

The median PFS was 13.3 months in the duvelisib arm compared with 9.9 months in the ofatumumab arm (hazard ratio [HR], 0.52; P <.0001). In patients with a 17p deletion, the median PFS was 12.7 versus 9.0 months, respectively (HR, 0.41; P = .0011).

Safety data were consistent with results observed across other studies of single-agent duvelisib in hematologic malignancies, according to Verastem, the manufacturer of the PI3K inhibitor. The company plans to present the complete findings from DUO at a future medical meeting and submit the data for publication in a peer-reviewed journal.

“We are extremely grateful to the patients, caregivers, and investigators who participated in the DUO study and we are pleased to be that much closer to delivering on our mission to develop drugs that improve the lives of patients with cancer,” Robert Forrester, president and CEO of Verastem, said in a statement.

“Both of our late-stage trials with duvelisib monotherapy (DUO and DYNAMO) have now achieved their primary endpoints, highlighting the significant potential of duvelisib in the treatment of advanced hematologic malignancies. We anticipate sharing these results with the FDA in preparation for a potential new drug application filing during the first half of 2018 and look forward to exploring subsequent development opportunities for duvelisib in additional cancers,” added Forrester.

In previously released data from the phase II DYNAMO study, duvelisib demonstrated an overall response rate (ORR) of 46% for patients with indolent non-Hodgkin lymphoma (iNHL).

The study enrolled 129 patients with iNHL, which included follicular lymphoma (n = 83), SLL (n = 28), and marginal zone lymphoma (n = 18). The ORRs in each of these groups, respectively, were 41%, 68%, and 33%. The median duration of response was 9.9 months.

The open-label phase II DYNAMO study, which began enrolling in May 2013, included patients with iNHL who were refractory to rituximab and either chemotherapy or radioimmunotherapy. Continuous duvelisib was administered at 25 mg twice daily.

At a median follow-up of 11.5 months, the median overall survival in the entire iNHL population was 18.4 months and the median PFS was 8.4 months.

The most common grade ≥3 AEs were neutropenia (23%), anemia (12%), thrombocytopenia (10%), and diarrhea (15%). Seventeen percent of patients discontinued duvelisib due to an AE. There were 6 patient deaths related to AEs.

Zinzani P, Wagner-Johnston N, Miller C, et al. DYNAMO: a phase 2 study demonstrating the clinical activity of duvelisib in patients with double-refractory indolent non-Hodgkin lymphoma. Hematol Oncol. 2017;35(52):69-70.