A Phase Ib Study of Linperlisib in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

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. PI3K inhibitors, blocking tumor cell proliferation, survival, migration, and modulating multiple functions on the tumor microenvironment have previously shown to be active in T cell lymphomas, as well as B-cell lymphomas and chronic lymphocytic leukemia. However, the use of these agents has been hampered by tolerability issues, including toxicities such as diarrhea, colitis, hepatotoxicity, pneumonitis, hyperglycemia, and rash. The PI3Kδ selective inhibitor, linperlisib, is a structurally novel oral agent that has been demonstrated to be clinically efficacious with a favorable safety profile in Phase 1 and Phase 2 trials in B-cell malignancies previously. Here we report updated clinical data with longer follow-up from a Phase 1b clinical trial of linperlisib monotherapy in relapsed or refractory PTCL.

Methods

The Phase 1b PTCL clinical trial (NCT04108325) was conducted at 10 sites in China. There were 43 patients (pts) with different PTCL histologies enrolled in the study, including PTCL-NOS (17 pts), AITL (16 pts), ALCL (6 pts), NKT (3 pts), and MEITL (1 pt). Tumor assessments are performed every two treatment cycles with 28 days as one treatment cycle using IWG 2007 criteria. Safety was evaluated according to CTCAE v5.0. Linperlisib was dosed at 80 mg QD (RP2D) orally until disease progression, intolerable toxicity or withdrawal from the study.

Results

In the Phase 1b study of linperlisib monotherapy in r/r PTCL, as of a date cut-off of July 22, 2021, there were 43 pts enrolled with a median age of 58 years, ECOG 0-1 (41 pts, 95.3%), Stage III or IV (39 pts, 90.7%). The pts had a median of 2 prior systemic therapies, and 36 pts (83.7%) were refractory to their last treatment. The majority (83.7%) of pts had prior CHOP or CHOP-like therapy.

Thirty-eight out of 43 pts (88.4%) experienced a treatment related adverse event (TRAE), majority (90.3%) of AEs were Grade 1 or Grade 2. The most common TRAEs (≥10%) were neutropenia (60.5%), leukopenia (37.2%), hypertriglyceridemia (37.2%), hypercholesterolemia (32.6%), AST increase (20.9%), ALT increase (23.3%), pneumonia (16.3%), anemia (16.3%), gamma glutamyl transpeptidase increase (16.3%), thrombocytopenia (14.0%), alkaline phosphatase increase (14.0%) and lymphocyte count increase (11.6%). The observed safety profile of linperlisib in r/r PTCL is similar to that observed in r/r follicular lymphoma, with no new toxicities reported. The Grade 3 and above AE occurring in >5% of pts was neutropenia (16.3%). Three pts had dose reductions to 60 mg QD due to AEs, and 5 pts discontinued from the study due to an SAE.

Forty-one pts were evaluable for efficacy, 1 pt discontinued from study due to SAE occurred at C1D12, 1 pt discontinued from the study due to withdrawing consent at C1D12, there were no post baseline imaging assessment for these patients. The overall response rate (ORR) was 61.0%, including 34.1% Complete Response (CR), 26.8% Partial Response (PR) and 26.8% Stable Disease, contributing to a 90.0% Disease Control Rate (DCR). CR and/or PR were observed in all PTCL histologies enrolled in this study. Nearly all responses occurred by the first assessment at day 58. AS of a data cut-off of July 22，2021, the median PFS was 10.3 months (95%CI: 4.4-NR) , and the duration of response was not reached (95%CI: 8.5-NR). As of a data cut-off of July 22, 2021, 17 pts still remain on the study treatment, 7 pts had received at least 10 months of linperlisib treatment. Discontinuations were most frequently due to disease progression (18, 41.9%), intolerable SAE (5, 11.6%), or withdrawal consent from the study (3, 7.0%).

Conclusions

The PI3Kd-selective oral agent, linperlisib, demonstrated promising efficacy and durable responses with a 61.0% ORR and 10.3 months median PFS in patients with r/r PTCL. Additional clinical studies of linperlisib in r/r PTCL, including a Phase 2 registration study, are currently ongoing.