In the phase III DUO trial, treatment with the oral phosphoinositide 3-kinase (PI3K) dual inhibitor duvelisib improved progression-free survival (PFS) and overall response, compared with ofatumumab, in patients with relapsed and refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to results published in Blood.
The findings from this study supported the U.S. Food and Drug Administration’s approval of duvelisib for the treatment of patients with relapsed or refractory CLL/SLL who have received at least two prior therapies.
In this global, multicenter, randomized, open-label trial, Ian W. Flinn, MD, PhD, from Sarah Cannon Research Institute and Tennessee Oncology, and authors compared the efficacy and safety of single-agent duvelisib or ofatumumab in 319 patients (median age = 69 years; range = 39-90 years). Participants were enrolled between January 2014 and December 2015. All patients were required to have active disease necessitating treatment that had progressed during or relapsed after at least one previous CLL/SLL therapy. People who received prior treatment with a Bruton tyrosine kinase or PI3K inhibitor or who were refractory to prior ofatumumab therapy were excluded from the analysis.
Patients were randomized 1:1 to receive either:
- oral duvelisib 25 mg twice daily (n=160)
- intravenous ofatumumab at a starting dose of 300 mg, then weekly and monthly doses of 2,000 mg (n=159)
The median number of prior therapies was two in each arm (range not reported), and most patients had previously received an alkylating agent (93% in the duvelisib arm and 95% in the ofatumumab arm), a monoclonal antibody (78% and 83%, respectively), and/or a purine analog (60% and 71%, respectively).
Approximately one-third of patients in each arm had del17p and/or TP53 mutation (31% and 33%), while approximately two-thirds had unmutated IGHV status (69% and 73%).
At a median follow-up of 22.4 months (range not provided), the median PFS, determined by blinded independent review committee (IRC), was significantly longer in the duvelisib group: 13.3 months vs. 9.9 months (hazard ratio [HR] = 0.52; p<0.001). Duvelisib also was associated with higher six- and 12-month PFS rates:
- 6-month PFS: 78% for duvelisib vs. 72% for ofatumumab
- 12-month PFS: 60% for duvelisib vs. 39% for ofatumumab (p values not reported)
Duvelisib treatment also extended PFS in multiple predefined CLL/SLL subgroups, including patients with high-risk cytogenetic markers (TABLE).
More patients in the duvelisib group responded to treatment, compared with those in the ofatumumab group, on IRC assessment: 73.8 percent vs. 45.3 percent (p<0.0001). In the duvelisib arm, nearly all of these were partial responses (PR; 72.5%), except for one patient achieving a complete response (CR) (0.6%) and another achieving a PR with lymphocytosis (0.6%).
Responses on the ofatumumab arm were also predominantly PRs (44.7%), with one CR (0.6%).
“Duvelisib treatment was particularly effective in targeting the lymph node disease compartment, with a lymph node response by IRC assessment of 85.0 percent, compared to 15.7 percent in the ofatumumab arm (p<0.001),” the investigators reported.
Median overall survival was not reached on either treatment arm, with a 12-month OS rate of 86 percent in both groups (HR=0.99; 95% CI 0.65-1.50; p value not provided).
Median treatment exposure was twice as long in the duvelisib-treated patients than in the ofatumumab- treated patients (median duration = 50 weeks vs. 23 weeks), which resulted in a longer adverse event (AE)–reporting period for duvelisib.
AEs led to treatment discontinuation in 43 patients in the duvelisib arm and 6 patients in the ofatumumab arm.
The most common hematologic AEs with duvelisib and ofatumumab included: neutropenia (33% and 21%, respectively), anemia (23% and 10%), and thrombocytopenia (15% and 6%). The most common nonhematologic AEs included: diarrhea (51% and 19%), pyrexia (29% and 10%), nausea (23% and 11%), and cough (21% and 14%).
Eighty-seven percent of duvelisib-treated patients experienced a grade ≥3 AE (most commonly neutropenia, diarrhea, pneumonia, and anemia), while 48 percent of ofatumumab-treated patients experienced a grade ≥3 AE. In the ofatumumab arm, only neutropenia (17%) occurred in more than 10 percent of patients.
“Incidences of neutropenia, diarrhea, colitis, transaminase elevations, pneumonitis, and rash with duvelisib therapy were moderate and manageable with early intervention and dose modification as required per protocol,” the researchers wrote, adding that these immune-mediated toxicities infrequently led to duvelisib discontinuation.
There were 19 fatal AEs on the duvelisib arm, four of which were deemed treatment-related; in the ofatumumab arm, seven patients had fatal AEs, although none were attributed to treatment.
“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 … need for additional, novel, targeted therapies for patients with relapsed/refractory CLL/SLL, especially those with del17p/TP53 mutations,” wrote the study authors. “These combined safety and efficacy results suggest that duvelisib monotherapy may offer an effective treatment for CLL/SLL patients in need of additional therapeutic options.”
However, the researchers noted that while duvelisib compared favorably with single-agent ofatumumab, “ofatumumab for the treatment of relapsed CLL has diminished in recent years, being supplanted by newer agents that target the B-cell receptor pathway,” they wrote, which may limit the applicability of this study’s findings.
The authors report financial relationships with Verastem Oncology and Infinity Pharmaceuticals, which supported the trial.
Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 October 4. [Epub ahead of print]