Final Results from the First-in-Human Phase 1/2 Study of Modakafusp Alfa, an Immune-Targeting Attenuated Cytokine, in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction Modakafusp alfa is a first-in-class, immune-targeting, attenuated cytokine. It consists of 2 attenuated interferon (IFN)α2b molecules genetically fused to the Fc portion of an anti-CD38 IgG4 monoclonal antibody (mAb), allowing targeted delivery of IFNα to innate and adaptive immune cells, as well as myeloma cells. We previously reported preliminary results from a cohort of 30 pts who received modakafusp 1.5 mg/kg every 4 weeks (Q4W) in this phase 1/2 study (NCT03215030) (Kaufman EHA 2022, S181). We now report the final safety and efficacy results of the study (parts 1 and 2), including minimal residual disease (MRD) status.

Methods Pts had received ≥3 prior lines of treatment and were refractory to or intolerant of ≥1 proteasome inhibitor and ≥1 immunomodulatory drug. During dose escalation, modakafusp was administered intravenously at 10 dose levels between 0.001-6 mg/kg; weekly (QW; cycles 1-2 only; 0.001-0.75 mg/kg), every 2 weeks (Q2W; 0.2-0.3 mg/kg), every 3 weeks (Q3W; 0.4-0.75 mg/kg), or Q4W (0.75-6 mg/kg). As anti-myeloma response was detected during dose escalation, expansion cohorts were opened at 0.4 mg/kg Q3W and 1.5 mg/kg Q4W as a single agent. As dexamethasone (dex) is part of standard of care in MM, but could counteract the immune activation elicited by modakafusp, additional cohorts at 0.4 mg/kg Q3W and 1.5 mg/kg Q4W in combination with 40 mg dex QW were opened. Bone marrow aspirates (BMA) for MRD evaluation were collected at screening and at suspected CR and were assessed utilizing the clonoSEQ® next generation sequencing assay at a threshold of 10^-5. Peripheral blood samples were collected and evaluated for CD38 receptor density determination by flow cytometry.

Results At data cut-off (April 2022), 100 pts had been treated with modakafusp; 56 pts in dose escalation and 44 pts in expansion cohorts. During dose escalation, dose-limiting toxicities were reported with QW and Q2W dosing schedules. In the Q4W dosing schedule, the maximum tolerated dose (MTD) of modakafusp was exceeded at 6 mg/kg due to a grade (G) 3 infusion-related reaction (IRR) in 1 pt and a prolonged thrombocytopenia and neutropenia in 1 pt; the MTD was therefore determined as 3 mg/kg Q4W. During dose escalation, PRs were reported with 0.1 mg/kg and 0.4 mg/kg QW (n=1 each), an unconfirmed VGPR was observed with 0.4 mg/kg Q3W, and PRs (n=3) and a CR (n=1) were reported with 1.5-6 mg/kg Q4W.

During expansion, of 8 pts receiving modakafusp 0.4 mg/kg Q3W, 5 had SD and 3 had PD. Of 3 pts in the 0.4 mg/kg Q3W + dex cohort, 2 had SD and 1 had PD.

Among 30 pts treated with modakafusp 1.5 mg/kg Q4W (5 in dose escalation and 25 in expansion), the ORR was 43% (Table), median time to response was 1.2 months, and median duration of response was not reached (range 1.0-18.9 months). Median progression-free survival was 5.7 months (95% confidence interval 1.2-15.9). At 1.5 mg/kg Q4W, G≥3 treatment-emergent adverse events (TEAEs) occurred in 26 (87%) pts, including neutropenia (n=19, 63% [G4 n=9, 30%]), thrombocytopenia (n=14, 47% [G4 n=6, 20%]), and lymphopenia (n=11, 37% [G4 n=7, 23%]); 3 (10%) pts had G3 infections, and 1 (3%) pt had a G3 bleeding event. Except for 1 report of G4 hyperuricemia, there were no G4 non-hematological TEAEs; IRRs occurred in 11 pts (37% [G3 n=1, 3%]).

Of 8 pts treated with modakafusp 1.5 mg/kg Q4W + dex, 1 pt had a VGPR and 1 pt had SD (1 pt was not evaluable and 5 pts had no post-baseline response assessment). At 1.5 mg/kg Q4W + dex, G≥3 TEAEs occurred in 7 (88%) pts, including thrombocytopenia (n=4, 50% [G4 n=1, 13%]), anemia (n=2, 25%), lymphopenia (n=2, 25% [G4 n=1, 13%]), pneumonia (n=2, 25%), and neutropenia (n=1, 13%). IRRs occurred in 2 pts (25%, none G≥3).

Of 4 pts treated at 1.5 mg/kg Q4W with MRD samples collected at screening and suspected CR, 1 pt was MRD- at 10^-5. Preliminary analysis showed no correlation between CD38 receptor density on peripheral blood immune cells and clinical response. Further evaluation to explore the association between clinical response and CD38 receptor density on MM cells within BMAs is underway.

Conclusions Modakafusp alfa has a novel mechanism of action, a manageable safety profile, and encouraging anti-myeloma activity at 1.5 mg/kg Q4W, independent of peripheral blood immune cell CD38 expression. A randomized phase 2 study to compare fixed-dose levels of 120 and 240 mg (equivalent to 1.5 and 3.0 mg/kg) Q4W and to define the single-agent dose with the optimal benefit/risk profile is currently enrolling.

Vogl:Oncopeptides: Consultancy; Karyopharm: Consultancy; CSL/Behring: Consultancy; Sanofi/Genzyme: Consultancy; GSK: Consultancy; Takeda: Consultancy, Research Funding; Active Biotech: Research Funding. Atrash:AMGEN: Research Funding; GSK consultancy: Honoraria, Research Funding; Jansen oncology: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squib: Research Funding; Sanofi: Research Funding. Holstein:Genentech: Consultancy; Oncopeptides: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Sanofi: Consultancy; BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding. Nadeem:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Suryanarayan:Takeda: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Liu:Takeda Pharmaceutical Company: Current Employment. Collins:Takeda Development Center Americas, Inc (TDCA): Current Employment, Current equity holder in publicly-traded company. Parot:Takeda Pharmaceuticals: Current Employment. Kaufman:Incyte: Other: Member of data safety monitoring committee ; AbbVie, Genentech, and Bristol Myers Squibb: Consultancy; AbbVie: Other: Member of steering committee.

This abstract contains information about investigational use of modakafusp alfa in patients with relapsed/refractory multiple myeloma. Safety and efficacy have not been determined.