A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-specific Inhibitor, with Letrozole in ER+/HER2-Negative Metastatic Breast Cancer
Mené sur 26 patientes atteintes d'un cancer métastatique du sein ER+, cet essai de phase I évalue la dose maximale tolérée et l'activité antitumorale de l'alpelisib en combinaison avec le létrozole
Purpose:Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic anti-tumor activity with endocrine therapy against ER+/PIK3CA mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. Experimental Design:Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and Next Generation Sequencing. Results:Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression {greater than or equal to}6 months) was 35% (44% in patients with PIK3CA mutated and 20% in PIK3CA wild-type tumors; 95% CI [17%; 56%]), including five objective responses. Of eight patients remaining on treatment {greater than or equal to}12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro. Conclusions:The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status although clinical benefit was seen in a higher proportion of patients with PIK3CA mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing.