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Duvelisib improves outcomes in leukemia, lymphoma subtypes
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Duvelisib monotherapy demonstrated significantly longer PFS and higher overall response rates than standard ofatumumab monotherapy among patients with relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma, according to results of the phase 3 DUO trial published in Blood.
“The way we treat patients with CLL is changing rapidly as we move from standard chemotherapy-based approaches to more targeted therapies,” Ian W. Flinn, MD, PhD, director of the lymphoma research program at Sarah Cannon Research Institute, said in a press release.
Duvelisib (Copiktra, Verastem Oncology) — a novel oral PI3K inhibitor — received FDA approval in September for adults with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) after at least two prior therapies based, in part, on results from this study.
In the global, multicenter DUO trial, Flinn and colleagues assessed the efficacy of twice-daily oral duvelisib compared with IV ofatumumab (Arzerra, Novartis) among 319 patients (median age, 69 years; 60% men) with relapsed or refractory CLL or SLL.
Researchers randomly assigned patients 1:1 to duvelisib (n = 160) or ofatumumab (n = 159). PFS as assessed by an independent review committee (IRC) served as the primary endpoint. Secondary endpoints included ORR and OS.
Median time from initial diagnosis was 7.5 years in the duvelisib arm and 6.7 years in the ofatumumab arm. More than half of patients in both arms were at or above Rai stage III at baseline, and all patients had previously received a median of two prior therapies.
At a median follow-up of 22.4 months, median PFS was longer in the duvelisib arm than the ofatumumab arm by both blinded IRC review (13.3 months vs. 9.9 months, HR = 0.52; P < .0001) and investigator assessment (17.6 months vs. 9.7 months; HR = 0.4; P < .0001).
The researchers estimated the probability of PFS as 78% at 6 months and 60% at 1 year with duvelisib, compared with 72% at 6 months and 39% at 1 year with ofatumumab.
Among patients with p17 deletion or TP53 mutations, median PFS by IRC assessment was 12.7 months with duvelisib compared with 9 months with ofatumumab (HR = 0.4; P = .0002). In this subgroup, the estimated probability of PFS was higher at 6 months (73% vs. 63%) and 1 year (55% vs. 30%) with duvelisib.
By investigator assessment, median PFS for this subgroup was 13.8 months with duvelisib and 9.5 months with ofatumumab (HR = 0.41; P = .0003). The estimated probability of PFS was 77% at 6 months and 66% at 1 year with duvelisib vs. 53% at 6 months and 33% at 1 year with ofatumumab.
The ORR according to the IRC review was 73.8% (72.5% partial responses) in the duvelisib arm and 45.3% (44.7% partial responses) in the ofatumumab arm (P < .0001).
According to the researchers, median OS was not reached for either arm. The 1-year probability of survival for both was 86% (HR = 0.99; 95% CI, 0.65-1.5).
At a median treatment duration of 50 weeks with duvelisib vs. 23 weeks with ofatumumab, researchers observed lymph node responses among 85% of patients treated with duvelisib compared with only 15.7% of patients treated with ofatumumab (P < .0001).
Common hematologic adverse events with duvelisib and ofatumumab included neutropenia (33% vs. 21%), anemia (23% vs. 10%) and thrombocytopenia (15% vs. 6%).
The most common nonhematologic adverse events in the duvelisib arm included diarrhea (51%), pyrexia (29%), nausea (23%) and cough (21%).
“For people who face aggressive CLL, there is a continuing need for new advancements and therapies,” Flinn said in the release. “Based on these data, duvelisib may offer a new treatment option for patients who otherwise may have limited options. Through continued research for targeted treatments, we have seen improved response rates and PFS, easing symptoms and improvements in patients’ quality of life.” – by Jennifer Southall
Disclosures: The study was sponsored by Verastem Oncology and Infinity Pharmaceuticals, Inc. Flinn reports funding for trial participation from Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead, Incyte, Infinity, Janssen, KITE, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium and Verastem. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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In the past few years, patients who suffer from CLL have observed that new drugs which are both effective and that can be taken by mouth (instead of by IV infusion) are becoming available for their use. These new drugs are called “targeted agents” and are not typical chemotherapy. The newest of such targeted agents is duvelisib, which Flinn and colleagues have just introduced. Physicians treating CLL, now, will have one more drug to choose from when they are faced with someone whose disease has returned after they already have been treated a couple of times.
This new drug is clearly effective in controlling active CLL and the side effects are tolerable. This new addition to our armamentarium is most welcome, because we know that patients are known to develop resistance to most of the currently used agents. Clinicians know that when a large randomized multi-institutional study at phase 3 level proves that a new drug clearly emerges as superior to the control arm — in this case an effective and FDA-approved anti-CD20 monoclonal antibody, ofatumumab — the next step was for the FDA to give its approval for duvelisib. Then clinicians around the country now will, cautiously, start using duvelisib in their practice and start to develop their own hands-on experience.
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