IGM-2323 Induces Tumor Shrinkage in R/R Non-Hodgkin Lymphoma

Elizabeth Budde, MD, PhD

Treatment with IGM-2323, a bispecific IgM antibody, resulted in tumor shrinkage in 9 of 14 patients with CD20-positive relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) in a phase 1 study, according to the preliminary findings presented during the 2020 American Society of Hematology (ASH) Annual Meeting.¹

Elizabeth Budde, MD, PhD, an assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope National Medical Center in Duarte, California, called these results “particularly encouraging.”

“IGM-2323 is generally well tolerated, with no DLTs [dose-limiting toxicities] and no neurotoxicities despite minimal premedication,” she said. “IGM-2323 showed evidence of early clinical activity, with responses observed in a [patient following treatment with] CAR [chimeric antigen receptor] T-cell [therapy] despite low doses tested to date.”

IGM-2323 targets CD20 and CD3 and is engineered with 10 high affinity and high-specificity binding site to CD20 and a single high-specificity binding site to CD3. Investigators initiated the multicenter, open-label phase 1 dose escalation trial (NCT04082936) to assess the safety, pharmacokinetics, and preliminary efficacy of intravenous IGM-2323 in patients with R/R B cell NHLs. Sixteen patients were enrolled and treated at escalating dose levels of IGM-2323 as of the October 30, 2020 data cutoff. Dose escalation continues toward the anticipated recommended phase 2 dose range of 100 mg to 1000 mg.

Ten patients in the study had follicular lymphoma (FL) or marginal zone NHL. Six others had diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma. Patients in both groups had received a median of 4 prior therapies (range, 2-6). Patients were required to receive premedication with 10 mg dexamethasone prior to receiving the study drug. Patients were allowed subsequent premedication at investigator’s discretion.

Patients were assigned to 1 of 5 dose levels of IGM-2323: 100 mg (n =1), 30 mg (n = 3), 10 mg (n = 3), 2.5 mg (n = 1), or 0.5 mg (n = 1). All patients were treated weekly for one 21-day cycle.

Investigators initiated dose expansion cohorts in parallel with continued dose escalation to better assess safety and efficacy. One patient was assigned to 50/100 mg titration dose and 3 were assigned to 30 mg.

Of the 14 patients treated in the 0.5-, 2.5-, 10-, 30-, and 50/100-mg dose cohorts, 9 (64.2%) data showed evidence of tumor size reduction. Two patients had partial responses, including 1 patient with FL treated at the 50/100 mg dose level and 1 patient with DLBCL at the 30 mg level who previously failed CAR T-cell therapy. Subsequent to the data cutoff, 2 patients with FL treated in the 50/100 mg titration dose cohort converted to complete responses.

“In contrast to observations with other T-cell engagers, IGM-2323 treatment resulted in a repeatable interferon gamma-dominant immune activation,” Budde said. Following treatment with IGM-2323, the vast majority of patients had levels of interferon-6 gamma, TNFa, and other cytokines above baseline, she added.

“[In patients treated at] 30 mg and above, interferon gamma spikes were repeatedly observed, demonstrating preservation or strengthening of T-cell function.”

Investigators observed no grade 3 treatment-emergent adverse events (TRAEs). The most common grade 2 TRAEs were hypophosphatemia (25%) and infusion-related reactions (19%). Budde added that no grade 3 cytokine release syndrome (CRS) was observed at the 50/100 mg level and said that TRAEs in the study “were generally transient and low grade.”

“Bispecific antibodies that bridge lymphoma cells to T cells have shown promise in treating B-cell malignancies, but existing T-cell engaging antibodies are often associated with toxicity, especially CRS, and have a limited therapeutic window potentially related to downregulation of T-cell function,” Budde said in a news release.² “IGM-2323 may provide more physiologic T cell activation, with evidence for preservation of T cell activation in the majority of patients in this study, as compared with the global reduction in T cell function associated with existing bispecific T cell engaging antibodies.”

In addition to the 50/100 mg titration dose, investigators are enrolling patients to a 50/300 mg titration dose cohort.²

_References

1. _{Budde E, Gopal AK, Flinn IW, et al. Preliminary results of a phase 1 dose escalation study of the first-in-class IgM based bispecific antibody Igm-2323 (anti-CD20 x anti-CD3) in patients with advanced b-cell malignancies. Blood. 2020;136(suppl 1):45-46. doi:10.1182/blood-2020-134983}
2. _{IGM Biosciences presents first clinical data from IGM-2323 in non-Hodgkin’s lymphoma at 2020 ASH Annual Meeting. News release. IGM Biosciennces. December 5, 2020. Accessed December 6, 2020. https://bit.ly/33Ne3kn}