Verastem, focused on discovering and developing drugs to improve the survival and quality of life of cancer patients, announced the presentation of the results from the Phase 3 DUO study evaluating the efficacy and safety of duvelisib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) at the American Society of Hematology (ASH) 2017 Annual Meeting held December 9-12, 2017 in Atlanta. Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma which is currently being developed for the treatment of CLL/SLL and follicular lymphoma (FL). In addition, duvelisib is being studied in other hematologic malignancies including peripheral T cell lymphoma (PTCL).
“In the Phase 3 DUO study, oral duvelisib monotherapy achieved a statistically significant improvement in Progression-Free Survival (PFS) versus the approved standard of care treatment ofatumumab, along with a well characterized and manageable safety profile, in patients with previously treated CLL/SLL,” said Ian Flinn, MD, PhD, Director of the Blood Cancer Research Program at Sarah Cannon Research Institute and lead investigator of the DUO study. “Similar PFS advantages were also observed across all analyzed patient subgroups, including patients with 17p deletion, a genotype that historically correlates with poorer clinical outcomes. Duvelisib also achieved a statistically significant improvement in Overall Response Rate (ORR) and significantly reduced lymph node burden in the vast majority of patients. These data are encouraging for patients with CLL/SLL who progress or relapse following initial treatment.”
“CLL/SLL mostly affects elderly patients and many are unable or unwilling to be hospitalized or come into the clinic for frequent IV infusions. The CLL/SLL treatment landscape therefore is moving away from chemotherapies and toward more targeted, preferably oral regimens,” said Diep Le, MD, PhD, Chief Medical Officer of Verastem. “While patients are living longer many will be intolerant to, or relapse following, their initial therapy emphasizing the need for new options. Oral duvelisib is the first PI3K inhibitor to show efficacy as an oral monotherapy in a randomized Phase 3 study in patients with relapsed or refractory CLL/SLL and may offer an appealing alternative for patients who have progressed or relapsed. We remain on track to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) during the first quarter of 2018 requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL).”
DUO Efficacy Results
The DUO study met its primary endpoint with oral duvelisib monotherapy achieving a statistically significant improvement in median PFS (mPFS) compared to ofatumumab in patients with relapsed or refractory CLL/ SLL per a blinded Independent Review Committee (IRC) using iwCLL or revised IWG Response Criteria (modified iwCLL/IWG; 13.3 months vs 9.9 months, respectively; HR=0.52; p<0.0001), representing a 48% reduction in the risk of progression or death. Similar efficacy of duvelisib was observed regardless of whether patients had 17p deletion (del[17p]). The primary outcome of mPFS via IRC review in the del[17p] subpopulation significantly favored duvelisib over ofatumumab (12.7 months vs 9.0 months, respectively; HR=0.41; p=0.0011), representing a 59% reduction in the risk of progression or death. Per investigator assessment, duvelisib demonstrated a mPFS of 17.6 months, compared to 9.7 months for ofatumumab (HR=0.40, p<0.0001). Duvelisib maintained a PFS advantage in all patient subgroups analyzed as a subset of pre-specified sensitivity analyses.
The secondary efficacy outcome of ORR via IRC assessment according to modified iwCLL/IWG, significantly favored duvelisib over ofatumumab (73.8% vs 45.3%, respectively; p<0.0001), and reduced lymph node burden >50% in most patients vs ofatumumab (85% vs 16%). In the del[17p] subpopulation of patients, ORR was also significantly higher for duvelisib compared to ofatumumab, 70.0% versus 43.0%, respectively (p=0.0182). The Overall Survival (OS) in the ITT population was similar for those randomized to duvelisib and to ofatumumab during the study (HR=0.99; p=0.4807), demonstrating no detrimental effect on OS and was likely due to other available therapies following progression. Patients who progressed in the DUO study were given option to enroll in a crossover study to receive the opposite treatment. In the optional crossover study, 89 patients who were previously treated with ofatumumab in DUO and experienced disease progression were subsequently treated with duvelisib monotherapy. As in the parent DUO study, duvelisib demonstrated robust clinical activity in this crossover study with an ORR of 73%, a median duration of response of 12.7 months and a mPFS of 15 months by investigator assessments.
DUO Safety Results
Duvelisib monotherapy demonstrated a manageable safety profile, with results from this study consistent with the well-characterized safety profile of duvelisib monotherapy in patients with advanced hematologic malignancies in previous studies. For duvelisib-treated patients, the median time on treatment was 50.3 weeks (range, 0.9 – 160.0) compared to 23.1 weeks (range, 0.1 – 26.1) for ofatumumab. The most common Grade ≥3 treatment-emergent hematologic adverse events (occurring in >10% of patients) were neutropenia (30%) and anemia (13%). The most common Grade ≥3 non-hematologic treatment-emergent adverse events (occurring in >10% of patients) were diarrhea (15%), pneumonia (14%) and colitis (12%). The rate of severe opportunistic infections was 6%, including 2 patients (1%) with Pneumocystis jirovecii pneumonia (PJP), neither of whom was on prophylaxis for PJP at the time of the event. 35% of patients discontinued duvelisib treatment due to an adverse event; ~40% of patients treated with duvelisib remained on treatment for over 18 months, with a median total follow-up of nearly 2 years. Adverse Events of Interest infrequently led to discontinuation of duvelisib treatment (e.g., diarrhea (5.1%), colitis (5.1%), pneumonitis (1.9%), neutropenia (1.3%), pneumonia (1.3%), transaminase elevations (0.6%), and rash (0.6%). Duvelisib treatment-related AEs leading to death (n=4) include general physical health deterioration (n=1); pneumonia staphylococcal (n=2) and sepsis (n=1)).
A copy of the DUO oral presentation will be available here following the conclusion of the session.
Regulatory Plan
Verastem plans to submit a NDA to the U.S. FDA requesting full approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory FL. The Company expects to submit the duvelisib NDA during the first quarter of 2018. Along with the clinical data from the DUO study, the duvelisib NDA submission will also contain the results from the Phase 2 DYNAMO™ study in patients with indolent non-Hodgkin’s lymphoma that are double-refractory to both rituximab and chemotherapy or radioimmunotherapy.
About the Phase 3 DUO Study Design
In the Phase 3 DUO study, 319 patients were randomized 1:1 to receive either duvelisib 25mg orally twice daily or ofatumumab monotherapy, an approved standard of care treatment for use in CLL/SLL, per its label with an initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg. In addition to the primary endpoint of PFS per IRC in the ITT population, additional analyses to evaluate the outcome in several patient subgroups, including those with 17p deletion CLL/SLL, a known poor prognostic subgroup, were also conducted. PFS and other efficacy endpoints were analyzed using response determinations per the IRC using modified iwCLL/IWG criteria.
