Two analyses of the phase II DUO trial show that modifying the dosage of duvelisib or interrupting treatment in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, does not compromise outcomes or increase toxicity.
Ian W. Flinn, MD
Two analyses of the phase II DUO trial show that modifying the dosage of duvelisib (Copiktra) or interrupting treatment in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), does not compromise outcomes or increase toxicity.
Additionally, superior progression-free survival as well as durable responses were seen with the PI3K inhibitor compared with the monoclonal antibody, ofatumumab (Arzerra) in heavily pretreated patients. These results, which were presented during the 2019 SOHO Annual Meeting, suggest that duvelisib monotherapy is a viable therapy for a patient population that has limited treatment options.
“Those patients who were dose reduced or if [we] held the drug and waited for the adverse event to resolve, [we] could restart and they would have the same outcomes as people who never had any interruptions,” said Ian W. Flinn, MD, PhD, director of lymphoma research at Sarah Cannon Research Institute. He led 1 study and coauthored the other.
“Doctors and patients, if they have an adverse event, they should not be afraid that something bad is going to happen if they stop the drug. In reality, they should be encouraged to stop the drug or dose reduce so they have a better outcome without the adverse events.”
DUO (NCT02004522) was a randomized phase III superiority trial designed to evaluate the efficacy and safety of duvelisib compared with ofatumumab. At a dose of 25 mg twice daily, the PI3K inhibitor induced superior results for median PFS (13.3 vs 9.9 months; HR, 0.52;P<.0001) and overall response rate (ORR; 74% vs 45%; P<.0001) compared with ofatumumab.1
Based on these data, the FDA approved duvelisib in September 2018 for the treatment of patients with relapsed/refractory CLL/SLL.
In the first study,1led by Flinn, investigators sought to determine whether patients could reduce their duvelisib dose or temporarily discontinue treatment without compromising safety or efficacy.
Most (84%) patients evaluated for response who had ≥1 dose interruption for >1 week or >2 weeks (82%) followed by ≥3 weeks on treatment improved or maintained response. Following dose reduction, 53% of patients maintained treatment response following dose reduction for at least 30 days, 45% of patients maintained response ≥90 days, and 44% maintained response ≥120 days.
Dose interruptions (80%) were more common than reductions (27%). Some patients had multiple interruptions, including 26% who had ≥3. Patients who had dose reductions did so only once; 2 patients required dose re-escalations.
The median time to dose reduction was 5.6 months (range, 1-21.3) among the 25 patients who had a reduction following complete or partial response. The median duration of response at a reduced dose was 3.4 months.
The median duration of exposure was 11.6 months (range, 0.2-36.8) among 158 patients treated with duvelisib. The median overall dose intensity was 97.7 (range, 34.7-100). The median dose intensity was highest during the first 3 months of treatment, then decreased slightly during months 3 to 6.
The median time to onset for treatment-emergent adverse events (TEAEs) ranged from 2.2 to 4.3 months and the median duration of TEAEs of special interestincluding diarrhea, colitis, neutropenia, and cutaneous reactions among others—was up to 4 weeks.
Investigators found that the percentage of patients who experienced TEAEs of special interest remained stable or decreased over time. At 3 to 6 months, the rate of such events was 64% compared with 52% beyond 9 to 12 months.
In the second analysis,2investigators sought to understand the risk/benefit profile for duvelisib in patients with relapsed/refractory CLL/SLL who received ≥2 prior lines of therapy.
At a median overall follow-up of 22.4 months, a blinded independent review committee (IRC) found that median PFS significantly favored patients assigned to duvelisib compared with those assigned to ofatumumab (16.4 vs 9.1 months; HR, 0.4; 95% CI, 0.27-0.59;P<.0001). The median PFS was also superior as observed per investigator assessment (17.8 vs 9.3 months; HR, 0.35; 95% CI, 0.24-0.51; P<.0001).
“The risk-benefit ratio is better in this patient population with 2 prior therapies than it is with 1 prior therapy,” Flinn said. Investigators aren’t sure why that is the case and Flinn said more research is necessary to find an answer.
The subgroup analysis included 196 patients with CLL/SLL who had received ≥2 prior lines of therapy. Among these patients, 95 received 25 mg of oral duvelisib twice daily and 101 patients were assigned to a 300 mg IV initial dose of ofatumumab on day 1, followed by 7 weekly doses of 2000 mg of ofatumumab, and then 4 monthly doses of 2000 mg of ofatumumab. Patients received 12 total doses of duvelisib.
Per IRC assessment, the ORR was significantly higher for patients in the duvelisib arm (79% vs 39%;P<.0001). The same was true for lymph node response (88% vs 14%; P<.0001).
At 12 months, the rate of overall survival was also superior for patients assigned to duvelisib compared with those assigned to ofatumumab (75% vs 70%; HR, 0.82; 95% CI, 0.49-1.37).
Flinn said investigators are working to figure out the best dosing schedule for duvelisib. The schedules used in DUO were based on results from phase I studies conducted 7 years ago. Since then, investigators have come to appreciate the cumulative risk for toxicities associated with the drug. He added that some investigators believe that patients may not need continuous PI3K inhibitors. Instead, intermittent dosing or a high initial dose followed by a lower ongoing dose may be the way forward.