Background: Peripheral T-cell lymphoma (PTCL) is a family of aggressive lymphomas, with a short median overall survival when relapsed or refractory (R/R). Current single-agent therapies for R/R PTCL have modest overall response rates (ORR) of <30%. Use of duvelisib (DUV), an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms, in PTCL is as an investigational agent only. Both Phase 1 data and prior interim analyses of this Phase 2, open-label, multi-center, parallel cohort PRIMO Trial (NCT03372057; supported by Secura Bio) demonstrated promising efficacy (ORR ~ 50%) of DUV in patients (pts) with R/R PTCL. Based on interim PRIMO data, DUV was added to the National Comprehensive Cancer Network® T-cell Lymphoma Guidelines® (Version 1.2022, 12/22/21) as a Category 2A other recommended regimen for pts with R/R PTCL of all subtypes. Here we present the latest PRIMO Expansion Phase (EP) data.
Aims: The primary objective of the PRIMO EP is to determine the efficacy of DUV given at a recommended dose in pts with R/R PTCL; secondary objectives include additional efficacy measures, safety, and pharmacokinetics.
Methods: EP eligibility criteria includes adults with pathologically confirmed PTCL, defined per WHO criteria, after ≥ 2 cycles of 1 prior standard regimen, and a CD4 lymphocyte count of ≥ 50/mm3. Based on the dose optimization results, the dose in the EP is DUV at 75 mg BID for 2 cycles, to maximize disease control, followed by 25 mg BID, to mitigate late toxicities, until progressive disease (PD) or unacceptable toxicity. Pneumocystis jirovecii prophylaxis is required; herpes simplex and varicella zoster virus prophylaxis are strongly recommended. The primary endpoint is ORR by IRC assessment using the Lugano 2014 criteria; efficacy is assessed in all pts that received at least 1 dose of DUV.
Results: This updated analysis of the EP included 101 pts (data cutoff Oct 1, 2021); median 10.4 months follow-up from first dose. Pts had a median age of 67.0 years (range, 21-92) with a median of 3 prior lines of therapy (range 1-9). Fourteen pts remain on treatment with 87 pts withdrawn from treatment for: PD (44), clinical deterioration due to PD (4), adverse events (AE; 20), death (5), other (13), and withdrawal of consent (1). The ORR by IRC was 49% with a CR rate of 34%; responses were seen across multiple subtypes (Table 1 Median PFS was 3.6 months, though not yet fully mature. Five pts discontinued therapy to undergo stem cell transplantation. There were 3 treatment-related AEs associated with death (1 each): pneumonitis, Epstein-Barr associated lymphoproliferative disorder, and sepsis. AEs of special interest ≥ Grade 3 (all causality, number of events) were transaminase elevation increased (23), neutropenia (19), infections (10), cutaneous reactions (9), diarrhea (7), pneumonia (2), and pneumonitis (1). There was 1 event of colitis (Grade 1). ALT and/or AST elevations were the most common AEs leading to treatment discontinuations (15).
Image:
Summary/Conclusion: This updated analysis of 101 patients in the PRIMO EP demonstrated an ORR of 49% and a CR rate of 34%, which compares favorably to currently available single-agent options. Duvelisib was generally manageable with per-protocol dose modifications in this population, showing an AE profile consistent with what has been observed previously and no unexpected or novel toxicities. These data confirm duvelisib to be a promising agent for a disease set with high unmet needs, poor prognoses, and limited effective treatment options.