NCCN Lists Duvelisib in Updated Clinical Practice Guidelines

Barbara Pro, MD

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology has been updated to include duvelisib (Copiktra) as a category 2A designated option for second-line and subsequent treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), regardless of intent to proceed to transplant.¹

“The NCCN guidelines provide a roadmap for treatment for patients with different diseases and they are useful for practicing community oncologists who may only see a few cases of different diseases every year. [The guidelines] bring [clinicians] up to date with the most recent references and the most recent recommendations that are evidence based. [The guidelines are] critical in terms of having some uniform pattern of treatment for our patients, especially when we have treatment algorithms that are highly effective for certain diseases,” Francine Foss, MD, professor of medicine, Yale School of Medicine, said in an interview with OncLive^®.

In October 2019, duvelisib, a dual PI3K-δ,γ inhibitor, received an orphan drug designation for the treatment of patients with T-cell lymphoma.² Duvelisib’s orphan drug status succeeded its fast track designation, which was granted in September 2017 for patients with PTCL who have received at least 1 prior therapy.³

“[Because] duvelisib has not been approved yet for T-cell lymphoma, it’s not easy to get approval from payers. The fact that now duvelisib is listed in the NCCN guidelines can make things a little bit easier for us,” Barbara Pro, MD, clinical director of the lymphoma program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Irving Medical Center, and a professor of medicine in the Department of Medicine and Division of Hematology/Oncology at Columbia University Vagelos College of Physicians and Surgeons, said in an interview with OncLive^®.

The agent is currently under study in patients with relapsed/refractory PTCL in the phase 2, open-label, multicenter PRIMO trial (NCT03372057), consisting of a dose-optimization and a dose-expansion phase.

Initial results of the dose-optimization phase (n = 33) demonstrated objective response rates (ORRs) of 54% and 35% in the 75-mg twice daily (n = 13) and 25-mg twice daily (n = 20) cohorts, respectively.

“The ongoing PRIMO trial, as well as an earlier phase 1/2 study shows high activity [with duvelisib] in T-cell lymphoma. We felt that the data were clinically significant enough that we should at least be able to offer this drug to our patients, so we did list it as one of the options for second-line therapy,” Foss said. “The significance of listing a drug in the guidelines is that it helps with third-party reimbursement, which is key for many of our patients, especially if there are high co-pays for some of these drugs. In addition, having it listed in the guidelines tells physicians that the drug is available and that the drug has activity.”

To be eligible for enrollment in the expansion phase, patients had to have histologically confirmed relapsed/refractory PTCL, measurable disease per International Working Group criteria, no prior history of allogeneic stem cell transplant or treatment with a PI3K inhibitor, and an ECOG performance status between 0 and 2.

Relapsed/refractory was defined such that patients had to have received at least 2 cycles of 1 prior regimen administered with curative intent and failed to achieve a partial response (PR) or better after at least 2 treatment cycles, or failed to achieve complete response (CR) after at least 6 treatment cycles, or progressed after initial response.

Based on the dose-optimization results, patients in the expansion phase receive duvelisib at 75 mg twice daily for 2 cycles. Patients who achieved CR, PR, or stable disease went on to receive 25 mg of duvelisib twice daily until progressive disease or unacceptable toxicity.

Disease response was evaluated by PET at the start of cycle 2 and every 2 months thereafter.

The primary end point was ORR by independent review committee assessment. Secondary end points included ORR by investigator assessment, duration of response (DOR), progression-free survival, overall survival (OS), disease control rate, and safety. All analyses consisted of patients who received at least 1 dose of duvelisib.

The median patient age was 66.5 years (range, 21-92), and approximately half of patients were male (52%). The median time from initial diagnosis was 2.74 years (range, 1.21-17.38).

Represented subtypes included PTCL not otherwise specified (n = 42; 53.8%), angioimmunoblastic T-cell lymphoma (n = 20; 29.6%), anaplastic large cell lymphoma (n = 11; 14.1%), and other (n = 4; 5.2%). The median number of prior therapies was 3 (range, 1-7).

In primary results of the expansion portion of the study, which included the first 6 months of data for 78 evaluable patients and were presented during the 2021 ASH Annual Meeting and Exposition, the agent demonstrated an ORR of 50% (n = 39), which also consisted of a CR rate of 32.1% (n = 25).⁴

The median time to response was 53 days (range, 15-114), and the median DOR was 233 days (range, 1+ to 420+).

At data cutoff, 82.1% (n = 64) of patients had discontinued treatment because of disease progression (n = 34; 43.6%), death (n = 4; 5.1%), transplant (n = 5; 6.4%), adverse effects (AEs; n = 14; 17.9%), and other (n = 7; 8.9%).

“This updated analysis continues to confirm the activity of duvelisib,” Pro said.

In terms of safety, any-grade treatment-emergent AEs (TEAEs) were infections (n = 31; 39.7%), colitis (n = 1; 1.3%), cutaneous reactions (n = 26; 33.3%), diarrhea (n = 20; 25.6%), neutropenia (n = 30; 38.5%), pneumonia (n = 2; 2.6%), pneumonitis (n = 2; 2.6%), and transaminitis elevation (n = 38; 48.7%).

Grade 3 or greater TEAEs were infections (n = 9; 11.5%), cutaneous reactions (n = 6; 7.7%), diarrhea (n = 2; 2.6%), neutropenia (n = 17; 21.8%), pneumonia (n = 1; 1.3%), pneumonitis (n = 2; 2.6%), and transaminitis elevation (n = 21; 26.9%).

Alanine aminotransferase and aspartate aminotransferase elevations (n = 13) were the most common TEAEs leading to treatment discontinuation, followed by progressive disease (n = 3) and diarrhea (n = 2).

Serious TEAEs leading to death were pneumonitis, vascular dementia, suicide, pulmonary edema, Epstein-Barr virus–associated lymphoproliferative disorder, gastrointestinal hemorrhage, sepsis, febrile infection, infection, and disease progression.

“In our patients treated on the PRIMO trial, we have observed transaminitis, which is an expected and common toxicity with this class of drugs that we should try to pay attention to, because we need to stop the treatment or decrease the dose according to the guidelines,” Pro said.

“It’s important to recognize that patients with relapsed/refractory PTCL have a very poor prognosis, with an OS that is less than 6 months. A number of agents have been FDA approved for patients with this disease, but overall, the response rates have been quite modest, so targeting [the PI3K] pathway could be a very important strategy in this disease,” Pro concluded.

References

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) T-cell lymphomas version 2.2022 –– March 7, 2022. NCCN. Accessed March 11, 2022. NCCN.org
2. Verastem Oncology receives orphan drug designation from FDA for COPIKTRA for the treatment of T-cell lymphoma. News release. Verastem, Inc. October 3, 2019. Accessed March 11, 2022. https://bwnews.pr/3CCCD7O
3. Verastem expands duvelisib development program to include peripheral T-cell lymphoma. News release. Verastem, Inc. September 6, 2017. Accessed March 11, 2022. https://bwnews.pr/3ML2b72
4. Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 Primo trial: results of an interim analysis. Blood. 2021;138(suppl 1):2456. doi:10.1182/blood-2021-148939