Duvelisib Demonstrates Higher Activity in Angioimmunoblastic Peripheral T-Cell Lymphoma

Treatment with duvelisib (Copiktra) led to a high response rate in patients with peripheral T-cell lymphoma (PTCL), with activity favoring patients with PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL), according to histology-specific outcomes from the phase 2 PRIMO trial (NCT03372057) presented at the International Conference on Malignant Lymphoma.

Among all enrolled patients with PTCL (n = 101), the objective response rate (ORR) by independent review committee (IRC) assessment was 48.5% (95% CI, 38.8%-58.3%) with a complete response (CR) rate of 33.7%. ORRs across the PTCL-NOS (n = 52), AITL (n = 30), anaplastic large cell lymphoma (ALCL; n = 15), and other subtypes were 48.1%, 66.7%, 13.3%, and 50.0%, respectively. CR rates across the PTCL-NOS, AITL, ALCL, and other subtypes were 26.9%, 53.3%, 13.3%, and 50.0%, respectively. Overall, 14.9% and 2.0% of patients had partial responses (PRs) and stable disease, respectively. PRs across the PTCL-NOS, AITL, and ALCL subgroups were 21.2%, 13.3%, and not calculable (NC), respectively.

“Responses by histology were higher in patients with AITL and PTCL-NOS compared with ALCL. These preliminary duvelisib data warrant further research into the variation in treatment outcomes when stratified by baseline histology,” lead study author Neha Mehta-Shah, MD, MSCI, associate professor in the Department of Medicine, Division of Oncology at the Washington University School of Medicine in St Louis, Missouri, and coauthors wrote in the poster.

PTCL is a heterogeneous disease with over 39 listings of natural killer and T-cell lymphomas in the 5th edition of the World Health Organization (WHO) classification. As such, single agents may have variable activity across subtypes. Investigators sought to delineate responses based on subtype of patients treated with the dual oral PI3K-δ/PI3K-γ inhibitor duvelisib in the PRIMO trial.

The study enrolled patients with relapsed or refractory pathologically confirmed PTCL per WHO classification of lymphoid neoplasms following at least 2 cycles of 1 prior standard therapy, with measurable disease per Lugano criteria. An ECOG performance status of 2 or less, and no prior history of allogeneic stem cell transplant or treatment with a PI3K inhibitor were also required. Notably, a CD4 lymphocyte count of at least 50/mm3 was added to eligibility criteria in the expansion phase.

In dose optimization, patients were randomly assigned to 25 mg of duvelisib twice daily (n = 20) or 75 mg of duvelisib twice daily (n = 13). In dose expansion (n = 101), patients received 75 mg of duvelisib twice daily for 2 cycles, and those who achieved CR, PR, or stable disease continued 25 mg of duvelisib twice daily. Dosing was based on dose-optimization results, indicating that the higher dose could be used to maximize disease control, followed by a lower dose to reduce the likelihood of developing late toxicities.

Pneumocystis jirovecii prophylaxis was required, and herpes simplex and varicella zoster virus prophylaxis were recommended as needed.

Response was evaluated by PET at the start of the second cycle and was continued every 2 months thereafter.

IRC-assessed ORR served as the primary end point. Secondary end points included safety, duration of response (DOR), progression-free survival (PFS), disease control rate––defined as CR, PR, and stable disease for at least 8 weeks––overall survival (OS), and pharmacokinetics.

Baseline characteristics demonstrated that the median patient age was 67.0 years (range, 21-92), and most patients were 65 years of age or older (54.5%), male (53.5%), and White (72.3%).

Median time from initial and relapsed/refractory diagnosis was 19.7 months (range, 0-196) and 1.2 months (range, 0-143), respectively. Baseline histologies included PTCL-NOS (51.5%), AITL (29.7%), ALCL (14.9%), and other (4.0%).

Median number of prior lines of therapy was 3 (range, 1-9) and included CHOEP/EPOCH (36.6%), CHOP/R-CHOP (36.6%), brentuximab vedotin (Adcetris)/brentuximab vedotin–containing chemotherapy (36.6%), salvage chemotherapy after CHOP/R-CHOP or CHOEP/EPOCH (37.6%), or autologous stem cell transplant (21.8%).

Additionally, 39.6% of patients remained on study, including those in survival follow-up. Most patients (92.1%) had discontinued treatment because of an adverse effect (AE; 18.8%), and others discontinued due to clinical deterioration due to progressive disease (4.0%), progressive disease (45.5%), death (5.9%), or other reason (16.8%). No patients required dose interruption after 42 days of treatment initiation because of duvelisib-related toxicity. One patient withdrew their consent.

The median follow-up from first response was 8.7 months (range, 0.03-25.3). Median time to CR/PR or CR alone was 1.8 months.

Median PFS overall was 3.6 months (95% CI, 1.9-8.3). Median PFS was 9.1 months (95% CI, 6.2–not calculable [NC]), 1.5 months (95% CI, 0.7-1.7), and 3.4 months (95% CI, 1.8-8.1) in the AITL, ALCL, and PTCL-NOS subgroups, respectively. Median OS was 15.5 months (95% CI, 9.5-18.1), 4.8 months (95% CI, 1.7-15.7), and 10.9 months (95% CI, 5.1-NC), respectively.

Median DOR overall was 7.7 months (95% CI, 5.5-9.4). Median DOR was 8.8 months (95% CI, 7.7-NC), 1.9 months (95% CI, 1.9-2.0), and 5.5 months (95% CI, 2.0-9.2) in the AITL, ALCL, and PTCL-NOS subgroups, respectively. Duration of CR was 7.9 months (95% CI, 3.3-NC), 1.9 months (95% CI, 1.9-2.0), and 7.4 months (95% CI, 6.4-NC), respectively. Median DOR among all patients who experienced CR was 7.4 months (95% CI, 6.4-NC).

Median time to response was 1.8 months (95% CI, 1.4-3.7), 2.6 months (range, 1.7-3.5), and 1.7 months (range, 0.5-3.6), in the AITL, ALCL, and PTCL-NOS subgroups, respectively.

Regarding safety, grade 3 or lower AEs included alanine aminotransferase increase (14.9%; grade 4, 5.9%), aspartate aminotransferase increase (13.9%), diarrhea (7.9%), neutropenia/neutrophil count decrease (13.9%), and maculopapular rash (7.9%).

Treatment-emergent AEs (TEAEs) leading to dose holds or dose reductions occurred in 37.6% and 3.0% of patients, respectively. TEAEs leading to death for reasons other than progressive disease occurred in 8 patients and included pneumonitis, Epstein-Barr virus–associated lymphoproliferative disorder, sepsis, gastrointestinal hemorrhage, hypoxia, vascular dementia, acute cholecystitis, and suicide.

“The types of AEs seen were consistent with those observed previously in the PRIMO trial with no additional unexpected treatment-related toxicities,” the authors added.

Reference

Mehta-Shah N, Jacobsen E, Zinzani PL, et al. Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma from the phase 2 PRIMO trial expansion phase: outcomes by baseline histology. Presented at: International Conference on Malignant Lymphoma. June 13-17, 2023; Lugano, Switzerland. Abstract 367.