FDA Issues Warning for Increased Risk of Death, Serious AEs with Duvelisib in CLL/SLL

The FDA has warned that treatment with duvelisib (Copiktra) has shown a possible increased risk of death and serious adverse effects (AEs) compared with ofatumumab (Arzerra) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).¹

The warning was based on 5-year survival results from the phase 3 DUO trial (NCT02004522). At a median follow-up of 63 months, data showed that duvelisib elicited a median overall survival (OS) of 52.3 months (95% CI, 41.8-68), compared with 63.3 months (95% CI, 41.2–not estimable) for ofatumumab (HR, 1.09; 95% CI, 0.79-1.51).

Notably, among patients with CLL and SLL who received at least 2 prior lines of treatment, which is the current FDA-approved use of duvelisib, the hazard ratio for death was 1.06 (95% CI, 0.71-1.58).

Additionally, duvelisib was associated with a higher incidence of deaths due to AEs, serious AEs, grade 3 or higher AEs, and treatment modifications. Regarding serious AEs, infections, diarrhea, inflammation of the intestine and/or lungs, skin reactions, and elevated liver enzymes all occurred at a higher frequency in patients who received duvelisib.

“Health care professionals should consider the risks and benefits of continuing [duvelisib] in the context of other available treatments. Advise patients receiving [duvelisib[ of the possible increased risk of death and higher risk of serious AEs,” the FDA wrote in a press release.

In September 2018, the FDA approved duvelisib for the treatment of patients with relapsed/refractory CLL and SLL or relapsed/refractory follicular lymphoma, based on findings from the DUO trial and the phase 2 DYNAMO trial (NCT01882803).² However, in December 2021, Secura Bio withdrew the indication of duvelisib for relapsed/refractory follicular lymphoma in the United States.³

The randomized, open-label DUO trial enrolled 319 patients with relapsed/refractory CLL (n = 312) or SLL (n = 7) who had received at least 1 prior line of therapy. Patients were required to have hepatic transaminases of no more than 3 times the upper limit of normal (ULN), a total bilirubin of no more than 1.5 times the ULN, and serum creatinine of no more than 2 times the ULN.⁴ Patients who underwent autologous stem cell transplant within 6 months of enrollment or an allogeneic stem cell transplant at any point were excluded. Patients were also excluded if they had prior exposure to a PI3K inhibitor or a BTK inhibitor.

Once enrolled, patients were randomized 1:1 to received 25 mg of duvelisib twice daily until progressive disease or unacceptable toxicity, or ofatumumab for 7 cycles. Patients who were administered ofatumumab received an initial dose of 300 mg, followed by 2000 mg weekly for 7 doses, then 2000 mg weekly for 4 doses.

The primary end point of the trial was progression-free survival. Secondary end points included overall response rate, hematologic improvements, OS, lymph node response rate, duration of response, treatment-emergent AEs, and pharmacokinetics.

References

1. FDA warns about possible increased risk of death and serious side effects with cancer drug Copiktra (duvelisib). News release. FDA. June 30, 2022. Accessed July 1, 2022. https://bit.ly/3OUyTDh
2. Verastem Oncology Receives FDA Approval of COPIKTRA™ (duvelisib) Capsules. Published September 24, 2018. Accessed July 1, 2022. https://bit.ly/2NDQm80
3. Secura Bio announces Copiktra (duvelisib) strategic focus on T-cell lymphoma and voluntary US withdrawal of the relapsed or refractory follicular lymphoma indication. News release. Secura Bio, Inc.; December 3, 2021. Accessed July 1, 2022. https://prn.to/31zvqH8
4. A phase 3 study of duvelisib versus ofatumumab in patients with relapsed or refractory CLL/SLL (DUO). ClinicalTrials.gov. Updated January 5, 2022. Accessed July 1, 2022. https://clinicaltrials.gov/ct2/show/NCT02004522