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The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial.

ABSTRACT: Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had received ≥2 lines of chemoimmunotherapy. Secondary endpoints demonstrated sustained clinical responses, favorable pharmacokinetic parameters and a 6-month progression-free survival of 82%. Vactosertib combined with pomalidomide was well-tolerated at all dose levels and displayed a manageable adverse event profile. Exploratory analysis indicated that vactosertib co-treatment with pomalidomide also reduced TGFβ levels in patient bone marrow as well as the level of CD8⁺ T-cells that expressed the immunoinhibitory marker PD-1. In vitro experiments indicated that vactosertib+pomalidomide co-treatment decreased the viability of MM cell lines and patient tumor cells, and increased CD8⁺ T-cell cytotoxic activity. Vactosertib is a safe therapeutic that demonstrates tumor-intrinsic activity and can overcome immunosuppressive challenges within the tumor microenvironment to reinvigorate T-cell fitness. Vactosertib offers promise to improve immunotherapeutic responses in heavily-pretreated MM patients refractory to conventional agents.

SUBMITTER: Malek E

PROVIDER: S-EPMC11350185 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial.

Malek Ehsan E Rana Priyanka S PS Swamydas Muthulekha M Daunov Michael M Miyagi Masaru M Murphy Elena E Ignatz-Hoover James J JJ Metheny Leland L Kim Seong Jin SJ Driscoll James J JJ

Nature communications 20240827 1

Functional blockade of the transforming growth factor-beta (TGFβ) signalling pathway improves the efficacy of cytotoxic and immunotherapies. Here, we conducted a phase 1b study (ClinicalTrials.gov., NCT03143985) to determine the primary endpoints of safety, tolerability, and maximal tolerated dose (200 mg twice daily) for the orally-available TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed and/or refractory multiple myeloma (RRMM) patients who had r ...[more]

PMID: 39191755

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Project description:Functional blockade of the transforming growth factor-beta (TGF-β) signaling pathway improves the efficacy of cytotoxic and immunotherapies. We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF-β type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma patients who had received ≥2 lines of chemoimmunotherapy. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, while pomalidomide alone historically achieved 20% PFS-6. Following treatment, the immunosuppressive marker PD-1 expression was reduced on patient CD8+ T-cells. Following ex vivo treatment, vactosertib decreased PD-1 expression on patient CD138+ cells, reduced PD-L1/PD-L2 on patient CD138+ cells and enhanced the anti-myeloma activity of autologous T-cells. Taken together, vactosertib is a safe immunotherapy that modulates the T-cell immunophenotype to reinvigorate T-cell fitness. Multiple myeloma (MM) is a genetically heterogeneous hematologic malignancy characterized by the excessive proliferation of clonal plasma cells (1, 2). MM remains mostly incurable but a small group of patients can achieve long-term remission (3). Treatment of MM presents unique challenges due to the complex molecular pathophysiology and genetic heterogeneity (4, 5). Given that MM is the second most common blood cancer characterized by cycles of remission and relapse, the development of new therapeutic modalities is crucial (6, 7). The prognosis for MM patients has improved substantially over the past two decades with the development of more effective therapeutics, e.g., proteasome inhibitors, and regimens that demonstrate greater anti-tumor activity (8-10). The management of RRMM represents a vital aspect of the overall care for patients with disease and a critical area of ongoing scientific and clinical research (10-12).

Dataset Information

The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial.

Publications

The TGFβ type I receptor kinase inhibitor vactosertib in combination with pomalidomide in relapsed/refractory multiple myeloma: a phase 1b trial.

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