Duvelisib in patients with relapsed/refractory peripheral T-cell lymphoma: Final results from the phase 2 PRIMO trial - impact of prior therapy and expanded safety analysis

Abstract Introduction Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive lymphomas that have a poor prognosis, with a median overall survival (mOS) of <6 months (mos) for relapsed/refractory (R/R) disease. Current single agent therapies deliver modest overall response rates (ORR), typically <30% (except brentuximab vedotin [BV] in anaplastic large cell lymphoma; ALCL). Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms approved in the US for treatment of R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after ≥2 prior systemic therapies. The PRIMO trial (NCT03372057; sponsor: Secura Bio, Inc.) was a phase 2, open-label, single-arm trial evaluating duvelisib monotherapy in R/R PTCL. Methods PRIMO enrolled patients (pts) with R/R PTCL after ≥1 standard regimen. After a dose optimization phase, the recommended dose for the expansion phase (PRIMO-EP) was duvelisib 75 mg BID for 2 cycles to maximize early disease control, followed by 25 mg BID to mitigate late toxicities, continued until progressive disease or unacceptable toxicity. Primary endpoint of the PRIMO-EP was ORR by Independent Review Committee (Lugano 2014). Here we report the impact of prior treatments and expanded safety analyses from the PRIMO-EP. Results PRIMO-EP included 123 pts with median age 65 (21-92) years and 2 (1-9) prior lines of therapy. The most common baseline histologies were PTCL-NOS (n=53), angioimmunoblastic TCL (AITL) (n=37), and ALCL (n=20). Median follow-up time was 11.5 mos; median treatment duration was 8.3 weeks. Efficacy outcomes were ORR 48%, complete response rate (CRR) 33%, median duration of response (mDOR) 7.9 mos, median progression free survival (mPFS) 3.4 mos, and mOS 12.4 mos. AITL subgroup outcomes were ORR 62%, CRR 51%, mDOR 11.7 mos, mPFS 8.3 mos, and mOS 18.1 mos. Thirty-four pts (28%) had 1, 29 (24%) had 2, and 59 (48%) had ≥3 prior lines of therapy (AITL subgroup only: 20.6% had 1, 48.3% had 2, and 27.1% had ≥3 prior lines). In the total population, there was no consistent impact on efficacy outcomes by number of prior lines, with ORR: 29%, 66%, 49%; CRR: 18%, 52%, 32%; mDOR: 6.5, 11.7, 7.9 mos; mPFS: 1.9, 9.0, 3.0 mos, and mOS: 30.2, 22.7, 7.3 mos in pts with 1, 2, and ≥3 prior lines of therapy, respectively. Eighty-three pts (68%) received prior CHOP-based therapy, 43 (35%) had salvage chemotherapy, 25 (20%) had autologous stem cell transplant (SCT), 21 (17%) had HDAC inhibitor (HDACi), and 47 (38%) had BV. For the AITL subgroup, prior therapies included: CHOP-based (70%), salvage therapy (35%), SCT (16%), HDACi (19%), and BV (32%). Considering that this regimen included 2 cycles of 75 mg BID, we also analyzed safety according to number of cycles; 123 pts received ≤2 cycles, 63 pts (51%) received >2 to 6 cycles, and 25 pts (20%) received >6 cycles. Adverse events (AEs) in ≥20% of pts by treatment duration category (cycles ≤2/cycles >2-6/ cycles >6) included: neutropenia (29%/22%/16%), aspartate aminotransferase (AST) increased (29%/29%/4%), alanine aminotransferase (ALT) increased (25%/35%/4%), thrombocytopenia (19%/13%/28%), fatigue (15%/13%/24%), and diarrhea (20%/25%/32%). Grade ≥3 AEs in ≥5% of pts by treatment duration category included: neutropenia (14%/13%/12%), ALT increased (13%/22%/0%), AST increased (12%/13%/4%), thrombocytopenia (4%/8%/8%), lymphopenia (4%/8%/4%), maculopapular rash (6%/6%/0%), diarrhea (3%/8%/20%), hypokalemia (1%/0%/12%), and hypoxia (1%/0/8%). Conclusions In a heavily treated, R/R population, duvelisib efficacy outcomes did not show a consistent pattern based on prior lines of therapy; notably, pts with more heavily pretreated disease (where unmet need may be the greatest) demonstrated numerically favorable outcomes. For R/R PTCL, a 75 mg BID dose was administered for the first 2 cycles (in CLL/SLL, the indicated dose is 25 mg BID). Despite the higher initial dose, generally there was no consistent pattern of higher rates of persisting or emerging AEs with longer treatment duration. Rates of diarrhea showed a modest trend of increase, but there was no increase in rates of colitis. These data support the tolerability of this regimen in R/R PTCL despite a higher starting dose. Efficacy in the AITL group stands out; based on these results, the sponsor has initiated a randomized phase 3 study to investigate duvelisib in a homogeneous population of R/R nodal T-follicular helper cell lymphoma (NCT06522737; TERZO™).