A Phase 1/2, Open-Label, Multicenter Study of Isatuximab in Combination with Cemiplimab in Patients with Lymphoma (2021)

Abstract Introduction: Immune checkpoint blockade of programmed death-1 (PD-1) receptor and its ligand (PD-L1) has contributed to efficacy in many tumor types, with clinical responses observed in a proportion of patients (pts) with Hodgkin lymphoma and rare non-Hodgkin lymphoma subtypes. A recent study demonstrated that combination treatment with anti-PD-L1 and anti-CD38 agents contributed to a stronger anti-tumor immune response compared with anti-PD-L1 monotherapy. Isatuximab, an anti-CD38 monoclonal antibody, is approved for use in multiple myeloma. Cemiplimab, an anti-PD-1 monoclonal antibody, is approved for use in cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Methods: This Phase 1/2 open-label study (NCT03769181) was designed to assess the safety, tolerability, and efficacy of isatuximab in combination with cemiplimab (Isa+Cemi) in pts with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). The primary objectives of Phase 1 were to characterize the safety and tolerability of Isa+Cemi and to confirm the recommended Phase 2 dose. Phase 2 used a Simon's 2-stage design to assess the complete response rate in Cohort A1 (anti-PD-1/PD-L1 naïve cHL; n=18; median age, 36 years; 55.6% male; ≥2 prior regimens, 100%) and to assess the objective response rate in Cohorts A2 (cHL progressing after PD-1/PD-L1 therapy; n=12; median age, 33 years; 58.3% male; ≥2 prior regimens, 100%), B (DLBCL; n=17; median age, 64 years; 70.6% male; ≥2 prior regimens, 100%), and C (PTCL; n=11; median age, 69 years; 63.6% male; ≥2 prior regimens, 9.1%). Pts received Isa+Cemi for up to 96 weeks. In Phase 1, the isatuximab dose was 10 mg/kg every week (Cycle 1), every 2 weeks (Cycle 2-6), or every 3 weeks (Cycle 7+). The cemiplimab dose was 250 mg every 2 weeks (Cycle 1-6) or 350 mg every 3 weeks (Cycle 7+). An interim analysis was performed when the last pt in Phase 2 was followed up for 24 weeks. The efficacy evaluation was based on Simon's 2-stage design with 85% power at a 5% 1-sided alpha level for each cohort. At least 8 (44.4%) and 3 (30.0%) responses were required in Cohorts B and C, respectively, in Phase 2 Stage 1 to advance to Phase 2 Stage 2. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed, confirming the recommended Phase 2 dose. Treatment-emergent adverse events (TEAEs) were reported in 83.3% (Cohort A1) and 100% (Cohorts A2, B, C) of pts. Grade ≥3 TEAEs occurred in 5.6%, 8.3%, 70.6%, and 81.8% of pts in Cohorts A1, A2, B, and C, respectively. There were no pts in Cohorts A1 or A2 who reported TEAEs leading to definitive discontinuation; 5.9% and 27.3% of pts in Cohorts B and C experienced TEAEs leading to definitive discontinuation. No Grade 5 TEAEs with fatal outcome were reported in Cohorts A1 or A2. There were 4 deaths reported during the on-treatment period in Cohort B (progressive disease, n=2; intestinal perforation, n=1; urinary tract infection, n=1) and 2 in Cohort C (unknown, n=1; progressive disease, n=1). Infusion reactions were reported in 38.9%, 75.0%, 52.9%, and 72.7% of pts in Cohorts A1, A2, B, and C, respectively; there was 1 (9.1%) Grade ≥3 infusion reaction reported in Cohort C. Pharmacokinetics (PK) analyses suggested no effect of cemiplimab on isatuximab PK, and vice versa. Based on Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of pts in the all-treated population achieved a complete or partial response. Median progression-free survival was 8.38 months (95% CI: 2.72-not calculable [NC]), 8.28 months (95% CI: 2.6-NC), 2.37 months (95% CI: 0.46-2.69), and 2.66 months (95% CI: 0.43-2.99) in Cohorts A1, A2, B, and C, respectively. Conclusion: In this study, Isa+Cemi had a manageable safety profile. Clinical efficacy was observed in pts with cHL, with increased responses observed in pts who had not previously received anti-PD-1/PD-L1 therapy compared with those who progressed on anti-PD-1/PD-L1 therapy. For Cohorts B (DLBCL) and C (PTCL), results of the interim efficacy analysis did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Most pts with DLBCL were primary refractory/bulky and discontinued rapidly, which may have contributed to the lack of activity with this combination. Disclosures Carlo-Stella: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp &amp; Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Casasnovas: TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy; ROCHE: Consultancy, Research Funding. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Bouabdallah: Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Kim: Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Sanofi: Research Funding; IGM Biosc