Phase 2 basket trial of ponatinib in tumors with FGFR alterations and other genomic targets

Genomic alterations in tyrosine kinase receptors, such as FGFR , KIT , RET , VEGFR , PDGFRα, are driver mutations in many solid tumors. Ponatinib is a potent inhibitor of members of the FGFR family, particularly FGFR1, as well as KIT, RET, VEGFR, PDGFR α , and other tyrosine kinase proteins. Prior to the broader availability of selective kinase inhibitors, we conducted a phase 2 signal-finding basket trial evaluating the efficacy and safety of oral ponatinib in solid tumors with select gain-of-function alterations. There is an unmet need for inhibitors of FGFR1 in solid tumors. The primary endpoint was overall response rate; key secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. All 22 enrolled patients were included in the prespecified primary efficacy analysis. In the primary cohort (cohort A – FGFR alteration), the overall response rate (ORR) was 5.9% (1/17), median PFS was 1.9 months (95% CI, 0.5–3.9 months), and median OS was 5.3 months (95% CI, 3.4–25.0 months). In the secondary cohort (cohort B - RET , KIT , VEGFR , or PDGFRα alteration ) , the ORR was 0% (0/5), median PFS was 9.5 months, and the median OS was 11.8 months. The ponatinib basket trial did not meet its primary endpoint for patients with FGFR genomic alterations; however, it resulted in prolonged disease control in several patients with manageable toxicity. Ponatinib is not a therapy of choice for patients with FGFR alterations but could be considered for patients who are intolerant of FGFR-selective inhibitors.