Oral Duvelisib Yields Deep Responses in Relapsed/Refractory PTCL

Final data from the phase 2 PRIMO trial (NCT03372057) demonstrate significant activity with the oral small molecule inhibitor duvelisib (Copiktra) in patients with relapsed or refractory peripheral T-cell lymphoma (R/R PTCL), especially in those with angioimmunoblastic lymphoma (AITL).¹

Independent review committee-assessed outcomes for 123 evaluable patients included an objective response rate (ORR) of 48.0%, complete response (CR) rate of 33.3%, median duration of response (DOR) of 7.9 months (95% CI, 6.4-21.0), median progression-free survival (PFS) of 3.4 months (95% CI, 1.8-3.9), and a median overall survival (OS) of 12.4 months (95% CI, 8.4-22.7). The data, published in the Journal of Clinical Oncology, represent response rates that compare favorably with those reported with currently available single-agent options for this difficult-to-treat population.

Pronounced Benefit in AITL Subgroup

Among histologic subgroups, patients with AITL (n = 37) derived the greatest benefit. In this subset, the ORR was 62.2%, the CR rate was 51.4%, median PFS was 8.3 months, median OS was 18.1 months, and median DOR was 11.3 months. In patients with PTCL-not otherwise specified (PTCL-NOS; n = 53), the ORR was 49.1%, CR rate was 30.2%, median DOR was 7.4 months, and median OS was 11.0 months (95% CI, 5.1-30.4).

These findings are notable given the limited treatment landscape for R/R PTCL. Currently approved single agents for this indication carry ORRs of 25% to 30%, CR rates of 11% to 15%, and median OS ranging from 8 to 15 months. The AITL-specific activity observed in PRIMO is consistent with other studies evaluating PI3K inhibitors as single agents or combinations in this histologic subtype.

About Duvelisib

Duvelisib is a first-in-class, oral dual inhibitor of the phosphoinositide 3-kinase (PI3K)-δ and PI3K-γ isoforms, targeting key signaling pathways involved in the proliferation and survival of malignant T cells while also modulating the tumor microenvironment. By inhibiting PI3K-δ, which is predominantly expressed in hematopoietic cells, and PI3K-γ, which plays a role in T-cell signaling and the function of supportive immune cells, duvelisib exerts both direct antitumor activity and indirect immunomodulatory effects. This dual mechanism is thought to contribute to the depth and durability of responses observed in T-cell lymphomas, particularly in AITL, a subtype characterized by a complex immune microenvironment.

Safety and Tolerability

Treatment-emergent adverse events (TEAEs) of any grade occurred in 120 patients (97.6%), and grade ≥3 TEAEs were reported in 91 patients (74.0%). TEAEs resulted in dose holds in 44.7% of patients, dose reductions in 9.8%, and treatment discontinuation (excluding progressive disease) in 33.3%. The most frequent reasons for discontinuation due to toxicity were aspartate aminotransferase (AST) elevation (7.3%), alanine aminotransferase (ALT) elevation (6.5%), and diarrhea (5.7%).

Infection occurred in 41.5% of patients (any grade) and 13.0% (grade ≥3). Notably, no cases of Pneumocystis jirovecii pneumonia were observed. Rates of immune-mediated AEs were low: colitis occurred in 2.4% of patients and pneumonitis in 1.6%. Cutaneous reactions were reported in 35.8%.

Ten patients experienced fatal TEAEs (excluding those attributed to progressive disease). Four were considered treatment-related: cryptococcosis, sepsis, Epstein-Barr virus–associated B-cell lymphoproliferative disorder (reported after approximately 6 months of therapy), and pneumonitis. The remaining 6 were unrelated to treatment.

About PRIMO: Study Design and Patient Population

PRIMO was a phase 2, multicenter, open-label study conducted at 45 centers globally to evaluate the efficacy and safety of duvelisib.² The trial comprised a dose-optimization phase and a dose-expansion phase. Based on dose optimization results, the treatment regimen consisted of duvelisib 75 mg twice daily for 2 cycles to maximize disease control, followed by 25 mg twice daily to reduce late toxicities, continued until progressive disease or unacceptable toxicity.

From February 2018 to December 2023, the trial enrolled 123 patients with R/R PTCL, with a data cutoff of February 2, 2024. The median patient age was 65 years (range, 21-92), and the median number of prior lines of therapy was 2 (range, 1-9). The most common baseline histologies were PTCL-NOS (n = 53), AITL (n = 37), and anaplastic large cell lymphoma (n = 20). Pneumocystis jirovecii prophylaxis was required for all patients, and a minimum baseline CD4+ count of ≥50/mm³ was required for enrollment.

REFERENCES

1. Mehta-Shah N, Zinzani PL, Jacobsen ED, et al. Duvelisib induces deep responses in PTCL: final results of the phase 2 PRIMO trial of duvelisib in relapsed/refractory peripheral T-cell lymphoma. J Clin Oncol. 2025. doi:10.1200/JCO-25-03120

2. A Study of Duvelisib in Participants With Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL) (PRIMO). ClinicalTrials.gov. Updated March 7, 2025. Accessed May 5, 2026. https://clinicaltrials.gov/study/NCT03372057