Modakafusp Alfa Elicits Single-Agent Activity, Represents a Novel Option in Relapsed/Refractory Myeloma

The novel agent modakafusp alfa (TAK-573) has a mechanism of action unlike other current treatments on the market and has the potential to become a new option for patients with relapsed/refractory multiple myeloma, according to Dan Vogl, MD, MSCE.

Vogl shared updated results from a first-in-human phase 1 trial (NCT03215030) of modakafusp alfa in patients with relapsed/refractory multiple myeloma at the 2021 ASH Annual Meeting and Exposition. The presentation focused on results from an expansion cohort with dosing every 4 weeks. In total, 24 patients were treated with 1.5 mg/kg modakafusp alfa.¹

Among the 21 patients who were anti-CD38 refractory, the overall response rate (ORR) was 43%. The 4 patients who received an anti-CD38 in their most recent line of therapy prior to enrollment yielded an ORR of 75%.

“It is like nothing else that we currently have for myeloma therapy,” Vogl said. “It appears to have single-agent activity in [patients with] relapsed and refractory multiple myeloma and has the potential to combine with other current standard-of-care treatments for myeloma, meaning it could advance the therapy of patients with myeloma and provide an exciting new treatment option in the future.”

In an interview with OncLive^®, Vogl, director, Abramson Cancer Center Clinical Research Unit, and assistant professor of medicine at the Hospital of the University of Pennsylvania, discussed the unique mechanism of action of modakafusp alfa and the updated results from an expansion cohort in patients with relapsed/refractory multiple myeloma.

OncLive^®: Could you explain the rationale for the first-in-human phase 1 study with modakafusp alfa in patients with relapsed/refractory multiple myeloma?

Vogl: This trial brings together 2 older concepts in treating multiple myeloma. One is the use of interferon alpha-2b (IFNa2b), which was used back in the 1990s as an anti-myeloma therapy but was very limited by side effects. The other [concept] is targeting CD38-positive cells because multiple myeloma cells express a lot of the CD38 molecule on their surface.

This drug, modakafusp alfa, previously known as TAK-573, is a fusion protein, combining a CD38 antibody with 2 attenuated IFNa2b signaling molecules to provide targeted signaling with interferon directly to CD38-positive cells.

What patient population did this study enroll and what were the methods for this study?

We conducted a first-in-human study, meaning the patients who are treated on this study at the beginning were the first people to ever receive modakafusp alfa. [The trial enrolled] patients with relapsed/refractory multiple myeloma who had been through all available standard-of-care treatments for their myeloma and did not have other good options for therapy.

What did you find?

We’re excited about the results of this study. In addition to showing that modakafusp alfa is overall well-tolerated in patients with relapsed and refractory myeloma, we were able to see [a confirmed partial response or better] in 38% of the patients who participated, including patients who were previously refractory to the current anti-CD38 antibodies on the market like daratumumab [Darzalex] and isatuximab [Sarclisa]. [This also included] patients with high-risk myeloma, and even patients who had been treated with the most recent, most effective novel agents for myeloma targeting BCMA, or B-cell maturation antigen.

Where could modakafusp alfa fit in this space in the future?

Building on the results of this study, we’re moving forward with a randomized, phase 2 study looking at 2 doses of modakafusp alfa, the 1.5 mg/kg dose that we’re currently looking at in this study and a double dose that has also been shown to be well-tolerated, trying to define what’s going to be the optimal dose of this drug, and hopefully move it forward into standard clinical care.

What were the toxicities associated with modakafusp alfa?

We saw 2 main toxicities with modakafusp: low platelet counts, or thrombocytopenia, and low neutrophils, the most helpful white blood cells, or neutropenia. Both of those [adverse] effects tended to happen during the first cycle [of treatment]. The [adverse effects] were manageable in general. Platelet counts and neutrophil counts tended to recover by the start of each next monthly cycle.

As patients who were responding to therapy moved through the study into later cycles of treatment, their neutrophil counts and platelet counts overall improved, showing that this was not going to be an ongoing problem for most patients as they received this treatment.

What is your take home message regarding this research?

Modakafusp alfa is a completely novel medication with a unique structure and a unique mechanism of action. It is like nothing else that we currently have for myeloma therapy. It appears to have single-agent activity in [patients with] relapsed and refractory multiple myeloma and has the potential to combine with other current standard-of-care treatments for myeloma, meaning it could advance the therapy of patients with myeloma and provide an exciting new treatment option in the future.

Is there anything else you want to highlight about this trial?

It might be tempting for some of my colleagues to look at this treatment and think of it as either another antibody drug conjugate [ADC], and we have at least 1 of currently in therapy for myeloma, or another anti-CD38 therapy, like daratumumab or isatuximab that are currently on the market. This molecule is neither of those. Unlike ADCs, it’s a fusion protein. It’s a single amino acid chain, and there’s no opportunity for the IFNa2b to separate from the antibody and circulate around in the blood independently.

Unlike other ADCs, the IFNa2b itself is an immunologically active cytokine and can interact with other CD38-positive cells, including immune cells, like T cells and NK cells and provide a stimulating signal to them.

Reference

1. Vogl DT, Kaufman JL, Holstein SA, et al. Modakafusp alfa (TAK-573), an immunocytokine, shows clinical activity in patients with relapsed/refractory multiple myeloma; updated results from a first-in-human phase 1 study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 898.