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

Introduction

Iberdomide (IBER; CC-220) is an oral cereblon E3 ligase modulator (CELMoD) agent that causes degradation of Ikaros and Aiolos, transcription factors essential for lymphoma cell survival. In vitro studies suggest IBER enhances T-cell immunostimulatory and direct cytotoxic effects versus lenalidomide. IBER demonstrated apoptotic activity in diffuse large B-cell lymphoma (DLBCL) cell lines independent of cell of origin (COO). We present data from an ongoing phase 1/2 open-label study (NCT04464798) assessing safety, pharmacokinetics (PK), and preliminary efficacy of IBER alone or in combination with an anti-CD20 monoclonal antibody (mAb) in patients (pts) with relapsed or refractory (RR) lymphomas.

Methods

Pts with RR lymphomas and ≥ 2 prior lines of treatment (tx) were given escalating doses of IBER alone (cohort A: all lymphomas), or with rituximab (cohort B: all B-cell lymphomas) or obinutuzumab (cohort C: marginal zone lymphoma [MZL] or grade 1–3a follicular lymphoma [FL]) to determine maximum tolerated dose (MTD). IBER starting dose was 1 mg daily (days 1–21 every 28 days) with sequential escalation to 1.3 mg and 1.6 mg. Pts received IBER for ≤ 24 cycles (12 for MZL/FL) or until disease progression or unacceptable toxicity. Pts in cohorts B and C received rituximab or obinutuzumab, respectively, for ≤ 6 cycles. Granulocyte-colony stimulating factor (G-CSF) was permitted after the dose limiting toxicity (DLT) evaluation period (tx cycle 1) was completed. Pts with measurable disease at baseline and a subsequent scan (after ≤ 3 months of tx based on clinical assessment) for response were response evaluable. The primary endpoint was MTD. Secondary endpoints included safety, PK characterization, overall response rate (ORR), and complete remission (CR) rate. Biomarker assessments were exploratory endpoints.

Results

Of the 46 pts enrolled at data cutoff (March 31, 2022), 18 had RR DLBCL (cohort A, n = 8; cohort B, n = 10) and 10 had RR FL (cohort A, n = 2; cohort C, n = 8). Pts were 73% male with a median age of 69 years. Most (76%) had stage III/IV disease, while 85% had an ECOG performance status of 0–1. Median (range) prior lines of tx was 4 (1–12).

The primary reasons for tx discontinuation (49%) were progressive disease or death. Relative IBER dose intensity per cycle was maintained at 92%. No cohort achieved MTD.

Tx-emergent adverse events (TEAEs) in ≥ 10% of pts included neutropenia, anemia, thrombocytopenia, and constipation (Table 1). Grade 3–4 TEAEs were primarily hematologic: neutropenia (49%), anemia (15%), and thrombocytopenia (13%). Febrile neutropenia occurred in 4% of pts, as did sepsis. In cohorts A and B, 1 (grade 4 thrombocytopenia) and 2 (both grade 4 neutropenia) DLTs occurred, respectively. In cohort C, 4 DLTs occurred: grade 4 neutropenia (n = 2), grade 3 facial edema (n = 1), and grade 3 hypercalcemia (n = 1). No grade 5 TEAEs occurred.

ORR in response-evaluable pts (n = 38) was 55%; 32% achieved CR (Table 2). In the 7 cohort B pts with RR DLBCL (median: 5 prior tx lines), ORR was 71%; 29% achieved CR. In cohort C (n = 13; MZL, n = 5; FL, n = 8), the ORR was 69%; CR rate was 39%. ORR and CR were independent of COO and were achieved in pts with prior exposure to lenalidomide and chimeric antigen receptor (CAR) T cell tx.

IBER was absorbed rapidly (median T_max, 2.5–4.0 hours) and PK exposure (C_max and area under curve) at steady state increased in a dose-related manner across the tested dose range. Consistent with preclinical data, higher doses increased Ikaros degradation in B cells (37% at 1.0 mg, 60% at 1.3 mg) but not in T cells (64% at 1.0 mg, 66% at 1.3 mg), at 6 hours post-dose. Peripheral immunophenotyping at C1D15 indicated IBER increased 2–3-fold the numbers of proliferating CD4+ T cells and activated natural killer cells. Naive T cells decreased 2-fold. Preliminary PK/pharmacodynamic analyses suggested a dose-response trend, with higher exposure related to greater reduction of Ikaros/Aiolos.

Conclusions

IBER alone and in combination with anti-CD20 mAbs showed promising activity in pts with RR lymphoma. CELMoD agent-associated neutropenia was a predictable on-target toxicity manageable with G-CSF use and did not appear to increase risk of febrile neutropenia or infections. These data highlight the potential of CELMoD agent-based tx in pts with RR lymphoma to address unmet needs such as treating disease progression after CAR T cell tx.

Study support: This study was funded by Bristol Myers Squibb.