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Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the phase III SOLAR-1 trial

2018; Elsevier BV; Volume: 29; Linguagem: Inglês

10.1093/annonc/mdy424.010

1569-8041

Fabrice André, Eva Ciruelos, Gábor Rubovszky, Mario Campone, Sibylle Loibl, Hope S. Rugo, Hiroji Iwata, Pierfranco Conté, Ingrid A. Mayer, Bella Kaufman, Toshinari Yamashita, Yen‐Shen Lu, Kenichi Inoue, Masato Takahashi, Zsuzsanna Pápai, A.-S. Longin, David Mills, C. Wilke, Samit Hirawat, Dejan Juric,

HER2/EGFR in Cancer Research

Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ∼40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC. The Phase 3 randomized, double-blind SOLAR1 trial (NCT02437318) investigated the efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2– ABC. Methods: Men/postmenopausal women with HR+, HER2– ABC and 1 prior line of endocrine therapy were randomized (1:1) to ALP (300 mg/day) + FUL (500 mg every 28 days + Cycle 1 Day 15) or placebo (PBO) + FUL. Primary endpoint was locally assessed progression-free survival (PFS) in the PIK3CA-mutant (mut) cohort; PFS was analyzed in the non-mut cohort as a proof of concept (PoC). Safety was assessed in the total population. Other analyses were tumor response and PFS by important prognostic subgroups, including PIK3CA mutation exon/domain and subtype. Results: 572 pts enrolled; 341 had PIK3CA-mut ABC by tissue. Primary endpoint was met; PFS in the mut cohort was significantly longer with ALP+FUL vs PBO+FUL (HR 0.65; 95% CI 0.50–0.85; P = 0.00065; median 11.0 vs 5.7 months [mo]); median follow-up was 20.0 mo. Secondary endpoint of locally assessed PFS in the non-mut cohort did not meet predefined PoC criteria (HR 0.85; 95% CI 0.58–1.25; median 7.4 vs 5.6 mo). In pts with measurable, PIK3CA-mut ABC (n = 262), overall response rate was 36% for ALP+FUL vs 16% for PBO+FUL (p = 0.0002). Overall, most frequent all-grade (G) adverse events (AEs; single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (64% vs 10%), diarrhea (58% vs 16%), nausea (45% vs 22%), decreased appetite (36% vs 10%) and rash (36% vs 6%). G 3/4 hyperglycemia (fasting plasma glucose >250 mg/dL) was observed in 37% of patients for ALP+FUL vs < 1% for PBO+FUL; G 3/4 rash in 10% vs < 1%. Discontinuations of ALP+FUL/PBO+FUL due to AEs were 5% vs 1%. Conclusions: ALP+FUL met the primary endpoint by significantly extending PFS vs PBO+FUL and demonstrated a manageable tolerability profile. This is the first study to show statistically significant, clinically meaningful PFS treatment improvement with an α-specific PI3K inhibitor in PIK3CA-mut HR+, HER2– ABC. Clinical trial identification: NCT02437318 (May 7, 2015). Editorial acknowledgement: Editorial assistance was provided by John Munro of ArticulateScience Ltd. Legal entity responsible for the study: Novartis Pharmaceutical Corporation. Funding: Novartis Pharmaceutical Corporation. Disclosure: F. André: Grants: Novartis during the conduct of the study; Grants: AstraZeneca, Pfizer, Eli Lilly, and Roche, outside of the submitted work. G. Rubovszky: Fees paid to institution: Novartis during the conduct of the study; Fees for advisory boards: Novartis outside of the submitted work. M. Campone: Consulting fees and fees for non-CME services related directly from commercial interest or their agents: Novartis, Pfizer, Astra Zeneca, Eli Lilly. S. Loibl: Grants to institution for research funding: Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Teva, Vifor, outside of the submitted work. H.S. Rugo: Grants to institution: Pfizer, Novartis, Eli Lilly, Genentech, Macrogenics, Plexxikon, Merck, OBI, Eisai; Travel support: Eli Lilly, Pfizer, Mylan, Amgen, Merck Puma, all outside of the submitted work. H. Iwata: Grants and personal fees: Daiichi Sankyo, during the study; Grants and personal fees: Chugai, AstraZeneca, Pfizer; Personal fees: Eisai; Grants: MSD, Kyowahakou Kirin, GSK, Lilly, Novartis, Bayer, outside the work. P. Conte: Speaker's bureau: Roche/Genentech, Novartis, AstraZeneca; Research funding to institution: Roche, Novartis; Merck Serono; Travel & accommodation: Novartis; Celgene; AstraZeneca. I.A. Mayer: Consulting/advisory relationship: Novartis, Genentech; Research funding: Novartis, Pfizer. B. Kaufman: Advisory boards: Novartis, outside of the submitted work. T. Yamashita: Grants and honoraria: Chugai; Honoraria: Eisai, Novartis, Taiho, Sanofi, AstraZeneca; Grants and honoraria: Kyowa Kirin; Honoraria from Pfizer Japan, outside the submitted work. K. Inoue: Grants to institution: Novartis, Pfizer, Chugai, DaiichiSankyo, Parexel / Puma Biotechnology, MSD, Bayer, Eli Lilly, Esai, during the conduct of the study. A-S. Longin: Employment: Novartis. D. Mills, C. Wilke, S. Hirawat: Employment, ownership of stocks: Novartis. D. Juric: Fees from advisory boards: Novartis, Genentech, Eisai, Ipsen, EMD Serono, during the conduct of the study. All other authors have declared no conflicts of interest.