P-509: Vactosertib, a novel TGF type I receptor kinase inhibitor, improves T-cell fitness:a single-arm, phase 1b trial in relapsed/refractory multiple myeloma

Introduction: CONTEXT: Functional blockade of the TGFβ signaling pathway improves the efficacy of cytotoxic and immune
therapies. Here, we evaluated the clinical safety and in vivo efficacy of the TGF receptor kinase inhibitor
vactosertib in patients with relapsed and/or refractory MM (RRMM).

Objective: The primary objective of the present study was to determine the safety profile and efficacy of
vactosertib in RRMM patients. The secondary objective was to determine the maximum tolerated dose and
pharmacokinetic (PK) properties of vactosertib in RRMM patients. Finally, we explored the molecular
mechanism of vactosertib on tumor and immune cells within the myeloma microenvironment.

Methods: Since TGFβ promotes myeloma growth and drug resistance, we hypothesized that inhibition of TGFreceptors represents a viable strategy to treat RRMM. Vactosertib (TEW-7197, Medpacto, Seoul, S. Korea) is a selective inhibitor of the serine/threonine TGFRI kinase that suppresses tumor progression and metastatic growth in preclinical models. We designed a standard 3+3, dose escalation phase 1b, IRB-approved study to evaluate vactosertib in RRMM patients who had received >2 lines of chemoimmunotherapy.
PATIENTS: Twenty-one patients with RRMM, adequate organ function and no secondary malignancies were
consented and included in the study.
Patients were treated with vactosertib at one of the four indicated dose levels. Dose level I
was 60 mg po qd; level II was 120 mg po qd; level III 100 mg po bid; and level V was 200 mg po bid. Vactosertib
was administered on days 1-5, 8-12, 15-19, 22-26 of 28 day cycles. Patients were simultaneously treated with
pomalidomide (POM) administered at four mg po qd on days 1-21 of each cycle.
Primary endpoint: Safety and of orally-administered vactosertib in RRMM patients, maximum tolerated dose determination (200 mg po bid). Secondary endpoint: Six month PFS.
Exploratory endpoints: PK analysis and T-cell fitness studies.

Results:

Results: Vactosertib combined with
POM was well-tolerated at all doses and had a manageable adverse event profile. Vactosertib + POM induced durable responses with 80% (PFS-6) at 6 months, while POM alone historically achieved 20% PFS-6. Vactosertib reduced TGFβ in patient bone marrow and suppressed PD-1
expression on CD8+ T-cells. Moreover, vactosertib reduced PD-L1/PD-L2 expression on CD138+ cells and enhanced autologous T-cell cytotoxicity.

Conclusions:

Conclusions: Combination vactosertib and pomalidomide oral therapy is a well-tolerated, steroid-free regimen with a promising response rate in the heavily pretreated MM patient population. Patients included in our study are representative of a cohort with limited remaining treatment options. Taken together, our results support the safety, efficacy and feasibility of vactosertib to treat RRMM. Moreover, vactosertib modulates the T-cell immunophenotype and reinvigorates T-cell fitness with the potential to reduce immunosuppression, revert T-cell exhaustion and reinvigorate anti-myeloma immunity.