A phase 1/2, open‐label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma

Abstract

Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti‐CD38 antibody) in combination with cemiplimab (Cemi, anti‐programmed death‐1 [PD‐1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B‐cell lymphoma (DLBCL), and peripheral T‐cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de‐escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti‐PD‐1/programmed death‐ligand 1 [PD‐L1] naïve), and objective response rate in Cohorts A2 (cHL anti‐PD‐1/PD‐L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose‐limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti‐PD‐1/PD‐L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant

“…24 In this study, where renal function was even worse due to majority of patients being on dialysis, isatuximab PK exposure was comparable with those from other studies. [25][26][27] Overall, these results complement the previous analyses mentioned above, showing no effect of renal impairment on isatuximab PK exposure. These results were expected as isatuximab is a monoclonal antibody, and thus a large molecule, and is eliminated by catabolism.…”

Education and Empowering Special Forces to Eradicate Secret Defectors: Immune System-Based Treatment Approaches for Mature T- and NK-Cell Malignancies

“…In the search for novel, specific target structures, the anti-CD38 mAbs Daratumumab and Isatuximab (both IgG1) are currently under investigation for the treatment of a subset of T cell lymphoma/leukemia entities [57,58]. In physiological conditions, CD38 surface expression is restricted to thymocytes, activated T cells, NK cells, and plasma cells.…”

“…This study is based on the hypothesis that blocking PD-L1 on PTCL cells might restore healthy T cell mediated immune effector functions and may thus generate an additive or even synergistic immune-modulatory effect with CDC/ADCC/ADCP inducing Isatixumab. An interim analysis published at the beginning of 2023 showed a complete or partial response in only 9.1% of 11 included PTCL patients [57]. With these results, Carlo-Stella and colleagues concluded that, for PTCL patients, interim efficacy analysis results did not meet prespecified criteria to continue enrolment and that no synergistic effect could be observed.…”