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Secura Bio, Inc. has decided to voluntarily withdraw the indication of duvelisib for use in patients with relapsed or refractory follicular lymphoma following at least 2 previous systemic therapies.
Secura Bio, Inc. has decided to voluntarily withdraw the indication of duvelisib (Copiktra) for use in patients with relapsed or refractory follicular lymphoma following at least 2 previous systemic therapies.1
The FDA granted an accelerated approval to the agent for use in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) or relapsed/refractory follicular lymphoma September 2018 based on data from the phase 3 DUO trial (NCT02004522) and the phase 2 DYNAMO trial (NCT01882803).2
Results from DUO showed that duvelisib resulted in a 60% reduction in the risk of disease progression or death vs ofatumumab (Arzerra) in patients with relapsed/refractory CLL/SLL who previously received at least 2 lines of therapy. The median progression-free survival (PFS) was 16.4 months in the investigative arm compared with 9.1 months in the control arm (HR, 0.40). Duvelisib elicited an ORR of 78% vs 39% with ofatumumab.
Data from DYNAMO indicated that the agent elicited an overall response rate (ORR) of 42% (95% CI, 31%-54%) in patients with follicular lymphoma. Duration of response ranged from 0 months to 41.9 months; 43% of patients maintained their response at 6 months and 17% continued to respond at 12 months.2
The indication for follicular lymphoma came with a requirement that an additional confirmatory trial would be needed for the product to receive full approval.
Secura Bio conducted a strategic evaluation of duvelisib and then subsequently consulted the regulatory agency to discuss the indication. The company decided that the current follicular lymphoma treatment paradigm in the United States, and the logistics, cost, and timing of post-marketing requirements for duvelisib in this disease was no longer merited.
“Secura Bio has determined that a more prudent application of future effort and resource is in new application for T-cell lymphoma where initial data appear encouraging,” the company stated in a press release. “The company is looking forward to working with the FDA and gaining guidance regarding an appropriate regulatory and clinical plan.”
The open-label, multicenter, phase 3 DUO trial enrolled 319 patients with either CLL (n = 312) or SLL (n = 7) who had previously received at least 1 therapy.2 To be eligible for enrollment, patients needed to have hepatic transaminases of ≤ 3 times the upper limit of normal (ULN), a total bilirubin of ≤ 1.5 times the ULN, and serum creatinine of ≤ 2 times the ULN. Those who previously underwent autologous transplant within 6 months or allogeneic transplant, or who were previously exposed to a PI3K inhibitor or a BTK inhibitor, were excluded.
Study participants were randomized 1:1 to receive either duvelisib at a dose of 25 mg twice daily until progressive disease or intolerable toxicity or ofatumumab for 7 cycles. Those in the control arm received ofatumumab at an initial dose of 300 mg, followed 1 week later by 2000 mg once weekly for 7 doses, and then 2000 mg once weekly for 4 additional doses.
In a subset of patients, 95 who received duvelisib and 101 who received ofatumumab, the median age was 69 years (range, 40-90), 59% were male, and 88% had an ECOG performance status of 0 or 1. Moreover, 46% of patients previously received 2 prior lines of treatment, and 54% received 3 prior lines. Fifty-two percent of patients had at least 1 tumor that was 5 cm or larger at baseline, and 22% of patients had tumors that harbored 17p deletion.
Key efficacy end points focused on PFS per independent review committee and ORR.
Patients in the investigative arm had a median exposure to duvelisib was 13 months (range, 0.2-37). Eighty percent of patients received at least 6 months of treatment with the agent and 52% received the agent for at least 1 year. Those in the control arm had a median drug exposure of 5 months (range, < 0.1-6).
The safety analysis of the trial looked at the total study population, which was comprised of 313 patients who received treatment; of these patients, 158 were given duvelisib and 155 received ofatumumab. The most common adverse effects reported with duvelisib, which were reported in 20% or more of patients, included diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia, and cough.
Twelve percent of patients who received duvelisib experienced fatal adverse reactions vs 12% of those who were given ofatumumab. Seventy-three percent of patients who received duvelisib experienced serious adverse reactions; 38% of these patients experienced infection and 23% reported diarrhea or colitis.
Twenty-nine percent of patients in the investigative arm required dose reductions because of toxicities. Moreover, 36% of patients discontinued treatment with duvelisib, mostly because of diarrhea or colitis, infection, and rash.
The single-arm, multicenter DYNAMO trial enrolled previously treated patients with follicular lymphoma who were refractory to rituximab (Rituxan) and to either chemotherapy or radioimmunotherapy. Patients with grade 3b follicular lymphoma, large cell transformation, or who previously underwent an allogeneic transplant or were previously exposed to a PI3K or BTK inhibitor, were excluded.
Study participants were given duvelisib at a twice daily dose of 25 mg (n = 83). The median age of these patients was 64 years (range, 30-82), 68% were male, and 37% had bulky disease at baseline. Moreover, the median number of prior lines of therapy received was 3 (range, 1-10), and 94% were refractory to their last therapy. Eighty-one percent of patients were refractory to 2 or more previous lines of treatment. Moreover, 93% of patients had an ECOG performance status of 0 or 1.
Participants who received duvelisib had a median exposure of 5 months (range, 0.4-24); 41% of patients received the agent for at least 6 months and 10% received it for at least 1 year.
Safety was evaluated in 96 patients with relapsed or refractory follicular lymphoma who received duvelisib; these patients were included in a 442-patient safety analysis. Serious toxicities were reported in 58% of patients and included diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis.
The most common toxicities comprised diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.
Twenty-nine percent of patients discontinued treatment with duvelisib because of toxicities, and this most often happened because of diarrhea or colitis and rash. Twenty-three percent of patients needed dose reductions because of adverse effects.
The decision to withdraw the application was not associated with changes in safety and efficacy with the agent, according to Secura Bio, Inc. The decision only impacts the US indication of the agent in relapsed/refractory follicular lymphoma and does not impact other approved indications of the agent in the United States and other countries, including use in adult patients with relapsed or refractory SLL or SLL following at least 2 prior therapies.