Linperlisib in Combination with CHOP for Newly-Diagnosed Peripheral T-Cell Lymphoma: Preliminary Results from the Phase 1b/2 Linch Study
Authors: Cai Qingqing , Xia Yi , Huang Huiqiang , Zhao Ying , Yang Fan , Xu Wenning , Tong Hongyan , Yang Chunmei , Fang Xiaojie , Nie Man , Fang Yu , Yan Gao , Zhang Xuanye , Tao Rong , Sun Xiuhua , Pan Xueyi , Wu Tao , Zhang Yuchen , Cai Jun 
Published: December 2024

Introduction

Peripheral T-cell lymphoma (PTCL), except for the anaplastic large cell lymphoma (ALCL) subtype, is characterized by a poor prognosis, with a 5-year overall survial rate of 30%. Despite CHOP being the cornerstone first-line therapy, its therapeutic efficacy remains suboptimal. The PI3Kδ inhibitor linperlisib has shown promising anti-tumor activity with a manageable safety profile in relapsed or refractory (R/R) PTCL in the pivotal phase 2 trial (NCT05274997). This study aimed to evaluate the efficacy and safety of linperlisib combined with CHOP (L-CHOP) as first-line treatment for patients with PTCL.

Methods

The LINCH trial is an ongoing multicenter, single-arm, phase 1b/2 study (NCT05949944) enrolling patients aged ≥18 years with histologically confirmed, newly diagnosed PTCL (including PTCL-not otherwise specified [NOS], angioimmunoblastic T-cell lymphoma [AITL], enteropathy-associated T-cell lymphoma [EATL], and hepatosplenic T-cell lymphoma [HSTCL]; ALCL patients will not be included after protocol amendment). In phase 1b, 6 patients received 6 cycles of L-CHOP regimen: linperlisib 80 mg orally once daily on days 1 to 21, cyclophosphamide 750 mg/m² intravenously on day 1, doxorubicin 50 mg/m² intravenously on day 1, vincristine 1.4 mg/m² intravenously on day 1, and prednisone 100 mg orally once daily on days 1 to 5 of each 21-day cycle. The dose of linperlisib would be reduced to 60 mg once daily if ≥2 dose-limiting toxicities (DLTs; defined as grade 4 hematologic toxicities lasting ≥1 week, or grade ≥3 non-hematologic toxicities) occurred during cycle 1. In phase 2, patients received 6 cycles of L-CHOP with the established recommended phase 2 dose (RP2D) of linperlisib. Patients achieving remission after 6 cycles of L-CHOP treatment would receive linperlisib maintenance therapy until disease progression, intolerable toxicity, or up to 24 months. Consolidative stem cell transplantation or radiotherapy was allowed at the investigator's discretion. The primary endpoint of the phase 1b part was the incidence of DLT. The primary endpoint of the phase 2 part was the complete response (CR) rate after 6 cycles of L-CHOP treatment.

Results

In phase 1b, only one DLT (grade 3 febrile neutropenia) was identified during cycle 1, and linperlisib 80 mg once daily was administered in phase 2. By the data cutoff date on July 19, 2024, a total of 18 patients (including 6 patients in phase 1b) were enrolled. The median age was 58 years (range, 27-72), 11 patients (83.3%) were males, 17 (94.4%) had an Eastern Cooperative Oncology Group performance status of 0-1, 11 (83.3%) had stage III-IV disease, and 3 (16.7%) had an International Prognostic Index of 3-5. Pathological types included PTCL-NOS (n=8), AITL (n=7), follicular helper T-cell lymphoma (TFHL)-NOS (n=1), and ALCL (n=2; enrolled before protocol amendment). Fifteen patients were evaluable for efficacy, with a CR rate of 46.7% (7/15) and an objective response rate of 80.0% (12/15). Five patients are currently on linperlisib maintenance therapy. Three patients with PTCL-NOS discontinued treatment due to disease progression. All patients received at least 1 cycle of treatment and were evaluable for safety. Treatment-related adverse events (TRAEs) were observed in 15 patients (83.3%), with hematological toxicities being the most common, including neutropenia (n=8, 44.4%), leukopenia (n=6, 33.3%), anemia (n=3, 16.7%), and thrombocytopenia (n=2, 11.1%). Grade 3 or worse TRAEs occurred in 6 patients (33.3%), with the most common being neutropenia (n=4, 22.2%) and leukopenia (n=4, 22.2%). A total of 6 serious adverse events (SAEs) occurred, including febrile neutropenia (n=3, 16.7%), pneumocystisjirovecii pneumonia (n=1, 5.6%), pneumonia (n=1, 5.6%), and fever (n=1, 5.6%). Of these SAEs, fever was judged to be unrelated to the treatment. SAEs were finally relieved by discontinuation of linperlisib and symptomatic treatment.

Conclusions

These preliminary findings indicate the feasibility of PI3Kδ inhibitor linperlisib combined with CHOP regimen as first-line treatment for patients with newly-diagnosed PTCL.