Initial results in RRMM with modakafusp alfa: a first-in-class CD38-targeted immunocytokine

Modakafusp alfa is a first-in-class antibody–cytokine fusion protein (immunocytokine) consisting of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody (mAb).¹ The INF-α fusion protein exhibits a 10,000-fold greater specificity for CD38⁺ cells versus CD38⁻ when compared with native INF-α.²

Mechanism of action

Modakafusp alfa, previously known as TAK-573, selectively binds to a unique epitope on CD38, different to the binding epitope of the anti-CD38 mAbs approved for the treatment of multiple myeloma (MM), i.e., daratumumab and isatuximab.^1,2 Through the INF-α receptor, modakafusp alfa directs anti-proliferative/apoptotic signals to tumor cells, inducing tumor cell death.² Besides the anti-myeloma activity, modakafusp alfa also activates innate and adaptive immune cells.² It is hypothesized that the activated immune cells and dead myeloma cells can produce a synergistic effect in destroying more malignant plasma cells in the bone marrow (Figure 1).² Furthermore, the specificity of targeting interferon directly to the myeloma cells reduces the potential risk for off-target binding and toxicity in patients with relapsed/refractory multiple myeloma (RRMM).¹

Figure 1. Proposed mechanism of action*

NK, natural killer.
*Adapted from Vogel.²

Study design and endpoints

• Design³: An ongoing first-in-human, phase 1/2, open-label, randomized study of modakafusp alpha as a single agent and in combination with dexamethasone in patients with RRMM in the United States (NCT03215030); the study consists of two parts (Part 1 and Part 2), with an expected enrollment of 51 and 100 patients, respectively
• Eligibility criteria³: Age ≥18 years; disease progression having previously received ≥3 lines of therapy; refractory to or intolerant of at least one proteasome inhibitor and a least one immunomodulatory drug; European Cooperative Oncology Group (ECOG) performance status of 0 to 1

• Endpoints³: Incidence of treatment-emergent adverse events (TEAEs), serious adverse events, dose-limiting toxicities, maximum tolerated dose or optimal biological dose, pharmacokinetics, pharmacodynamics, efficacy

Preliminary results from the ongoing first-in-human, phase I trial of modakafusp alfa in patients with RRMM show clinical activity in response to single-agent therapy with doses starting at 0.1 mg/kg weekly.¹

At the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, Dan Vogl presented updated interim results of the first-in-human outcomes of modakafusp alfa, focusing on outcomes from an expansion cohort with dosing every 4 weeks (Q4W) in patients with RRMM.² The key findings are summarized below.

Results²

Overall, 29 patients were treated with 1.5 mg/kg Q4W modakafusp alfa: five in the dose-escalation part and 24 in the ongoing dose-expansion part. The analysis includes data from all 29 patients.

Safety

• Grade 3 or higher TEAEs were reported in 18 patients (75%).
• The most frequently reported hematologic TEAEs (>25%) were neutropenia, leukopenia, decreased lymphocyte count, anemia, and thrombocytopenia.

Overall response rate

• Modakafusp alfa has shown promising results in heavily pre-treated patients with RRMM, including some who have received an anti-CD38 mAb in their most recent line of treatment.
• Overall, 38% of patients responded to the treatment, with 28% achieving at least a very good partial response. Further details on best response and by patient cohort are presented in Figure 2.

Figure 2. ORR in patients who received 1.5 mg/kg Q4W modakafusp alfa*

BCMA, B-cell maturation antigen; CR, complete response; ORR, overall response rate; PR, partial response; Q4W, every 4 weeks; VGPR, very good partial response.
*Adapted from Vogel.²

Duration of response

• Among all 29 patients, the median progression-free survival was 5.7 months.
• Among 11 patients with a partial response or better:

• The median time to response was 1 month.
• The median time to best response was 2 months.
• The median duration of response has not been reached.

Conclusion

Modakafusp alfa represents a promising candidate for the treatment of patients with RRMM. The investigators considered that modakafusp alfa had a manageable safety profile, with anti-myeloma activity in heavily pre-treated patients.² The dose optimization and potential combinations are currently being explored in the dose-escalation part of the study.³