S181: MODAKAFUSP ALFA (TAK-573): UPDATED CLINICAL, PHARMACOKINETIC (PK), AND IMMUNOGENICITY RESULTS FROM A PHASE 1/2 STUDY IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM)

Abstract

Background: Modakafusp alfa (TAK-573) is a first-in-class immunocytokine designed to deliver attenuated interferon alpha-2b to CD38+ cells. In this phase 1/2 study (NCT03215030), the maximum tolerated dose of modakafusp alfa was defined as 3 mg/kg every 4 weeks (Q4W); preliminary data from 29 pts treated at 1.5 mg/kg Q4W (5 in dose escalation, 24 in dose expansion) showed single-agent, anti-myeloma activity with an overall response rate (ORR) of 38% after a median follow-up of 4.2 months (mos) (Vogl ASH 2021, #898). Aims: We present a clinical update on the efficacy and safety of modakafusp alfa 1.5 mg/kg Q4W after a median follow-up of 4.5 mos. We also present PK, immunogenicity, and dose-exposure-response data from the overall study. Methods: Eligible pts had received ≥3 prior lines of treatment. Pts received modakafusp alfa as a 1–4-hour IV infusion at 10 dose levels from 0.001–6 mg/kg at weekly (cycles 1–2 only; 0.001–0.75 mg/kg), every-2-week (0.2–0.3 mg/kg), every-3-week (Q3W; 0.4–0.75 mg/kg), or Q4W (0.75–6 mg/kg) dosing intervals; an expansion cohort was opened at 1.5 mg/kg Q4W after anti-myeloma activity was observed in 3/5 pts in the escalation cohort at that dose. Serum samples prepared from blood were used for PK and anti-modakafusp alfa antibody (ADA) assessments. Modakafusp alfa concentrations were determined via a validated enzyme-linked immunosorbent assay; ADA were detected using a validated bridging electrochemiluminescence assay. Results: As of Oct 2021, 30 pts had received modakafusp alfa 1.5 mg/kg Q4W. The median number of prior lines was 7 (range 3–16); 90% of pts were refractory to an anti-CD38 monoclonal antibody (mAb), while 37% were exposed to an anti-B-cell maturation agent (BCMA). Grade (G) 3–4 treatment-emergent adverse events (TEAEs) were reported in 25 pts (83%); the most frequent G3–4 TEAEs were neutropenia in 19 (63%), thrombocytopenia in 13 (43%), leukopenia in 12 (40%), anemia in 9 (30%), and decreased lymphocyte count in 9 (30%) pts. As reported previously, 1 pt in the 1.5 mg/kg Q4W cohort had a G3 bleeding event, while 3 pts had G3 infections. Among all pts, the ORR was 40% (complete response, 7%; very good partial response, 20%; partial response, 13%); among anti-CD38 mAb-refractory and anti BMCA-exposed pts, the ORR was 37% and 27%, respectively. Median progression-free survival was 6 mos and median duration of response had not been reached (Kaplan-Meier estimate, 91% at 6 mos). Based on pooled available data for the Q3W and Q4W cohorts (all doses) within the escalation and expansion phases, there was a strong trend for a dose-exposure-response relationship for ORR, with the apparent inflection point at 1.5 mg/kg Q4W dosing. No apparent relationship between dose-exposure-response and G3/4 thrombocytopenia or neutropenia was observed across all doses, whereas a correlation between dose-exposure-response and incidence of infusion-related reactions across the 0.4–6 mg/kg Q3W and Q4W dosing cohorts was found. There was an apparent non-linear (more than dose proportional) increase in exposure in the dose range of 0.1–3 mg/kg with a geometric mean terminal half-life of 13 hours in serum for modakafusp alfa 1.5 mg/kg. Based on the available data, 14% and 60% of pts were ADA positive at baseline and post-treatment, respectively. Summary/Conclusion: Modakafusp alfa has a novel mechanism of action and has shown encouraging activity with a manageable safety profile in pts with RRMM. Characterization of the potential clinical impact of immunogenicity is ongoing. The optimal dose for single-agent modakafusp alfa will be further investigated in a phase 2 study.