Modakafusp Alfa Shows Early Promise in RRMM

Dan T. Vogl, MD, MSCE

Modakafusp alfa (previously TAK-573) has shown to be a feasible treatment option for patients with relapsed/refractory multiple myeloma (RRMM), according to findings from a phase 1 study (NCT03215030). Further studies are investigating the optimal dose of the agent, as well as if it could be part of potential combinations.¹

Modakafusp alfa is a first-in-class immunocytokine designed to deliver interferon alpha-2b to CD38-positive cells. Previously, the agent has shown promising anti-myeloma activity in heavily pretreated patients with RRMM, including anti-CD38 mAb-refractory patients and those who have received an anti-CD38 mAb in their most recent line of treatment.² 

The phase 1 study enrolled patients with RRMM who received at least 3 prior lines of therapy. Patients were treated with modakafusp alfa as a 1- to 4-hour intravenous infusion at 11 dose levels, starting at 0.001 mg/kg and ranging to 6 mg/kg.

According to preliminary results, a total of 83 patients were treated across all planned dosing schedules with 24 patients treated with 1.5 mg/kg modakafusp alfa every 4 weeks. Among these patients, modakafusp alfa elicited an overall response rate of 42%, with complete responses observed in 2 patients, very good partial responses in 5, and partial responses in 3 patients. The median progression-free survival was 5.7 months and the median time to response was 1.9 months. Further, the median duration of response was 7.4 months.^1,2

More recent findings showed that 87% of patients experienced treatment-related adverse events, and the most common adverse events among patients were neutropenia and thrombocytopenia, or low blood platelet count; and about one-third of patients had mild reactions after infusion of the medication.

In an interview with Targeted Oncology^TM, Dan T. Vogl, MD, MSCE, of Abramson Cancer Center, associate professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, discussed a phase 1 study which evaluated modakafusp alfa for the treatment of patients with RRMM.

Targeted Oncology: Can you discuss the mechanism of action of modakafusp alfa?

Vogl: Modakafusp alfa, which we are calling moda, is a targeted interferon therapy. It's an immunocytokine fusion protein combining attenuated interferon alpha to be molecules attached to an anti-CD38 antibody backbone. It is a way of delivering interferon alpha signaling directly to CD38-expressing cells, which includes both myeloma plasma cells in a variety of cells in the immune system.

Can you discuss the phase 1 study of modakafusp alfa in relapsed/refractory multiple myeloma?

We are presenting the final results from our phase 1 trial of modakafusp alfa comprising a total of 100 patients treated at a variety of doses, including a 30 patient expansion cohort at 1 of the 2 doses that we think would be a recommended phase 2 dose of 1.5 mg per kg IV every 4 weeks. We are really excited about the results of the trial. We are seeing an exciting response rate of 43% at our recommended phase 2 dose, including responses in patients who are refractory to prior anti-CD38 monoclonal antibodies, and responses in heavily refractory patients, including patients refractory to anti-BCMA therapies.

What are the implications of the findings from this study?

We think that modakafusp alfa provides a novel way of simultaneously targeting myeloma plasma cells, while also stimulating an immune response that can result in single-agent responses, and is completely unlike any other agent currently on the market.

Like the monoclonal antibodies daratumumab [Darzalex] and isatuximab [Sarclisa], modakafusp alfa is targeted against CD38 on the surface of plasma cells. But unlike those 2, modakafusp alfa is not an IgG1 antibody. It does not elicit direct anti-myeloma cell immune responses, but instead, delivers interferon to myeloma cells. Moda also binds to the CD38 molecule at a different spot than daratumumab or isatuximab, which means that moda could even be given simultaneously with those agents.

Most importantly, we're seeing a robust response rate of 39% in patients who had previously been refractory to an anti-CD38 antibody, meaning that moda is completely different from other anti CD38 treatments. Moda is also not an antibody drug conjugate. It's not carrying a toxic payload, but an immunologically active cytokine, which makes it unlike anything else being developed for myeloma.

What are the next steps for this research?

The current trial has moved on to the next phase, which is going to be a phase 2 expansion trial and will randomize patients to either 1 of 2 doses of moda, either the phase 2 dose that we had currently expanded with our 30 patients or a double dose of 3 mg/kg, although the phase 2 trial is moving forward with fixed dose equivalents instead of weight-based dosing.

What practice changing data have you seen in this field in the past year?

I think the biggest change that's coming to myeloma therapy this year has come with the approval of teclistamab-cavy [Tecvidli], the first bispecific T-cell engaging antibody for myeloma with a host of other exciting bispecific T-cell engagers being developed, both targeting BCMA and 2 other exciting targets. I think that as all of these agents get approved and become available to our patients, it will be a revolution for how well we can treat our patients.

REFERENCES:

1. Vogl DT, Atrash S, Holstein SA, et al. 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). Presented at: 2022 ASH Annual Meeting; December 10-13. New Orleans, LA. Abstract 565.

2. 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.