alpelisib + infigratinib

The combination of alpelisib and infigratinib is a dual-targeting therapy that combines a PI3Kα selective inhibitor (alpelisib) with an FGFR1-4 selective inhibitor (infigratinib). This combination has been studied in a first-in-human clinical trial for patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations. In the clinical trial, both agents were escalated to their full single-agent recommended doses: alpelisib at 300 mg per day continuously, and infigratinib at 125 mg per day for 3 weeks followed by 1 week off. The toxicity profile of the combination was consistent with the established safety profiles of each individual agent, although 71% of patients required at least one treatment interruption or dose reduction, suggesting that long-term tolerability may be challenging. The pharmacokinetic properties of infigratinib and alpelisib when administered in combination were similar to those observed in monotherapy, with no significant drug-drug interactions reported between the two agents. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed. The combination identified sporadic responses, predominantly in tumor types and genotypes previously defined to have sensitivity to these agents individually. The combination has been studied in various cancer types, including estrogen receptor-positive breast cancer, bladder cancer, and endometrial cancer, where concurrent PIK3CA mutations and FGFR alterations occur. ## Mechanisms of Action Alpelisib is a PI3Kα selective inhibitor that targets the phosphatidylinositol 3-kinase (PI3K) pathway, which is frequently dysregulated in cancer. Specifically, it inhibits the PI3Kα catalytic subunit, which is encoded by the PIK3CA gene. Infigratinib is a pan-FGFR kinase inhibitor that targets all four FGFR receptor subtypes (FGFR1-4). It works as an ATP-competitive inhibitor of these receptors, suppressing tumor growth in cancers where the FGFR pathway is aberrated. The combination therapy approach was designed to target two frequently co-occurring genetic alterations in cancer: PIK3CA mutations and FGFR alterations. However, clinical trials have not demonstrated clear synergistic activity between these two mechanisms.

Brand names

Piqray

Other names

infigratinib + alpelisib