A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

Abstract

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. Patients and Methods 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 ≥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 ≥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. Conclusion 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.

Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study

“…The ORR in PIK3CA -mutant ER-positive/HER2-negative breast cancer was 4.3%, and these patients experienced the highest CBR (17.4%) and a high DCR (60.9%) compared with other cancer types. Although alpelisib single-agent activity was moderate in this group of patients, the combination of alpelisib with letrozole in patients with ER-positive/HER2-negative breast cancer resulted in an ORR of 19% and CBR of 35% 22 ; CBR was higher in PIK3CA -altered versus PIK3CA -wild-type tumors (44% v 20%, respectively) in this study. In addition, translational research indicates the potential mechanistic synergy of combining PI3K inhibitors and endocrine therapies, particularly for patients with activating mutations of PIK3CA .…”

The PI3K Pathway in Human Disease

“…Early clinical trials of the isoform-selective inhibitors, alpelisib and taselisib, in breast cancer have produced results consistent with a previous meta-analysis of clinical trials of PI3K pathway inhibitors in patients with diverse cancers, revealing that patients with H1047R mutations had higher response rates than those with other PIK3CA mutations, or no mutations in this gene (Janku et al, 2013; Mayer et al, 2017). The p110β-sparing inhibitor, taselisib, (Table S1) was reported to induce degradation of mutant p110α (Friedman et al, 2017).…”

“…Although treatment discontinuation remained an issue in this study, the safety profile was considered sufficiently acceptable to warrant a phase 3 trial. In an open-label trial of the p110α-selective inhibitor alpelisib with fulvestrant, ER+ breast cancer patients with PIK3CA mutations displayed a significantly improved clinical benefit rate compared to patients with wild type PIK3CA (Juric et al, 2016 abstract), and a similar selectivity for mutant PIK3CA tumors was observed in a phase 1b trial of alpelisib with letrozole (Mayer et al, 2017). Importantly, the safety profile of alpelisib plus letrozole was superior to that of buparlisib plus fulvestrant in the BELLE-2 and 3 trials, and there were fewer discontinuations due to adverse events.…”

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer

“…There is increasing evidence that in HR+ BC cells, PI3K hyperactivation promotes estrogen-dependent and -independent ER transcriptional activity [65]. Moreover, inhibition of PI3K prevents the emergence of hormone-independent cells, which suggests that an early intervention with antiestrogens and PI3K inhibitors could limit escape from endocrine therapy [66].…”

“…Treatment-related AEs included G2 mucositis (21%), dyspepsia (14%), fatigue (14%) and G3 maculopapular rash (50%), hyperglycemia (7%), and abdominal pain (7%). A second phase 1 study tested the safety, tolerability, and preliminary antitumor activity of alpelisib plus letrozole in patients with ER+/HER2 MBC refractory to endocrine therapy [66]. Twenty-six patients received letrozole and alpelisib daily.…”