The combination of duvelisib (Copiktra) plus venetoclax (Venclexta) is a promising all-oral regimen for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Of 12 patients who received treatment with this combination in the phase 1 portion of an open-label, single-arm study, 11 patients had a response, for an objective response rate of 92%, including 4 (33%) patients who had a complete response or complete response with incomplete hematologic recovery, according to data presented at ASH 2019.
“With some treatments, even novel agents, patients often require indefinite therapy. For patients with high-risk biologics, including those with TP53 mutations or deletion 17p [del 17p], or patients in whom prior Bruton tyrosine kinase [BTK] inhibitors have failed, the duration of response to these agents as monotherapy is short, so there is an unmet need,” said lead investigator Jennifer L. Crombie, MD, Medical Oncologist, Hematologic Oncology Treatment Center, Dana-Farber Cancer Institute, Boston, MA.
Duvelisib and venetoclax are each currently approved by the FDA as monotherapy for the treatment of patients with CLL, “but this is the first time these agents are being combined,” she said.
Patients in the study received treatment with duvelisib 25 mg twice daily, and then venetoclax was added on day 8 at 10 mg daily in the first 9 patients, and 20 mg daily was added in the last 3 patients. Venetoclax was ramped up weekly to 1 of 3 doses (100 mg, 200 mg, and 400 mg).
Patients received treatment with this combination for 1 year, and if they had undetectable minimal residual disease (MRD) at 1 year, they had the option of discontinuing therapy.
“This was a high-risk patient population,” said Dr Crombie. The median patient age was 69 years, 83% of patients did not respond to previous BTK inhibitor therapy, del 17p was present in 25% of patients, and 42% of patients had a TP53 mutation.
The median number of cycles was 7, and 2 patients completed 12 cycles. One patient who completed the 12 cycles had an undetectable MRD with a complete response and was able to discontinue therapy. Overall, 4 (33%) patients had undetectable MRD in the blood, and 4 (33%) had undetectable MRD in the marrow.
This combination therapy was generally well-tolerated, and there was no evidence of tumor lysis syndrome. Pharmacokinetic studies did not show evidence of significant drug–drug interactions. No dose-limiting toxicities were observed. Grade 3 serious adverse events included asymptomatic elevation in amylase and/or lipase (N = 2), febrile neutropenia (N = 1), and pneumonia (N = 1).
Duvelisib had to be stopped or its dose reduced in 7 patients. A total of 7 patients received treatment with steroids to manage presumed immune-mediated toxicity, and they were then able to resume duvelisib therapy.
The recommended dose for the phase 2 study is duvelisib 25 mg twice daily and venetoclax 400 mg daily, which are the 2 current FDA-approved doses as monotherapy.
“We’re excited about this potentially being an all-oral and possibly time-limited treatment option,” said Dr Crombie. “The phase 2 trial to further evaluate efficacy is now open and accruing.”