A Study of Linperlisib in the Treatment of Patients with Relapsed and/or Refractory Peripheral T-Cell Lymphoma

Abstract

Introduction Peripheral T cell lymphoma (PTCL) is an aggressive tumor type with poor survival, where treatment options for relapsed and/or refractory (r/r) disease are very limited. Standard treatments have a median progression free survival (PFS) of only 3-4 months. The novel PI3Kd-selective inhibitor, linperlisib (YY-20394), has indicated a clinical benefit with a favorable safety profile in Phase 1 and Phase 2 trials in B-cell malignancies previously. Here we report the full efficacy and safety data for a linperlisib Phase 1b trial in r/r PTCL. Methods The Phase 1b PTCL clinical trial (NCT04108325) was conducted from April, 2020 to September, 2021 at 10 sites in China enrolling 43 patients (pts) with different PTCL histologies, including PTCL-NOS (17 pts), AITL (16 pts), ALCL (6 pts), NKT (3 pts), and MEITL (1 pt). Linperlisib was orally dosed at 80 mg QD (RP2D) until disease progression, intolerable toxicity or withdrawal from the study. Tumor assessments were performed according to IWG 2007 every 2 treatment cycles (28-day/cycle). Safety was evaluated according to CTCAE v5.0. A final data cut off on September 26, 2021 was conducted for safety and efficacy assessments per protocol which defined the study closure 6 months after the LPI. After September 26, 2021, 15 patients who were receiving clinical benefits from study treatment per protocol definition continued linperlisib treatment until disease progression, or intolerable toxicity under a compassionate use program and were monitored and followed up for survival in accordance with institutional standard. Results In this linperlisib Phase 1b study in r/r PTCL, 43 pts enrolled. Pts were a median age of 58 years, ECOG 0-1 (41 pts, 95%), Stage III or IV Anne-Cotswold criteria (39 pts, 91%), and had a median of 2 prior systemic therapies, with 84% having prior CHOP or CHOP-like therapy. Thirty six pts (84%) were refractory to their last treatment. At the data cutoff date of September 26th 2021, 39 of 43 pts (91%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were neutropenia (65%), leukopenia (42%), hypertriglyceridemia (40%), hypercholesterolemia (35%), anaemia (26%), elevated alanine aminotransferase (26%), elevated aspartate aminotransferase (23%), pneumonia (23%), elevated gamma-glutamyltransferase (16%), hyperamylasemia (16%), thrombocytopenia (16%), elevated alkaline phosphatase (14%), lymphocytopenia (12%) and elevated lipase (12%). AEs of ≥Grade 3 (≥5%) were neutropenia (21%), pneumonia (12%) and hypertriglyceridemia (7%). Three pts had dose reductions to 60 mg QD, and 8 pts discontinued from the study due to AEs. The safety profile was consistent to that had been observed in linperlisib studies. Among the 43 enrolled pts, the overall response rate (ORR) was 60% (26 pts), including 35% (15 pts) Complete Responses, 26% (11) Partial Responses and 23% (10) Stable Disease, contributing to an 84% Disease Control Rate. The median time to response was 1.9 months. As of May 31, 2022, the median follow up of the pts in the study was 17 month (95%CI: 0.6, 26.2). The median Duration of Response was 15 months (95%CI: 6.9, NE) and median Progression Free Survival was 10 months (95%CI: 3.7, NE). The 6-month and 12-month OS rates were 88% (95%CI: 74.3, 95.0) and 77% (95%CI: 61.1, 86.7) respectively. The median OS had not been reached. To that date, there were still 11 pts (26%) remained on linperlisib treatment. Conclusions The PI3Kd-selective oral agent, linperlisib, demonstrated promising efficacy r/r PTCL patients with deep and durable responses of a 60% ORR, 10 months median PFS, 15 months DOR, and median OS not reached at the median follow up of 17 months. The overall safety and efficacy profile of linperlisib is promising in this difficult to treat patient population. A Phase 2 r/r PTCL registration study in China and a US/EU Phase 2 study in r/r T-Cell lymphomas are currently ongoing.