A phase II study of penpulimab, an anti-PD-1 antibody, in patients with relapsed or refractoryclassic Hodgkin lymphoma (cHL).
Authors: Song Yuqin , Zhou Keshu , Jin Chuan , Qian Zhengzi , Hou Ming , Fan Lei , Li Fei , Ding Kaiyang , Zhou Hui , Li Xiaoling , Chen Bing , Sun Xiuhua , Song Xianmin , Jiang Ming , Zhang Qingyuan , Jin Xiaoping , Wang Zhongmin Maxwell , Li Baiyong , Xia Yu , Zhu Jun 
Published: June 2021

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Background: Penpulimab is a humanized IgG1 monoclonal antibody (mAb) that blocks PD-1 binding to PD-L1. Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. Fc-mediated effector functions, such as ADCC/ADCP, have been observed in most IgG4 anti-PD-1 mAbs but is absent in penpulimab, thereby potentially reducing the occurrence of immune-related adverse reactions. Penpulimab also demonstrated a slower PD-1 antigen binding off-rate than marketed anti-PD-1 mAbs, thereby resulting in better cellular activity and higher receptor occupancy. Penpulimab’s numerous contacts with N58 glycosylation on the BC loop of PD-1 may also contribute to a slower binding off-rate. These structural differentiations of penpulimab enhance its anti-tumor activity and produce a superior safety profile. Methods: AK105-201 is a multicenter, single-arm, open-label study of penpulimab in relapsed/refractory (R/R) cHL. All pts received penpulimab 200 mg Q2W until progression or unacceptable toxicity. Eligible pts had prior autologous stem cell transplant (ASCT) or at least 2 lines of prior chemotherapy. The primary endpoint was ORR based on the Lugano 2014 criteria as assessed by an independent review committee (IRC). Key secondary endpoints included CR rate, DCR, PFS, duration of response (DoR), safety, and tolerability. Results: As of 8 November 2020, of 94 pts (59.6% male, median age 32.0 yrs [31-71], 26.6% was ECOG 1) enrolled, 56 pts remained on treatment, 4 pts completed 24-months treatment and 25 had discontinued (17 due to disease progression, 3 due to AE). After a median follow-up of 15.8 months, the IRC-assessed ORR in the 85 pts evaluable for efficacy was 89.4% (95% CI: 80.8%, 95.0%). A total of 40 patients (47.1%) achieved CR. Median duration of response was not reached with range from 1.7 to 24.5+ months. Median PFS was not reached with 12-months PFS rate was 72.1% ( 95% CI: 60.5%, 80.8%). Treatment-related adverse events (TRAEs, with unlikely-related events included) occurred in 97.9% of pts ( ≥ G3 in 26.6% [25/94], treatment discontinuation in 5.3% [5/94]). Treatment-related SAEs occurred in 10.6%. Most frequent TRAEs (≥20%) were hypothyroidism (31.9%), upper respiratory tract infection (25.5%), fever (24.5%), and ALT elevations (23.4%). Grade ≥3 TRAEs reported in ≥2 pts were platelet count decreased (3.2%), hyperlipemia (3.2%), rash (3.2%), neutrophil count decreased (2.1%). Grade 3 immune-related AEs (irAEs) were reported in 4.3%: IgA nephropathy, pneumonitis, rash, psoriasis (each n = 1) and no G4 or G5 irAEs reported. Conclusions: Penpulimab was shown to be highly active in achieving in a CR rate of 47.1% in pts with R/R cHL while demonstrating lower rates of SAEs, TRAEs leading to discontinuation, and Grade ≥3 irAEs. Clinical trial information: NCT03722147.