As reported in Blood by Ian W. Flinn, MD, PhD, Director of the Lymphoma Research Program at Sarah Cannon Research Institute, and colleagues, the phase III DUO trial has shown significantly prolonged progression-free survival with the phosphoinositide 3-kinase (PI3K)-δ/γ inhibitor duvelisib (Copiktra) vs ofatumumab (Arzerra) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).1 Outcomes in a subgroup in this trial with two or more prior therapies supported the September 2018 approval of duvelisib in the treatment of relapsed or refractory CLL or SLL.
In the open-label trial, 319 patients from 62 sites in 11 countries were randomly assigned between January 2014 and December 2015 to receive oral duvelisib at 25 mg twice daily (n = 160) or intravenous ofatumumab (n = 159). Duvelisib was given in 28-day cycles except for the first cycle of 21 days to align with ofatumumab infusions. Ofatumumab was given at an initial dose of 300 mg followed 1 week later by 2,000 mg once weekly for 7 doses and then 2,000 mg once every 4 weeks for 4 additional doses.
Randomization was stratified by the presence or absence of chromosome 17p13.1 deletions such as del(17p), grade 4 cytopenia, and refractoriness or early relapse to purine analog-based therapy. Patients had to have measurable disease, defined as at least 1 lymph node or tumor mass measuring > 1.5 cm. The primary endpoint was progression-free survival on independent review committee assessment.
For the duvelisib vs ofatumumab groups, the median patient age was 69 years in both; 60% were male in both; 7% vs 10% had an Eastern Cooperative Oncology Group performance status of 2; 97% vs 99% had CLL; the median time from diagnosis was 7.5 vs 6.7 years; Rai stage was at least III in 56% in both; 46% vs 45% had bulky disease (≥ 5-cm target lesion); 11% in both had grade 4 cytopenia; refractory or early relapse to purine therapy occurred in 31% vs 30%; and del(17p) was present in 21% vs 28%, TP53 mutation was present in 20% vs 18%, and either or both were present in 31% vs 33%. Patients in both groups had received a median of two prior therapies.
The median follow-up was 22.4 months. The median progression-free survival on independent review committee review was 13.3 months in the duvelisib group vs 9.9 months in the ofatumumab group (hazard ratio [HR] = 0.52, P < .0001). Progression-free survival was 78% vs 72% at 6 months and 60% vs 39% at 12 months. On investigator assessment, the median progression-free survival was 17.6 months vs 9.7 months (HR = 0.40, P < .0001). The median progression-free survival on independent review committee assessment was 12.7 vs 9.0 months (HR = 0.40, P = .0002) among patients with del(17p)/TP53 mutation; progression-free survival was 73% vs 63% at 6 months and 55% vs 30% at 12 months in this subgroup. Hazard ratios also favored duvelisib in all other subgroups examined, including patients with refractory or early relapse (HR = 0.51, 95% confidence interval [CI] = 0.27–0.96), those who had received anticancer therapy within the past 12 months (HR = 0.40, 95% CI = 0.24–0.66), and the small subgroup with grade 4 cytopenia at baseline (HR = 0.14, 95% CI = 0.03–0.71).
Objective response rates were 73.8% in the duvelisib group vs 45.3% in the ofatumumab group (P < .0001), with lymph node response rates of 85.0% vs 15.7% (P < .0001). The median overall survival was not reached in either group, with both groups having a 12-month overall survival of 86%.
The median duration of treatment was 50 weeks in the duvelisib group vs 23 weeks in the ofatumumab group. The most common adverse events of any grade occurring in at least 10% of the duvelisib group were diarrhea (51% vs 12% in the ofatumumab group), neutropenia (33% vs 21%), pyrexia (29% vs 10%), nausea (23% vs 11%), anemia (23% vs 10%), and cough (21% vs 14%). Grade ≥ 3 adverse events occurred in 87% of the duvelisib group vs 48% of the ofatumumab group, with the most common side effects in the duvelisib group including neutropenia (30% vs 17%), diarrhea (15% vs 1%), pneumonia (14% vs 1%), anemia (13% vs 5%), and colitis (12% vs 1%).
[The] combined safety and efficacy results [of the DUO trial] suggest that duvelisib monotherapy may offer an effective treatment for patients with CLL/SLL in need of additional therapeutic options.— Ian W. Flinn, MD, PhD
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Serious adverse events occurred in 73% vs 32% of patients, with the most common side effect in the duvelisib group consisting of pneumonia (15% vs 3%), colitis (12% vs 1%), diarrhea (10% vs 1%), febrile neutropenia (6% vs 2%), pyrexia (4% vs 1%), and pneumonitis (4% vs 0%). Adverse events led to treatment discontinuation in 35% vs 4% of patients, with the most common causes in the duvelisib group being colitis and diarrhea (5% each). Adverse events led to death in 19 patients in the duvelisib group (12%), with 4 deaths considered related to study treatment. Adverse events led to death in 7 patients in the ofatumumab group (5%), with none of the deaths considered treatment-related.
The investigators concluded: “Given the unfortunate reality that many patients have or acquire resistance or intolerance to currently available targeted therapies, or have comorbidities that may preclude their safe use, there remains a critical medical need for additional, novel, targeted therapies for patients with [relapsed or refractory] CLL/SLL, especially those with del(17p)/TP53 mutations. [The] combined safety and efficacy results [of the DUO trial] suggest that duvelisib monotherapy may offer an effective treatment for patients with CLL/SLL in need of additional therapeutic options.” ■
DISCLOSURE: The study was supported by Verastem Oncology and Infinity Pharmaceuticals, Inc. For full disclosures of the study authors, visit www.bloodjournal.org.
1. Flinn IW, Hillmen P, Montillo M, et al: The phase 3 DUO trial: Duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood. October 4, 2018 (early release online).
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The phase III DUO trial, reported by Flinn et al and reviewed in this issue of The ASCO Post, has...