Vactosertib plus pomalidomide without corticosteroids for relapsed multiple myeloma

During the 2021 American Society of Clinical Oncology Annual Meeting, positive topline results from the phase Ib study (NCT03143985) of vactosertib in combination with pomalidomide for the treatment of relapsed multiple myeloma (MM) were presented. These results demonstrated that vactosertib is well-tolerated and effective for this indication.¹

Vactosertib^1,2

Vactosertib is an orally available, highly potent, small molecule TGF-β type I receptor kinase inhibitor that has shown single-agent activity against MM in syngeneic 5T33MM murine mouse models. It binds to the ATP-binding domain of TGF-β R kinase and inhibits ATP kinase activity, blocking the downstream signaling cascade. Mechanistically, vactosertib acts through tumor intrinsic and extrinsic mechanisms, exerting potent antitumor effects directly on malignant and other cell types, including:

• pro-apoptotic and overcoming drug-resistance effects on cancer cells;
• stemness prevention, epithelial-mesenchymal transition blocking, and metastasis reducing effects on cancer stem cells;
• anti-angiogenic effects;
• antitumor immunity effects; and
• osteolytic bone destruction impairment.

Study design¹

This study was a phase I, open-label trial of vactosertib in combination with standard doses of pomalidomide without corticosteroids.

• Enrollment: patients with relapsed MM, who had at least two prior lines of therapy.
• Study design: 3 + 3 dose escalation design of vactosertib 60 mg/day, 120 mg/day, 100 mg twice daily, and 200 mg twice daily in combination with a standard dose of pomalidomide (4 mg).
• Dosage: vactosertib tablets, taken once or twice daily for five days followed by two days without treatment. Administered in 28-day cycles until progressive disease or intolerable toxicity.
• Primary objectives included:
  • assessment of safety; and
  • determining the recommended phase II dose.
• Secondary objectives included:
  • overall response rate and clinical benefit rate based on the International Myeloma Working Group (IMWG) defined response criteria and the duration of response; and
  • progression-free survival (PFS) and PFS at 6 months (PFS-6).

Results¹

• In total, 15 patients aged between 56 years and 77 years were enrolled in the study.
• Three out of the 15 patients experienced progression of disease (PFS-6, 80%). The efficacy assessment was higher compared with the historical control with only pomalidomide treatment (PFS-6, 20%) and with pomalidomide combined with corticosteroids (PFS-6, 40%).
• The most common non-hematologic adverse events (AEs) were:
  • Grade II fatigue and pain (n = 1);
  • Grade III renal failure that took <7 days to get back to baseline (n = 1);
  • sinus bradycardia that reversed to sinus rhythm (n = 1); and
  • atrial fibrillation that was rate controlled with beta blockers (n = 1).
• No Grade IV non-hematologic AEs were observed.
• Three patients had Grade III hematologic AEs, and there were no Grade IV hematologic AEs.

Other TGF-β kinase inhibitors in pre-clinical development²

SB-431542 and SB-505124 are other notable TGF-β R inhibitors that block Smad2/3 phosphorylation. Agent SB-431542 has been shown to enhance osteoblast differentiation from bone marrow stromal cells and osteoblastic cell lines. TGF-β inhibition restored osteoblast differentiation suppressed by MM cell-conditioned medium as well as bone marrow plasma from patients with MM. Nevertheless, these are non-specific inhibitors and so can be relatively unpredictable and may generate unpredictable outcomes with unwanted adverse reactions.