First Results of Migoprotafib, a Potent and Highly Selective Src Homology-2 Domain–Containing Phosphatase 2 Inhibitor in Patients with Advanced Solid Tumors

Src homology-2 domain-containing phosphatase 2 promotes rat sarcoma viral oncogene homolog-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective Src homology-2 domain-containing phosphatase 2 inhibitor designed for the treatment of rat sarcoma viral oncogene homolog-MAPK-driven cancers, particularly in combination with other targeted agents. Here, we report first-in-human study results of single-agent migoprotafib in patients with advanced solid tumor. We conducted a phase Ia, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics (PK), pharmacodynamics (peripheral blood phosphorylated ERK), and preliminary antitumor activity. Fifty-six heavily pretreated patients were treated with migoprotafib (10-150 mg once daily). Migoprotafib had a rapid absorption rate (∼0.5-2 hours) with dose-dependent increases in exposure and pathway modulation (phosphorylated ERK changes). The maximum tolerated dose was 100 mg, and the recommended phase II dose was 60 mg daily (once daily) based on safety, PK, pharmacodynamics, and antitumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, aspartate aminotransferase increase, and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports once-daily dosing and demonstrated promising safety, tolerability, and clinical activity at the recommended phase II dose. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.