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Sunday, January 29, 2023

Iberdomide Alone or in Combination With Anti-CD20 Monoclonal Antibodies Shows Early Efficacy in R/R Lymphoma

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Iberdomide monotherapy or in combination with anti-CD20 antibodies was well tolerated and found to elicit encouraging responses in patients with relapsed or refractory lymphoma.

Iberdomide (CC-220) monotherapy or in combination with anti-CD20 antibodies was well tolerated and found to elicit encouraging responses in patients with relapsed or refractory lymphoma, according to data from an ongoing open-label, phase 1/2 study (NCT04464798) presented at the 2022 ASH Annual Meeting.

In the total population (n = 54), the overall response rate (ORR) was 50% (95% CI, 36%-64%); this included a complete response (CR) rate of 30% (95% CI, 18%-44%) and a partial response (PR) rate of 20%. The stable disease (SD) rate was 9%, and 20% of patients experienced progressive disease (PD).

In cohort A (n = 24), iberdomide monotherapy induced an ORR of 38%, which included a CR rate of 29% and a PR rate of 8%; 8% of patients had SD and 33% had PD. In cohort B (n = 14), the combination of iberdomide and rituximab (Rituxan) resulted in an ORR of 57%, which included a 29% CR rate and a 29% PR rate; in this group, the SD and PD rates were 7% and 14%, respectively. The highest ORR was achieved in cohort C (n = 16), who had received iberdomide plus obinutuxumab (Gazyva). In this group, the ORR was 63%, which comprised a CR rate of 31% and a PR rate of 31%; 13% of patients had SD and 6% had PD.

Notably, 6 of the 12 patients previously treated with CAR-T therapy achieved a CR with study treatment; 1 of these patients experienced a PR.

In her presentation, Catherine Thieblemont, MD, lead study author and head of the hemato-oncology department of Hôpital Saint-Louis in Paris, France, explained iberdomide’s function as a cereblon E3 ligase modulator (CELMoD) and the newly understood function of these drugs on cereblon to enhance tumor degradation: “What we have learned recently about cereblon is that cereblon has 2 states: an inactive open state and an active closed conformation, and these drugs… will drive these states from the open state to a closed conformation,” she said.

Patients diagnosed with relapsed/refractory lymphoma who were at least 18 years of age and who had been previously treated with 2 or more lines of therapy were eligible for the study. Patients were also required to have measurable disease per Lugano 2014 criteria and an ECOG performance status of 0 to 2.

The 54 patients enrolled were divided into 3 dose-escalation cohorts where the following would be examined: iberdomide monotherapy in patients with any lymphoma subtype (cohort A), iberdomide plus ritixumab in patients with B-cell lymphomas (cohort B), and iberdomide plus obinutuzumab in patients with indolent non-Hodgkin lymphoma (NHL; cohort C).

Treatment was administered as part of 28-day cycles (24 cycles for all lymphomas and 12 cycles for indolent NHL). Iberdomide was given at doses ranging from 0.6 mg to 2.0 mg on days 1 to 21. Rituximab was administered intravenously at a dose of 375 mg/m2 on days 1, 8, 15, and 22 of the first cycle; the agent was subsequently given at 1400 mg subcutaneously or 375 mg/m2 intravenously on day 1 of cycles 2 to 5. Obinutuzumab was given intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6.

The primary end point of the trial was to establish he maximum tolerated dose (MTD) and the recommended phase 2 dose of iberdomide alone and in combination with either rituximab or obinutuzumab. Secondary end points included safety, pharmacokinetics, and efficacy.

In the total population, the median patient age was 67.5 years (range, 28-83); 69% of patients were male. Regarding disease, 39% had aggressive B-cell NHL; of these patients, 20% previously received CAR T-cell therapy and 15% had prior lenalidomide (Revlimid). Moreover, 24% of patients had follicular lymphoma 1 to 3a, 15% had marginal zone lymphoma, and 22% had other.

Regarding Ann Arbor disease stage at diagnosis, 17% had stage I/II disease and 80% had stage III/IV disease. The median number of pior regimens received was 4 (range, 1-12). In terms of ECOG performance status, most patients (85%) had a status of 0 to 1, and the remainder (13%) had a status of 2.

At the time of data cutoff, which was September 1, 2022, 7 patients completed treatment, 14 patients were still receiving treatment, and 33 patients had discontinued treatment. Of those who discontinued, 31 continued to the follow-up period with 23 ongoing treatment and 8 ultimately discontinuing treatment.

Reasons for discontinued treatment include PD (n = 18), death (n = 6), adverse effects (AEs) unrelated to any study drug (n = 3), physician decision (n = 3), withdrawal (n = 2), or a second primary malignancy (multiple myeloma) unrelated to iberdomide or any study drug developed (n = 1). Patients who discontinued follow-up did so due to death (n = 7) or patients discretion (n = 1).

The median treatment duration in the overall population was 4.4 months; this was shortest with iberdomide monotherapy (3.0 months) and the longest for iberdomide plus ritixumab (6.4 months). The median treatment duration in those who received iberdomide and obinutuzumab was 5.2 months.

Overall, 72% of safety-evaluable patients (n = 54) experienced a grade 3 or 4 AE, with the majority being hematological events. Fifty percent of patients experienced neutropenia, and they were treated with granulocyte colony–stimulating factor. Other hematological adverse effects of the same grade include anemia (17%), thrombocytopenia (15%) and febrile neutropenia (6%). Some patients also experienced any-grade constipation (22%) and diarrhea (19%).

In the overall safety population, 80% of patients were evaluable for dose-limiting toxicities (DLTs) and 16% of patients were reported to have them. DLTs occurred in 1 patient who was receiving single-agent iberdomide and had thrombocytopenia, 2 patients who were receiving iberdomide plus rituximab who both had neutropenia, and 4 patients who were receiving iberdomide and obinutuzumab who had neutropenia (n = 2), hypercalcemia (n = 1), or face angioedema (n = 1).

Eighty-nine percent of patients required at least 1 dose interruption of iberdomide, 70% of these cases were due to toxicities. Moreover, 15% of patients required dose reductions of iberdomide. The median relative dose intensity was 89% (range, 12%-101%).

No cohort achieved the MTD. Twenty-four percent (n = 13) of patients dided during the study; 4 deaths were because of toxicities (acute respiratory failure, sepsis, COVID-19, and respiratory failure associated with COVID-19). However, none of the deaths were from TEAEs.

The higher response rate in cohorts who received iberdomide in addition to a monoclonal antibody indicate “promising activity and combinability of CELMoD agents in (relapsed/refractory) lymphoma,” Thieblemont concluded. “Oral administration may offer an attractive outpatient treatment option.”

Reference

Thieblemont C, Munoz J, Tucci A, et. al. Iberdomide (CC-220) monotherapy or in combination with an anti-CD20 monoclonal antibody as effective therapy in patients with relapsed/refractory lymphoma: early results from a phase 1/2 study. Blood. 2022;140(suppl 1):569-572. doi:10.1182/blood-2022-162559

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