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.

Keywords: cemiplimab; diffuse large B-cell lymphoma; isatuximab; non-Hodgkin lymphoma; peripheral T-cell lymphoma.

Conflict of interest statement

CC‐S: Advisory Role – Sanofi; Consultancy – Sanofi. PLZ: Honoraria – Gilead, Incyte, Merck, Novartis, Roche, Sanofi, Takeda. AS: Consultancy –Bluebird, BMS, Genmab, Janssen, Kite, MSD, Novartis, Roche, Takeda; Honoraria – BMS, Janssen, Kite, MSD, Novartis, Roche, Sanofi, Takeda. LA: Nothing to disclose. OC: Advisory Role – Gilead/Kite, Roche, Takeda; Consultancy – AbbVie, BMS, Gilead/Kite, Janssen, MSD, Roche, Takeda; Honoraria – Gilead/Kite, Roche; Research Funding – Gilead/Kite, Roche, Takeda. CC: Consultancy – Regeneron, Takeda; Honoraria – BMS, Novartis, Takeda. S‐PY: Advisory Role – AbbVie, Amgen, Astellas, Astex, Janssen, Novartis, Sanofi, Takeda; Honoraria – AbbVie, Amgen, Astellas, BMS, Janssen, AstraZeneca, Novartis, Roche, Sanofi, Takeda. KB: Nothing to disclose. GC: Consultancy – Celgene, Roche; Honoraria – AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Sanofi, Takeda. WSK: Research Funding – Celltrion, Kyowa Kirin, Pfizer, Roche, Sanofi. RC: Advisory Role – AbbVie, AstraZeneca, BeiGene, BMS, Incyte, Janssen, Kite, Kyowa Kirin, Lilly, Roche, Takeda; Consultancy – AbbVie, AstraZeneca, BeiGene, BMS, Incyte, Janssen, Kite, Kyowa Kirin, Lilly, Roche, Takeda; Honoraria – AbbVie, AstraZeneca, BMS, Janssen, Kite, Roche, Takeda; Research Funding ‐ Pfizer. YK: Nothing to disclose. AR: Nothing to disclose. DA: Advisory Role – AbbVie, Roche; Consultancy – AbbVie, AstraZeneca, Gilead, Janssen, Roche, Takeda; Honoraria – AbbVie, AstraZeneca, Gilead, Janssen, Roche, Takeda. MC: Advisory Role – Novartis; Research Funding – Celgene, Genmab, GiIead. SLG: Consultancy – Roche; Honoraria – Roche. AL‐G: Consultancy –Celgene/BMS, Gilead/Kite, Incyte, Janssen, Kern Pharma, Pfizer, Roche, Takeda; Honoraria – Roche; Research Funding – Celgene/BMS, Janssen, Roche. IM: Nothing to disclose. MWMvdP: Nothing to disclose. GA, RM, RJ, LL, and RS are employed by Sanofi and may hold stock and/or stock options in the company. VR: Advisory Role – AstraZeneca; Consultancy – AstraZeneca, Gilead, Incyte, NanoString, Roche; Honoraria – AstraZeneca; Research Funding – argenx, Astex Pharmaceuticals, GSK.

© 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Study design. Cemi, cemiplimab; cHL, classic Hodgkin lymphoma (HL); DLBCL, diffuse large B‐cell lymphoma; DLT, dose‐limiting toxicity; Isa, isatuximab; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PTCL, peripheral T‐cell lymphoma

FIGURE 2

Progression‐free survival (PFS): Kaplan–Meier estimates by cohort, all‐treated population. Cemi, cemiplimab; cHL, classic Hodgkin lymphoma (HL); DLBCL, diffuse large B‐cell lymphoma; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PTCL, peripheral T‐cell lymphoma; Isa, isatuximab