Received: 11 June 2022 DOI: 10.1002/hon.3089 ORIGINAL ARTICLE - - Revised: 30 September 2022 Accepted: 11 October 2022 A phase 1/2, open‐label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma Carmelo Carlo‐Stella1 | Pier Luigi Zinzani2 | Anna Sureda3 | Luis Araújo4 | Olivier Casasnovas5 | Cecilia Carpio6 | Su‐Peng Yeh7 | Krimo Bouabdallah8 | Guillaume Cartron9 | Won Seog Kim10 | Raul Cordoba11 | Youngil Koh12 | Alessandro Re13 | Daniela Alves14 | Martine Chamuleau15 | Steven Le Gouill16 | Armando López‐Guillermo17 | Ilídia Moreira18 | Marjolein W. M. van der Poel19 | Giovanni Abbadessa20 | Robin Meng20 | Ran Ji20 | Lucie Lépine21 | Rao Saleem20 | Vincent Ribrag22 1 Department of Biomedical Sciences, Humanitas University and Department of Oncology and Hematology, IRCCS Humanitas Research Hospital, Milano, Italy 2 IRCCS Azienda Ospedaliero‐Universitaria di Bologna Istituto di Ematologia “Seràgnoli” and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale Università di Bologna, Bologna, Italy 3 Institut Català D'Oncologia ‐ Hospital Duran i Reynals, IDIBELL, Universitat de Barcelona, Barcelona, Spain 4 Universitário de Coimbra, Coimbra, Portugal 5 Hématologie Clinique, CHU Dijon Bourgogne, Dijon, France 6 Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, Barcelona, Spain 7 China Medical University Hospital, Taichung, Taiwan 8 Hematology and Cellular Therapy Department, University Hospital of Bordeaux, Bordeaux, France 9 Department of Hematology, Centre Hospitalier Universitaire Montpellier, Montpellier, France 10 Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea 11 Fundación Jiménez Díaz University Hospital, Madrid, Spain 12 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea 13 Hematology Division, ASST Spedali Civili Brescia, Brescia, Italy 14 Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte (CHULN), Lisbon, Portugal 15 Department of Hematology, Cancer Center Amsterdam, on behalf of the LLPC (Lunenburg Lymphoma Phase I/II Consortium), Amsterdam University Medical Center, VU University Amsterdam, Amsterdam, The Netherlands 16 Department of Hematology, Institut Curie, Paris, France 17 Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain 18 Department of Onco‐Hematology, Portuguese Institute of Oncology of Porto, Porto, Portugal 19 Department of Internal Medicine, Division of Hematology, GROW School for Oncology and Developmental Biology, on behalf of the LLPC (Lunenburg Lymphoma Phase I/II Consortium), Maastricht University Medical Center, Maastricht, the Netherlands 20 Sanofi, Cambridge, Massachusetts, USA 21 Sanofi, Chilly‐Mazarin, France 22 Département d’Hématologie et Département des Essais Précoces (DITEP), Institut Gustave Roussy, Villejuif, France - This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, pro- vided the original work is properly cited. © 2022 The Authors. Hematological Oncology published by John Wiley & Sons Ltd. 108 Hematological Oncology. 2023;41:108–119. wileyonlinelibrary.com/journal/hon CARLO‐STELLA ET AL. - 109 Correspondence Carmelo Carlo‐Stella, Humanitas Research Abstract Hospital, via Manzoni 56, 20089, Milano, Italy. Patients with relapsed or refractory lymphoma have limited treatment options, Email: carmelo.carlostella@hunimed.eu requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the Funding information safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti‐CD38 antibody) in Sanofi 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 syn- ergistic effect in these patient populations. KEYWORDS cemiplimab, diffuse large B‐cell lymphoma, isatuximab, non‐Hodgkin lymphoma, peripheral T‐ cell lymphoma 1 | INTRODUCTION (MM), certain types of lymphoma, and leukemia; the prevalence and expression level of CD38 is lower and more variable in non‐MM Immune checkpoint blockade has contributed to the efficacy of tar- cancers.2,9–14 Monoclonal antibodies targeting CD38 have demon- geted anti‐programmed death 1 (PD‐1)/anti‐programmed death‐ strated deep clinical outcomes in patients with MM, but data sup- ligand 1 (PD‐L1) agents in many tumor types, with clinical re- porting their clinical utility in lymphoid malignancies are limited.15 sponses observed in a small proportion of patients with Hodgkin Preclinical studies demonstrated cytotoxic activity of anti‐CD38 1,2 lymphoma (HL) and rare non‐HL (NHL) subtypes. PD‐1 inhibitors, antibodies against CD38+ malignancies.9,16,17 Furthermore, in mu- nivolumab and pembrolizumab, received US Food and Drug Admin- rine models of lung cancer and melanoma, acquired resistance to istration approval for relapsed/refractory classic Hodgkin lymphoma anti‐PD‐1/PD‐L1 agents is associated with CD38 upregulation on (cHL); however, only a small fraction of patients achieved complete tumor cells, thereby leading to CD38‐mediated CD8+ T‐cell sup- 3,4 response (CR) in Phase 2 trials of these agents. Early‐phase studies pression via adenosine receptor signaling.18 Co‐inhibition of PD‐L1 with single‐agent anti‐PD‐1 antibodies produced low or modest and CD38 contributed to a stronger anti‐tumor immune response clinical activity in patients with diffuse large B‐cell lymphoma compared with anti‐PD‐L1 monotherapy in a mouse lung cancer (DLBCL) and peripheral T‐cell lymphoma (PTCL).5–8 New therapies model.18 Thus, the opportunity remains to develop regimens that that employ anti‐PD‐1/PD‐L1 antibodies in combination with other incorporate an anti‐CD38 monoclonal antibody as a partner for pa- therapies are being evaluated in patients with lymphoma. tients with lymphoma. Cemiplimab (Cemi) is a recombinant human The expression of the transmembrane glycoprotein CD38 is well IgG4 monoclonal antibody that binds to PD‐1 and blocks its inter- documented in hematological cancers, including multiple myeloma action with PD‐L1 and PD‐L2.19 Cemi is approved for treating 110 - CARLO‐STELLA ET AL. patients with metastatic or locally advanced cutaneous squamous cell 2 | PATIENTS AND METHODS carcinoma, basal cell carcinoma, and non‐small cell lung cancer with high PD‐L1 expression.19 Preliminary studies showed that Cemi 2.1 | Study design and participants monotherapy is well tolerated and has minimal clinical activity in patients with HL and B‐cell NHL.8 This was a Phase 1/2 multicenter, non‐comparative, open‐label Isatuximab (Isa) is an IgG1 monoclonal antibody that targets a study. Patients were enrolled at 23 study sites in seven countries specific epitope on CD38 and kills CD38+ cells from hematological (France, Italy, Republic of Korea, Netherlands, Portugal, Spain, and malignancies via multiple mechanisms.17,20 Notably, Isa demonstrated Taiwan). potent antitumor activity against diverse CD38+ B‐cell lymphoma, Eligible patients were ≥12 years old and had disease location DLBCL, MM, and leukemia cell lines as well as xenograft models amenable to tumor biopsy at baseline, measurable disease, and his- derived from these cell lines.17 Based on the Phase 3 ICARIA‐MM and tologically confirmed advanced cHL, DLBCL, or PTCL that had IKEMA studies (NCT02990338; NCT03275285),21,22 Isa has been relapsed or progressed after previous therapy. The number of pre- approved in combination with pomalidomide and dexamethasone or vious therapies required for inclusion differed by cohort: ≥3 (cHL carfilzomib and dexamethasone, respectively, in MM. anti‐PD‐1/PD‐L1 naïve), 1 anti–PD‐1/PD‐L1–containing regimen In view of preclinical evidence for the activity of Isa in lymphoma, (cHL anti‐PD‐1/PD‐L1 progressors), 2 (DLBCL), and 1 (PTCL). Key coupled with early studies showing suboptimal clinical activity of exclusion criteria were prior exposure to anti‐CD38, anti–PD‐1/PD‐ single‐agent anti‐PD‐1 antibodies in HL, DLBCL, and PTCL, we hy- L1 (except for cHL anti–PD‐1/PD‐L1 progressors), anti‐PD‐L2, anti‐ pothesize that Isa plus Cemi (Isa + Cemi) will have a synergistic effect CD137, anti‐CTLA4, or anti‐LAG3 agents, evidence of other in patients with lymphoma. Currently, data on Isa activity in PTCL are immune‐related disease/conditions, Eastern Cooperative Oncology lacking; however, we included patients with PTCL because CD38, Group (ECOG) performance status ≥2, poor bone marrow reserve, PD‐1, and PD‐L1 are expressed in certain types of PTCL.2 In this and poor organ function. Among cHL anti‐PD‐1/PD‐L1 progressors, 3 Phase 1/2 study (NCT03769181), we evaluated the safety, efficacy, patients were refractory to a prior anti‐PD‐1 agent. One patient who and pharmacokinetics of Isa + Cemi in patients with relapsed and had a partial response (PR) with prior pembrolizumab developed refractory cHL, DLBCL, and PTCL. Phase 1 primary objectives were progressive disease upon rechallenge. to characterize the safety and tolerability of Isa + Cemi and to The study was in two parts (study design in Figure 1). Eligible confirm the recommended Phase 2 dose (RP2D). In Phase 2, we patients with cHL, DLBCL, or PTCL were enrolled in Phase 1 and assessed the CR rate of Isa + Cemi in anti‐PD‐1/PD‐L1 naïve patients RP2D was determined according to the dose‐limiting toxic- with cHL (Cohort A1) and objective response rate (ORR) in anti‐PD‐ ities (DLTs) in Cycle 1. Patients were treated with Isa + Cemi at the 1/PD‐L1 progressors with cHL (Cohort A2), anti‐PD‐1/PD‐L1 naïve starting dose; dose de‐escalation to a dose level minus one or an patients with DLBCL (Cohort B), and anti‐PD‐1/PD‐L1 naïve patients alternative dose/schedule was planned if DLTs occurred in ≥2/3 with PTCL (Cohort C). patients in Cycle 1 (see Procedures for drug doses). Patients were F I G U R E 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 CARLO‐STELLA ET AL. - 111 treated in Stage 1 of Phase 2 at the RP2D until disease progression 2.4 | Pharmacokinetics or unacceptable toxicity. Phase 2 included four cohorts: A1, A2, B, and C. Patients treated at the RP2D of Isa + Cemi during Phase 1 Blood samples were collected at selected time points during Cycle 1 were included in the efficacy analysis together with participants of (predose, end of infusion [EOI], EOI+4h, start of infusion [SOI]+72h, the same indication in Stage 1 of Phase 2. Expected enrollment was SOI+144h) to perform Isa pharmacokinetics by non‐compartmental 3–12 DLT–evaluable patients in Phase 1 and 37 (Cohort A1), 25 analysis using Phoenix WinNonlin® version 8.2 (Pharsight). Gyrolab (Cohort A2), 29 (Cohort B), and 27 (Cohort C) patients in Phase 2 Platform, a quantitative Sandwich immunoassay using biotinylated (if Stages 1 and 2 were both completed). A prespecified, interim anti‐Isa antibodies bound by streptavidin beads within the Gyrolab efficacy analysis was planned independently for each cohort. The Bioaffy CD microstructure for capture and Alexa Fluor® 647‐ criteria required to advance a treatment cohort from Phase 2, Stage conjugated CD38 antibody for detection, was used to measure 1 to Stage 2 of Phase 2 were: CR in 4/17 (23.5%) patients in Cohort functional Isa (Isa with ≥1 site available to bind target) plasma levels, A1, and CR or PR in 3/12 (25.0%) patients in Cohort A2, 8/18 with a lower limit of quantitation of 5.0 μg/ml and an upper limit of (44.4%) patients in Cohort B, and 3/10 (30.0%) patients in Cohort quantitation of 500 μg/ml. C. The actual number of patients enrolled per cohort was based on the interim analysis results, which was preplanned specifically to avoid treating patients if the combination did not have a synergistic 2.5 | Statistical analysis effect. The sample size was determined based on the primary efficacy endpoint. An interim efficacy analysis was performed when the first 2.2 | Procedures 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and the last patient in Phase 2 In Phase 1, patients received a starting dose of Isa (10 mg/kg) every had been followed up for 24 weeks (data cutoff: 5 May 2020, for week in Cycle 1, every 2 weeks in Cycles 2–6, and every 3 weeks Cohorts B and C; 18 August 2020, for Cohort A1; 15 February 2021, thereafter. Cemi was given at 250 mg every 2 weeks in Cycles 1–6, for Cohort A2). and at 350 mg every 3 weeks thereafter. The cycle duration was CR and ORR rates were summarized using descriptive statistics. 28 days for Cycles 1–6, then 21 days in subsequent cycles. All par- A 90% two‐sided confidence interval (CI) was computed using the ticipants received the following premedications (or equivalent), 30– Clopper–Pearson method. Efficacy evaluation was based on Simon's 60 min before Isa infusion, to prevent or reduce the incidence or 2‐stage design with 85% power at a 1‐sided alpha level of 5% for severity of infusion reactions: oral acetaminophen 650–1000 mg, each cohort. Duration of response, median PFS, and 95% CIs were ranitidine 50 mg intravenously (IV), diphenhydramine 25–50 mg IV, calculated using the Kaplan–Meier method. Individual concentrations methylprednisolone 100 mg IV, and oral montelukast 10 mg. and pharmacokinetic parameters of Isa were summarized by descriptive statistics. 2.3 | Outcomes 3 | RESULTS In Phase 1, safety and tolerability were assessed based on DLTs in Cycle 1, treatment‐emergent adverse events (TEAEs) or serious 3.1 | Patients TEAEs, and laboratory abnormalities. TEAEs and laboratory abnor- malities were graded using the National Cancer Institute Common In cohorts A1, A2, B, and C, 18, 12, 17, and 11 patients were enrolled, Terminology Criteria for Adverse Events version 5.0. respectively. Patient baseline characteristics are shown in Table 1. In Disease response was determined using positron emission to- Phase 1, 6 patients in each cohort were treated with a starting dose mography and assessed using the Lugano response criteria, 2014.23 of Isa + Cemi to determine the RP2D. No DLTs were observed during For Phase 2, CR rate was defined as the proportion of participants Cycle 1; thus, the starting dose was confirmed as the RP2D, obviating who had complete metabolic response (CMR) as best overall dose de‐escalation. response. Objective response rate was defined as the proportion of Exposure to Isa + Cemi was longer in the cHL cohorts compared participants with CMR or PR as best overall response. with the DLBCL and PTCL cohorts. Median (range) duration of Key secondary endpoints were duration of response (DoR) and exposure and number of cycles, respectively were 33.0 (6–69) weeks progression‐free survival (PFS). and 8.5 (1–21) in the cHL anti‐PD‐1/PD‐L1 naïve cohort, 36.1 (4–83) The all‐treated population was the primary analysis population weeks and 10.0 (1–25) in the cHL anti‐PD‐1/PD‐L1 progressors for efficacy and safety analyses and included all participants who cohort, 4.0 (2–41) weeks and 1.0 (1–11) in the DLBCL cohort, and 4.1 received ≥1 Isa or Cemi dose. (2–38) weeks and 1.0 (1–10) in the PTCL cohort. 112 - CARLO‐STELLA ET AL. 3.2 | Safety (Table 2). Grade ≥3 and serious TEAEs, respectively, were more frequent in the DLBCL (70.6% and 58.8%) and PTCL (81.8% and TEAEs were reported in 83.3% of the patients in the cHL anti‐PD‐1/ 63.6%) cohorts than in the cHL cohorts (5.6% and 11.1% [cHL anti‐ PD‐L1 naïve cohort and in all patients in the remaining cohorts PD‐1/PD‐L1 naïve], 8.3% and 16.7% [cHL anti‐PD‐1/PD‐L1 TABLE 1 Patient baseline characteristics Cohort A1: cHL (anti‐PD‐1/ Cohort A2: cHL (anti‐PD‐1/PD‐ Cohort B: DLBCL Cohort C: PD‐L1 naïve) (n = 18) L1 progressors) (n = 12) (n = 17) PTCL (n = 11) Age, years, median (range) 36.0 (21–87) 33.0 (19–68) 64.0 (23–75) 69.0 (50–77) Male 10 (55.6) 7 (58.3) 12 (70.6) 7 (63.6) ECOG performance status 0 14 (77.8) 9 (75.0) 5 (29.4) 3 (27.3) 1 4 (22.2) 3 (25.0) 11 (64.7) 8 (72.7) 2 0 0 1 (5.9) 0 Staging Stage I 0 0 0 0 Stage II 1 (5.6) 4 (33.3) 1 (5.9) 1 (9.1) Stage II bulky 1 (5.6) 0 1 (5.9) 0 Stage III 4 (22.2) 4 (33.3) 3 (17.6) 1 (9.1) Stage IV 12 (66.7) 4 (33.3) 12 (70.6) 9 (81.8) Number of prior regimens 1 0 0 0 10 (90.9) 2 0 0 14 (82.4) 0 >2 18 (100) 12 (100) 3 (17.6) 1 (9.1) Subtype Lymphocyte‐rich cHL 1 (5.6) 1 (9.1) NA NA Mixed‐cellularity cHL 3 (16.7) 2 (18.2) NA NA Nodular‐sclerosis cHL 14 (77.8) 8 (72.7) NA NA DLBCL, NOS NA NA 12 (70.6) NA High‐grade lymphomas with translocations of NA NA 1 (5.9) NA MYC and BCL2 and/or BCL6 (double/triple‐ hit lymphoma) Other NA NA 3 (17.6) NA T‐cell/histiocyte‐rich large B‐cell lymphoma NA NA 1 (5.9) NA Angioimmunoblastic T‐cell lymphoma NA NA NA 5 (45.5) PTCL, NOS NA NA NA 6 (54.5) Time from initial diagnosis to first dose in years, 2.56 (0.8–8.3) 3.38 (1.3–20.9) 1.19 (0.3–7.7) 1.26 (0.3–6.5) median (range) International Prognostic Score at study entrya 0 0 2 (16.7) 0 0 1 4 (22.2) 4 (33.3) 1 (5.9) 1 (9.1) 2 6 (33.3) 3 (25.0) 1 (5.9) 2 (18.2) 3 4 (22.2) 3 (25.0) 10 (58.8) 5 (45.5) 4 1 (5.6) 0 4 (23.5) 3 (27.3) CARLO‐STELLA ET AL. - 113 T A B L E 1 (Continued) Cohort A1: cHL (anti‐PD‐1/ Cohort A2: cHL (anti‐PD‐1/PD‐ Cohort B: DLBCL Cohort C: PD‐L1 naïve) (n = 18) L1 progressors) (n = 12) (n = 17) PTCL (n = 11) 5 2 (11.1) 0 1 (5.9) 0 6 1 (5.6) 0 0 0 Note: All data are shown as n (%), except where otherwise indicated. Abbreviations: BCL, B‐cell lymphoma; cHL, classic Hodgkin's lymphoma; DLBCL, diffuse large B‐cell lymphoma; ECOG, Eastern Cooperative Oncology Group; MYC, myelocytomatosis; NA, not applicable; NOS, not otherwise specified; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PTCL, peripheral T‐cell lymphoma. a Different risk factors are used to calculate the International Prognostic Score for cHL, DLBCL, and PTCL. For cHL cohorts, 1 point is added with the presence of each of the following criteria: age ≥45 years; albumin <4 g/dl; hemoglobin <10.5 g/dl; leukocytosis (white blood cell count ≥15,000/mm3); lymphocytopenia (lymphocyte count <8% of white blood cell count, and/or lymphocyte count <600/mm3); male; stage IV disease. For DLBCL and PTCL cohorts, 1 point is added with the presence of each of the following criteria: age >60; Ann Arbor stage III or IV; ECOG performance status ≥2; serum lactate dehydrogenase level >1 � normal; >1 extranodal site. TABLE 2 Safety summary by cohort, all‐treated population Cohort A1: cHL (anti‐PD‐1/ Cohort A2: cHL (anti‐PD‐1/PD‐L1 Cohort B: DLBCL Cohort C: PTCL PD‐L1 naïve) (n = 18) progressors) (n = 12) (n = 17) (n = 11) Any TEAE 15 (83.3) 12 (100) 17 (100) 11 (100) Grade ≥3 TEAE 1 (5.6) 1 (8.3) 12 (70.6) 9 (81.8) Grade 5 TEAE (fatal outcome) 0 0 4 (23.5) 2 (18.2) SAEs 2 (11.1) 2 (16.7) 10 (58.8) 7 (63.6) Treatment‐relateda TEAEs 9 (50.0) 11 (91.7) 9 (52.9) 8 (72.7) Treatment‐relateda Grade ≥3 0 0 1 (5.9) 3 (27.3) TEAE Treatment‐related SAE 0 1 (8.3) 2 (11.8) 2 (18.2) TEAE leading to treatment 0 0 1 (5.9) 3 (27.3) discontinuation Any AESIb 7 (38.9) 8 (66.7) 7 (41.2) 7 (63.6) Any IR 7 (38.9) 9 (75.0) 8 (47.1) 8 (72.7) Note: All data are shown as n (%). Abbreviations: AE, adverse event; AESI, adverse event of special interest; cHL, classic Hodgkin's lymphoma; DLT, dose‐limiting toxicity; IR, infusion reaction; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PI3K, phosphoinositide 3‐kinase; PTCL, peripheral T‐cell lymphoma; SAE, serious adverse event; TEAE, treatment‐emergent adverse event. a Treatment‐related TEAEs are TEAEs related to at least one drug of the combination. b AESIs include Grade ≥2 IRs, Grade ≥3 immune‐related TEAEs, immune‐related AEs of any grade in a patient previously treated with a PI3K inhibitor (only applicable for patients who received cemiplimab), DLTs as defined in Phase 1, pregnancy, symptomatic overdose with investigational medicinal product/non‐investigational medicinal product. progressors]). However, treatment‐related any‐grade, Grade ≥3, and urinary tract infection) and 2 deaths in the PTCL cohort (1 unknown serious TEAEs, respectively, were less frequent across all cohorts cause, 1 progressive disease); however, no deaths were treatment‐ (50.0%, 0%, 0% [cHL anti‐PD‐1/PD‐L1 naïve]; 91.7%, 0%, 8.3% [cHL related (Table 2). anti‐PD‐1/PD‐L1 progressors]; 52.9%, 5.9%, 11.8% [DLBCL]; 72.7%, TEAEs reported in ≥20% of patients are shown in Table 3. Most 27.3%, 18.2% [PTCL]). No patients in the cHL cohorts reported TEAEs were Grade 1/2. Infusion‐related reactions were the most TEAEs leading to definitive discontinuation, compared with 5.9% in common, with an incidence of 38.9%, 75.0%, 52.9%, and 72.7% in cHL the DLBCL cohort and 27.3% in the PTCL cohort (Table 2). anti‐PD‐1/PD‐L1 naïve, cHL anti‐PD‐1/PD‐L1 progressor, DLBCL, No Grade 5 (fatal) TEAEs were reported in the cHL cohorts. and PTCL cohorts, respectively. Among Grade ≥3 TEAEs, infusion‐ There were 4 deaths reported during the on‐treatment period in the related reactions and pyrexia were reported in 1 (9.1%) patient DLBCL cohort (2 progressive disease, 1 intestinal perforation, 1 each in the PTCL cohort, peripheral edema and abdominal pain in 1 114 - CARLO‐STELLA ET AL. TABLE 3 TEAEs in ≥20% of patients by cohort Cohort A2: cHL (anti‐PD‐ Cohort A1: cHL (anti‐PD‐ 1/PD‐L1 progressors) 1/PD‐L1 naïve) (n = 18) (n = 12) Cohort B: DLBCL (n = 17) Cohort C: PTCL (n = 11) All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3 All grades Grade ≥3 Any event 15 (83.3) 1 (5.6) 12 (100) 1 (8.3) 17 (100) 12 (70.6) 11 (100) 9 (81.8) Infusion‐related reaction 7 (38.9) 0 9 (75.0) 0 9 (52.9) 0 8 (72.7) 1 (9.1) Pyrexia 4 (22.2) 0 3 (25.0) 0 2 (11.8) 0 2 (18.2) 1 (9.1) Diarrhea 3 (16.7) 0 3 (25.0) 0 4 (23.5) 0 1 (9.1) 0 Peripheral edema 3 (16.7) 0 0 0 5 (29.4) 1 (5.9) 1 (9.1) 0 Pruritus 2 (11.1) 0 3 (25.0) 0 0 0 1 (9.1) 0 Abdominal pain 2 (11.1) 0 1 (8.3) 0 5 (29.4) 1 (5.9) 0 0 Decreased appetite 2 (11.1) 0 0 0 4 (23.5) 2 (11.8) 0 0 Nausea 1 (5.6) 0 4 (33.3) 0 4 (23.5) 0 0 0 Fatigue 0 0 1 (8.3) 0 4 (23.5) 0 1 (9.1) 0 Hematological laboratory abnormalities Anemia 16 (88.9) 1 (5.6) 7 (58.3) 0 16 (100) 2 (12.5) 11 (100) 2 (18.2) Lymphopenia 12 (66.7) 5 (27.8) 3 (25.0) 1 (8.3) 14 (87.5) 7 (43.8) 10 (90.9) 4 (36.4) Neutropenia 3 (16.7) 0 – – 6 (37.5) 3 (18.8) 6 (54.5) 2 (18.2) Leukopenia 10 (55.6) 0 2 (16.7) 0 13 (81.3) 3 (18.8) 8 (72.7) 2 (18.2) Thrombocytopenia 7 (38.9) 0 3 (25.0) 0 11 (68.8) 2 (12.5) 8 (72.7) 4 (36.4) Note: All data are shown as n (%). Abbreviations: cHL, classic Hodgkin's lymphoma; DLBCL, diffuse large B‐cell lymphoma; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐ 1; PTCL, peripheral T‐cell lymphoma; TEAE, treatment‐emergent adverse event. (5.9%) patient each, and decreased appetite in 2 (11.8%) patients in and 1 (5.9%) DLBCL patient. No PTCL patients achieved CMR. the DLBCL cohort. Other commonly reported TEAEs were pyrexia Among the 10 responders in the cHL anti‐PD‐1/PD‐L1 naïve cohort, (22.2%) in the cHL anti‐PD‐1/PD‐L1 naïve cohort; nausea (33.3%), five experienced radiological progression or death with a median pyrexia (25.0%), diarrhea (25.0%), and pruritus (25.0%) in the cHL (range) DoR of 5.79 (1.41–9.3) months; 2/4 responders in the cHL anti‐PD‐1/PD‐L1 progressors cohort; and abdominal pain (29.4%), anti‐PD‐1/PD‐L1 progressors cohort had a DoR of 3.19 and peripheral edema (29.4%), decreased appetite (23.5%), diarrhea 7.56 months. (23.5%), fatigue (23.5%), and nausea (23.5%) in the DLBCL cohort. Median PFS (95% CI) was 8.38 months (2.73–not calculable The most commonly reported all‐grade hematological laboratory [NC]), 8.28 months (2.60–NC), 2.37 months (0.46–2.69), and abnormality was anemia (88.9% [cHL anti‐PD‐1/PD‐L1 naïve], 58.3% 2.66 months (0.43–2.99) in cHL anti‐PD‐1/PD‐L1 naïve, cHL anti‐PD‐ [cHL anti‐PD‐1/PD‐L1 progressors], 100% [DLBCL and PTCL]). The 1/PD‐L1 progressors, DLBCL, and PTCL cohorts, respectively most frequent Grade ≥3 hematological laboratory abnormalities (Figure 2). were lymphopenia in all cohorts (27.8% [cHL anti‐PD‐1/PD‐L1 naïve], 8.3% [cHL anti‐PD‐1/PD‐L1 progressors], 43.8% [DLBCL], and 36.4% [PTCL]), and thrombocytopenia (36.4%) in the PTCL cohort (Table 3). 3.4 | Pharmacokinetics Mean Isa maximum plasma concentration (Cmax) and area under the 3.3 | Efficacy concentration versus time curve over 1 week (AUC1 week) were, respectively, 226 μg/ml and 22,500 μg.h/ml in the cHL anti‐PD‐1/ Among the all‐treated population, response rate was 55.6%, 33.3%, PD‐L1 naïve cohort, 265 μg/ml and 26,600 μg.h/ml in the cHL anti‐ 5.9%, and 9.1% in cHL anti‐PD‐1/PD‐L1 naïve, cHL anti‐PD‐1/PD‐L1 PD‐1/PD‐L1 progressors cohort, 253 μg/ml and 23,700 μg.h/ml in progressor, DLBCL, and PTCL cohorts, respectively (Table 4). Com- the DLBCL cohort, and 181 μg/ml and 15,000 μg.h/ml in the PTCL plete metabolic response was observed in 5 (27.8%) cHL anti‐PD‐1/ cohort (Table 5). Pharmacokinetic analyses suggested no effect of PD‐L1 naïve patients, 2 (16.7%) cHL anti‐PD‐1/PD‐L1 progressors, Cemi on Isa exposure (Cmax, AUC1week). CARLO‐STELLA ET AL. - 115 TABLE 4 Summary of response rate per Lugano 2014 criteria, all‐treated population Cohort A1: cHL (anti‐PD‐1/ Cohort A2: cHL (anti‐PD‐1/ Cohort B: DLBCL Cohort C: PTCL PD‐L1 naïve) (n = 18) PD‐L1 progressors) (n = 12) (n = 17) (n = 11) Overall response Responders (CR or PR) 10 (55.6) 4 (33.3) 1 (5.9) 1 (9.1) Best overall response Complete metabolic response/complete 5 (27.8) 2 (16.7) 1 (5.9) 0 response Partial metabolic response/partial 5 (27.8) 2 (16.7) 0 1 (9.1) response No metabolic response/stable disease 1 (5.6) 3 (25.0) 0 1 (9.1) Progressive metabolic disease/ 6 (33.3) 5 (41.7) 7 (41.2) 4 (36.4) progressive disease Not evaluablea 1 (5.6) 0 9 (52.9) 5 (45.5) Note: All data are shown as n (%). Abbreviations: cHL, classic Hodgkin's lymphoma; CR, complete response; DLBCL, diffuse large B‐cell lymphoma; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PR, partial response; PTCL, peripheral T‐cell lymphoma. a Including patients with no post‐baseline evaluation prior to the initiation of a new anti‐cancer therapy or the data cutoff date. F I G U R E 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 4 | DISCUSSION Combining nivolumab with brentuximab vedotin (anti‐CD30 antibody–drug conjugate) increased CR rate to 61% in the interim In patients with relapsed/refractory lymphoma, treatment beyond analysis of a Phase 1/2 study of relapsed/refractory patients with the first line remains challenging and represents a significant unmet cHL.27 In a Phase 1b study with nivolumab monotherapy, ORR was 24–26 need. Monoclonal antibodies that block the PD‐1/PD‐L1 axis achieved in 4/11 (36%) patients with DLBCL and 2/5 (40%) patients have demonstrated limited clinical benefit in lymphoma. Although with PTCL.7 Among patients with DLBCL treated with Cemi mono- nivolumab and pembrolizumab are approved for relapsed/refractory therapy, ORR was achieved in 3/18 (17%) patients.8 Although the cHL, only a small subset (around 20%–28%) of the patients achieved reason for suboptimal efficacy of these agents in lymphoma is un- complete remission.3,4 Similar outcomes (12% CR) were reported clear, their promising anti‐tumor activity in a subset of lymphomas with Cemi monotherapy in an early‐phase study in patients with HL.8 has spurred interest in the development of newer, potentially more 116 - CARLO‐STELLA ET AL. TABLE 5 Isa pharmacokinetic parameters Mean ± SD (Geometric Cohort A1: cHL (anti‐PD‐1/PD‐ Cohort A2: cHL (anti‐PD‐1/PD‐L1 Cohort B: Cohort C: mean) [CV%] L1 naïve) (n = 17) progressors) (n = 12) DLBCL (n = 14) PTCL (n = 7) All (N = 50) Cmax 226 � 48.1 265 � 38.8 253 � 29.1 181 � 35.7 237 � 47.1 (μg/ml) (221) [21] (262) [15] (251) [12] (178) [20] (232) [20] tmaxa 5.95 5.23 5.26 4.57 5.17 b (h) (2.00–8.92) (3.00–8.83) (2.60–10.5) (2.33–7.45) (2.00–10.5) AUC1 week 22,500 � 5770 26,600 � 4030 23,700 � 4960 15,000 � 4680 22,700 � 6030 (μg•h/mL) (21,800) [26] (26,300) [15]c (23,200) [21] (14,300) [31] (21,800) [27]d a Median. b Min–max. c n = 11. d n = 49. Abbreviations: AUC, area under curve; cHL, classic Hodgkin's lymphoma; Cmax, maximum concentration; CV, coefficient of variation; DLBCL, diffuse large B‐cell lymphoma; Isa, isatuximab; PD‐1, programmed death‐1; PD‐L1, programmed death ligand‐1; PTCL, peripheral T‐cell lymphoma; SD, standard deviation; tmax, time to reach Cmax. effective checkpoint inhibitors and combinations of agents with terminated in view of other more efficacious therapeutic options different mechanisms of action for the treatment of patients with available for this patient population. For the DLBCL and PTCL co- lymphoma.1 horts, results of the interim efficacy analysis did not meet pre- The expression of CD38 in lymphoma, together with preclinical specified criteria (i.e., ≥8/17 and ≥3/11 responders in the DLBCL and evidence for anti‐CD38 antibodies against CD38+ lymphoma, sug- PTCL cohorts, respectively) to continue enrollment in Stage 2 of gests potential utility for these agents in patients with CD38+ lym- Phase 2. Consequently, accrual was stopped for the DLBCL and PTCL phoma. The anti‐CD38 antibodies, Isa, daratumumab, and MOR202 cohorts. kill CD38+ lymphoma cells via antibody‐dependent cellular cyto- Most patients with DLBCL were primary refractory/bulky and toxicity and antibody‐dependent cellular phagocytosis9,16,17 In addi- discontinued within weeks from treatment initiation; in such patients, tion, Isa has strong anti‐apoptotic activity in lymphoma cells in the a more aggressive combination therapy may be needed. Overall, absence of crosslinking agents.17 these results demonstrated that the combination was not very active Several studies suggest a role for CD38 in the immunomodula- in DLBCL and PTCL populations. This is consistent with limited tory and pro‐tumoral microenvironment. CD38 is expressed in many clinical benefit of daratumumab monotherapy in Phase 2 studies with 9,28–31 immunosuppressive cell types ; targeting CD38‐expressing patients with relapsed/refractory B‐cell NHL subtypes and natural immune cells triggers anti‐tumor immunomodulatory mecha- killer/T‐cell lymphoma.38,39 The clinical development of next‐ 17,32–36 nisms. CD38 is upregulated in mouse models of lung cancer generation anti‐CD38 antibodies, as well as new modalities target- and melanoma that have acquired resistance to anti‐PD‐1/anti‐ ing this tumor antigen, may provide more effective treatment options 28,29,37 PD‐L1 blockade, and correlates with CD8+ T‐cell impairment. for improved outcomes in the advanced lymphoid malignancy space. Concurrent inhibition of CD38 and PD‐L1 in these murine models Pharmacokinetic parameters of Isa in the current study were has been shown to substantially reduce primary tumor burden and consistent with those observed in a recent Phase 1/2 study of metastases.18 Isa + Cemi in patients with metastatic castration‐resistant prostate To address whether co‐inhibition of PD‐1 and CD38 may benefit cancer or advanced non‐small cell lung cancer, where the same assay patients with lymphoma, we assessed the safety, efficacy, and phar- method was used, suggesting no effect of Cemi on Isa exposure (Cmax, macokinetics of Isa + Cemi in patients with cHL, DLBCL, and PTCL. AUC1week).40 Similar to the current study in lymphoma, this study During the Phase 1 safety run‐in part of this study, no DLTs were demonstrated a lack of efficacy of Isa + Cemi in small patient cohorts observed during Cycle 1 and the RP2D was confirmed for Phase 2. with these advanced malignancies. Isa + Cemi had a manageable safety profile with no new safety sig- nals compared with known effects of the individual drugs. Infusion‐ related reactions were the most common events. Grade ≥3, Grade 5 | CONCLUSION 5, and serious TEAEs were higher in the DLBCL and PTCL cohorts compared with the cHL cohorts. Treatment‐related TEAEs were less Isa + Cemi had a manageable safety profile. Limited clinical efficacy frequent in all cohorts. was observed in patients with cHL who had prior anti‐PD‐1/PD‐L1 Modest clinical efficacy was observed in patients with cHL, with exposure, as well as in those who did not. However, we did not responses achieved in patients who had or had not previously observe a synergistic effect of Isa in combination with Cemi in pa- received anti‐PD‐1/PD‐L1 therapy. However, the study was tients with cHL, DLBCL, or PTCL. CARLO‐STELLA ET AL. - 117 A U TH O R C O N TR IB UT I O N S Honoraria – Roche; Research Funding – Celgene/BMS, Janssen, Roche. Rao Saleem was responsible for study oversight. Carmelo Carlo‐ IM: Nothing to disclose. MWMvdP: Nothing to disclose. GA, RM, RJ, Stella, Pier Luigi Zinzani, Anna Sureda, Luis Araújo, Olivier Casas- LL, and RS are employed by Sanofi and may hold stock and/or stock novas, Cecilia Carpio, Su‐Peng Yeh, Krimo Bouabdallah, Guillaume options in the company. VR: Advisory Role – AstraZeneca; Consultancy – Cartron, Won Seog Kim, Raul Cordoba, Youngil Koh, Alessandro Re, AstraZeneca, Gilead, Incyte, NanoString, Roche; Honoraria – Daniela Alves, Martine Chamuleau, Steven Le Gouill, Armando AstraZeneca; Research Funding – argenx, Astex Pharmaceuticals, GSK. López‐Guillermo, Ilídia Moreira, Marjolein W. M. van der Poel, and Vincent Ribrag were investigators in the study and contributed to DA T A A V A I L A B I L I T Y S T A T E M E N T data acquisition and analysis. Vincent Ribrag designed the overall Qualified researchers can request access to patient‐level data and study and for DLBCL, Carmelo Carlo‐Stella for cHL, and Pier Luigi related study documents including the clinical study report, study Zinzani for PTCL. Giovanni Abbadessa, Robin Meng, Ran Ji, Lucie protocol with any amendments, blank case report forms, statistical Lépine, and Rao Saleem contributed to analysis and interpretation of analysis plan, and dataset specifications. Patient‐level data will be data for the work. All authors revised the work for important intel- anonymized, and study documents will be redacted to protect the lectual content and assume responsibility for data integrity and the privacy of trial participants. Further details on Sanofi's data‐sharing decision to submit this manuscript for publication, had full access to criteria, eligible studies, and process for requesting access are at: the study data, edited and reviewed manuscript drafts, and approved https://www.vivli.org. the final version for submission. E T HI C S S T A T E M E N T A CK N O W LE DG M EN T S The study was conducted in accordance with the Declaration of This study was sponsored by Sanofi. The authors thank the partici- Helsinki, Council for International Organizations of Medical Sciences pating patients and their families, and the study centers and in- International Ethical Guidelines, and the International Conference on vestigators for their contributions to the study. Medical writing Harmonization Good Clinical Practice Guidelines. The relevant in- support was provided by Smitha Reddy, PhD, of Elevate Scientific dependent ethics committees and institutional review boards Solutions, contracted by Sanofi for publication support services. approved the study protocol. All participants provided written informed consent prior to study enrollment. Clinical trial registration: C O N F LI C T O F I N T E R ES T ClinicalTrials.gov, NCT03769181. CC‐S: Advisory Role – Sanofi; Consultancy – Sanofi. PLZ: Honoraria – Gilead, Incyte, Merck, Novartis, Roche, Sanofi, Takeda. AS: Consul- OR CI D tancy –Bluebird, BMS, Genmab, Janssen, Kite, MSD, Novartis, Roche, Pier Luigi Zinzani https://orcid.org/0000-0002-2112-2651 Takeda; Honoraria – BMS, Janssen, Kite, MSD, Novartis, Roche, Sanofi, Takeda. LA: Nothing to disclose. OC: Advisory Role – Gilead/ PEER REVIEW Kite, Roche, Takeda; Consultancy – AbbVie, BMS, Gilead/Kite, Jans- The peer review history for this article is available at https://publons. sen, MSD, Roche, Takeda; Honoraria – Gilead/Kite, Roche; Research com/publon/10.1002/hon.3089. Funding – Gilead/Kite, Roche, Takeda. CC: Consultancy – Regeneron, Takeda; Honoraria – BMS, Novartis, Takeda. S‐PY: Advisory Role – R EF ER E N CE S AbbVie, Amgen, Astellas, Astex, Janssen, Novartis, Sanofi, Takeda; 1. Tobin JWD, Bednarska K, Campbell A, Keane C. PD‐1 and LAG‐3 checkpoint blockade: potential avenues for therapy in B‐cell lymph- Honoraria – AbbVie, Amgen, Astellas, BMS, Janssen, AstraZeneca, oma. Cells. 2021;10(5):1152. https://doi.org/10.3390/cells10051152 Novartis, Roche, Sanofi, Takeda. KB: Nothing to disclose. GC: Con- 2. Zaja F, Tabanelli V, Agostinelli C, et al. 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