Phase 1/2 Isatuximab and Cemiplimab Study for Lymphoma Terminated

A study of isatuximab and cemiplimab in 3 lymphoma subtypes will not continue, for reasons unrelated to safety.

Image credit: © Dr_Microbe - Adobe Stock

Image credit: © Dr_Microbe - Adobe Stock

The combination of isatuximab (Sarclisa) and cemiplimab (Libtayo) had manageable safety and modest efficacy in patients with relapsed or refractory classic Hodgkin lymphoma (cHL), according to results of a phase 1/2 study (NCT03769181), published in Hematologic Oncology.1 However, the study was terminated per sponsor decision due to the limited efficacy and lack of synergy of the combination.1

Isatuximab and cemiplimab had an overall response rate of 55.6% in patients with cHL who received no prior anti–PD-1/PD-L1 therapy, and 33.3% of patients with cHL who had progressed on anti–PD-1/PD-L1 therapy. In diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) cohorts, it did not meet prespecified efficacy criteria to enroll patients in phase 2 Stage 2.

According to the study authors, the ORR shown with nivolumab (Opdivo) monotherapy in patients with DLBCL (36%) and PTCL (40%) surpassed that shown with the combination of isatuximab and cemiplimab.1,2

Anti-CD38 antibodies including isatuximab have been shown to be effective in treating hematologic malignancies, particularly multiple myeloma. Anti–PD-1/PD-L1 immune checkpoint blockade have been investigated in lymphoma subtypes but have had limited efficacy. Cemiplimab showed efficacy as monotherapy for lymphomas in a phase 1 trial [NCT02651662].3 Investigators in this trial hypothesized that combining these 2 mechanisms of action would enhance antitumor activity since CD38 upregulation in tumor cells is associated with acquired resistance to anti–PD-1/PD-L1 agents based on preclinical data.1

The primary end points for phase 1 were the safety and tolerability of isatuximab/cemiplimab and the recommended Phase 2 dose (RP2D). In phase 2, the primary end points were the complete response (CR) rate of isatuximab/cemiplimab in the PD-1/PD-L1–naive cHL cohort and the overall response rate in the other cohorts. Secondary end points included duration of response (DOR), progression-free survival, and the immunogenicity and pharmacokinetic profile of the combination. Stage 2 of phase 2 was planned; the patients with cHL would receive radiotherapy in combination with isatuximab/cemiplimab in this stage, whereas additional patients with DLBCL and PTCL would be added to their cohorts.

Patients who were at least 12 years old with histologically confirmed advanced cHL, DLBCL, or PTCL that had progressed or relapsed on prior therapy were enrolled at 23 sites in 7 countries.

In phase 1, patients received 10 mg/kg isatuximab every week in the first 28-day cycle, every 2 weeks in cycle 2 to 6, and every 21 days afterward. They received 250 mg cemiplimab every 2 weeks in the first 6 cycles and every 21 days afterward. No dose-limiting toxicities were observed in cycle 1 and the starting dose was confirmed as the RP2D.

There were 4 cohorts on the trial. There were 18 patients with cHL who received no prior anti–PD-1/PD-L1 therapy, 12 patients with cHL who had progressed on anti–PD-1/PD-L1 therapy, 17 patients with DLBCL, and 11 patients with PTCL.

The PD-1/PD-L1–naive cHL cohort had an ORR of 55.6% with a 27.8% CR rate; among the 10 responders there was a 5.79 (range, 1.41-9.3) month median DOR. The median PFS in this cohort was 8.38 months (95% CI, 2.73-not calculable [NC]). In the anti–PD-1/PD-L1 pretreated cHR cohort, there was a 33.3% ORR with 16.7% CR rate; among the 4 responders the 2 who progressed had DOR of 3.19 and 7.56 months. Their median PFS was 8.28 months (95% CI, 2.60–NC). One patient (5.9%) in the DLBCL cohort had a CR, whereas 1 (9.1) in the PTCL cohort had a partial response. A significant number in these cohorts were not evaluable (9 (52.9%) in the DLBCL cohort and 5 (45.5%) in the PTCL cohort.

Pharmacokinetic analysis suggested that there was no effect of cemiplimab on isatuximab exposure. Investigators noted that this was consistent with another study’s [NCT03367819] assessment of the combination in patients with prostate cancer or non–small cell lung cancer which failed to show synergistic pharmacokinetics.4

Any-grade treatment-emergent adverse events (TEAEs) were reported in 83.3% of the PD-1/PD-L1–naive cHL cohort and in all patients in the other cohorts.1 However, the cHL cohorts each reported only 1 patient with grade 3 or higher TEAE and 2 with serious AEs, whereas 12 (70.6%) with DLBCL and 9 (81.8%) with PTCL reported grade 3 or higher TEAEs and 10 (58.8%) with DLBCL and 7 (63.6%) with PTCL reported serious AEs. There were no grade 3 or higher AEs considered treatment related in the cHL cohorts, versus 1 (5.9%) in the DLBCL cohort and 3 (27.3%) in the PTCL cohort.

The most common TEAEs were infusion reactions; other common TEAEs were pyrexia, nausea, diarrhea, and pruritus in the cHL cohorts, and abdominal pain, peripheral edema, decreased appetite, diarrhea, fatigue, and nausea in the DLBCL cohort.

Accrual of patients for stage 2 of phase 2 was stopped in the other cohorts as they did not meet the required 8 out of 17 DLBCL responders and 3 out of 11 PTCL responders. Although clinical activity was observed in the cHL cohorts, the study was terminated in these patients as well in consideration of other more efficacious options available for these patients.


1. Carlo-Stella C, Zinzani PL, Sureda A, et al. A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma. Hematol Oncol. 2023;41(1):108-119. doi:10.1002/hon.3089

2. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698-2704.

3. Topp M, Borchmann P, Wagner-Johnston N, et al. Safety and preliminary antitumor activity of the anti-PD-1 monoclonal antibody cemiplimab (REGN2810) alone or in combination with REGN1979, an anti-CD20 x anti-CD3 bispecific antibody, in patients with B-lymphoid malignancies. Blood. 2017;130(suppl_1):1495. doi:10.1182/blood.V130.Suppl_1.1495.1495

4. Zucali PA, Lin CC, Carthon BC, et al. Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study. J Immunother Cancer. 2022;10(1):e003697. doi:10.1136/jitc-2021-003697

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