A Phase II Clinical Study Exploring the Safety and Efficacy of the Oral PI3Kδ Inhibitor, Linperlisib, in Relapsed Refractory T Cell Lymphoma

Peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) are aggressive heterogeneous non-Hodgkins lymphomas where the approved therapies for relapsed or refractory (r/r) disease are limited and ineffective. PI3Kδ inhibitors are active in T-cell and B-cell lymphomas, but clinical benefit has previously been compromised by less tolerability owing to immune-mediated toxicities, such as diarrhea/colitis, hepatoxicity, pneumonitis, and rash.

While linperlisib (80 mg QD, continuous dose] has been approved in China for follicular lymphoma and has demonstrated clinical benefit in Chinese r/r PTCL patients (pts) as well, this study evaluated the clinical benefit in r/r PTCL and CTCL pts from US and Italy with different race/ethnicity. In addition, an alternative dosing regimen has been explored.

Thirty-five r/r PTCL and 10 r/r CTCL pts were enrolled in an open-label phase II trial (NCT05274997) from August 2022 to November 2023 at 6 sites in the U.S. and Italy. Pts received linperlisib 80mg QD for four 28-day cycles or achieved a complete response (CR) prior to a prespecified reduction to a 40mg QD continuous maintenance dose. The primary endpoint of this study was the objective response rate (ORR) assessed by Investigator. Tumor assessments were performed every 2 treatment cycles using Lugano 2014 criteria for PTCL and Olsen Global Response Score for CTCL. Pts with CR were eligible to proceed to consolidative transplant, if warranted by investigator review. Safety was evaluated according to CTCAE v5.0.

This study enrolled a total of 35 PTCL pts of several subtypes: PTCL-NOS (18 pts), AITL (13 pts), ALCL (4 pts) of a median 66 years (29,79 min, max), 21 (60%) male, 14 (40%) female, Caucasian 25 (71.4%), Black 9 (25.7%), or Asian 1 (2.9%), ECOG status 0 (57.1%) or 1 (42.9%), and median prior systemic therapies of 2 (range 1-8). Among these, 68.9% were refractory to the last prior therapy, and 31.1% were relapsed. Total of 10 CTCL pts (100% Caucasian, 8 males, 2 females; 9 mycosis fungoides, 1 Sézary syndrome) were enrolled with a median 5 (range 2-10) prior therapies. A 45 pts Safety Analysis Set and a r/r PTCL 33 pt Full Analysis Set (FAS), 10 CTCL FAS were evaluated at the study data cutoff July 2, 2024, where all patients had ≥6 months of treatment.

Treatment related adverse events (TRAE) were observed in 25 pts (55.6%), with neutropenia (4/45, 8.9%) most frequent (>5%). TRAEs ≥Grade 3 were neutropenia (8.9%, 4/45), rash (4.4%, 2/45), leukocyte count decrease (2.2%, 1/45), thrombocytopenia (2.2%, 1/45), hypertriglyceridemia (2.2%, 1/45), pneumonia (4.4%, 2/45), transaminitis (2.2%, 1/45), GGT increased (2.2%, 1/45, cellulitis (2.2%, 1/45). One pt had two grade 4 neutropenia events which led to dose interruption. Twenty-two patients required temporary dose interruptions and 1 patient discontinued the study therapy due to PJP pneumonia. The discontinuation rate due to any AE was 4.4% (2/45). One death occurred due to a wound infection that was not drug-related. No new adverse events identified.

Among the 33 FAS evaluable PTCL pts, the ORR was 48.5% (16/33), with 11 CR (33.3%), 5 PR, 4 SD, and a 60.6% disease control rate. Responses most frequently occurred by the first assessment during the 80mg QD dose period. As in other linperlisib studies, responses were found in PTCL-NOS (7), AITL (8) and ALCL (1), and CRs were more frequent than PRs. The PTCL FAS had a mPFS of 3.6 mo (95% CI, 1.9,5.3), mDOR of 5.8 mo (1.9, NE), and a mOS that was not reached. Five of the PTCL pts with CR subsequently received transplant and were censored from the PFS analysis. For CR pts, mPFS and mDOR were not reached. Four CTCL pts achieved a PR and 4 pts had SD for 2-5 mo.

Seventeen of the 35 PTCL pts and 6 CTCL pt had a protocol-specified dose reduction to 40mg QD linperlisib maintenance. For these 17 PTCL pts, the mPFS was 7.6 mo (3.7, NE). At 40 mg QD, one patient converted from PR to CR. The median duration of treatment at 40 mg QD was 6 mo. Four pts remain on treatment at the data cutoff date.

Linperlisib, a PI3Kδ-selective oral drug, exhibited a well-tolerated safety profile consistent with previous linperlisib studies, and having low levels of gastrointestinal and liver toxicities seen with other PI3K agents. In r/r PTCL, linperlisib responses occurred early and eligible CR pts were able to proceed to transplant. With a high durable CR rate, the clinical benefit of linperlisib in non-Asian pts merits further investigation. A global r/r PTCL Phase 3 study is planned.