Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1

Abstract

Background: Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC.

Patients and methods: Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161.

Results: In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up.

Conclusions: Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS.

Gov id: NCT02437318.

Keywords: PI3Kα; PIK3CA; alpelisib; breast cancer; overall survival.

Conflict of interest statement

Disclosure FA reports research grants, paid to the institution, from Novartis, AstraZeneca, Pfizer, Eli Lilly, Daiichi Sankyo, and Roche. EMC reports honoraria from Novartis, Pfizer, Eli Lilly, Roche, and AstraZeneca; consulting and paid speakers' bureaus for Novartis, Pfizer, Eli Lilly, and Roche; and travel support from Roche and Pfizer. DJ reports personal fees from Novartis, Genentech, Eisai, Ipsen, EMD Serono, Syros, Relay Therapeutics, MapKure, Vibliome, and Petra Pharma; grant from Novartis; and research grants to institution from Genentech, Eisai, EMD Serono, Takeda, Amgen, Celgene, Placon Therapeutics, Syros, Petra Pharma, InventisBio, and Infinity Pharmaceuticals. SL reports grants and other (honoraria for lectures and ad boards) from AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, and Daiichi Sankyo; other (honoraria for lectures and ad boards) from Seattle Genetics, PriME/Medscape, Eli Lilly, Samsung, Eirgenix, BMS, Puma, and MSD; personal fees from Chugai; grants from Teva, Vifor, and Immunomedics, outside the submitted work and paid to her institution; and patent EP14153692.0 pending. MC reports grants and non-financial support from Novartis; grants and personal fees from Roche; grants from Tessaro; personal fees from AstraZeneca and Pfizer; and other support from Servier, Eli Lilly, Sanofi, and Accord. IAM reports consulting fees from Novartis, Genentech, Eli Lilly, AstraZeneca, GlaxoSmithKline, Immunomedics, MacroGenics, Seattle Genetics, AbbVie, and Puma; and research funding to institution from Novartis, Genentech, AbbVie, Puma, Immunomedics, Polyphor, and Pfizer. GR reports consulting fees from Novartis, Lilly, and Pfizer, speaker fee from Novartis, Pfizer, Roche, Swixx, Lilly, and Amgen. TY reports grants and honoraria from Chugai, Kyowa Kirin, and Nippon Kayaku; and honoraria from Eisai, Novartis, Taiho, AstraZeneca, Pfizer Japan, Eli Lilly, and Daiichi Sankyo. BK reports speaker's fees from Novartis, Roche, AstraZeneca, Pfizer, and AbbVie. Y-SL reports clinical trial grants, consultation fees, and speaker fees from Novartis; consultation fees from Pfizer and Boehringer Ingelheim; and contracted research grants from Roche, Pfizer, GlaxoSmithKline, and Merck, Sharp & Dohme. KI reports grants to institution from Novartis during the conduct of the study; grants to institution and personal fees from Pfizer, Chugai, and Eli Lilly; and grants to institution from Daiichi Sankyo, PAREXEL/Puma Biotechnology, MSD, AstraZeneca, and Sanofi, outside the submitted work. MT reports personal fees from AstraZeneca, Eisai, Eli Lilly, Novartis, and Pfizer; and grants from Chugai, Eisai, Nippon Kayaku, and Taiho. FG is employed by and owns stock in Novartis Pharmaceuticals Corporation. DM is employed by and owns stock in Novartis Pharma AG. MK is employed by and owns stock in Novartis Pharmaceuticals Corporation. MM is employed by and owns stock in Novartis Pharmaceuticals Corporation. PFC reports speakers' bureau for Roche/Genentech, Novartis, and AstraZeneca; research funding to institution from Roche, Novartis, and Merck Serono; and travel, accommodations, and expenses from Novartis, Celgene, and AstraZeneca. HI reports honoraria from Daiichi Sankyo, Chugai/Roche, AstraZeneca, Pfizer, Eli Lilly, Novartis, Taiho, and Eisai; consulting or advisory role for Daiichi Sankyo, Chugai/Roche, AstraZeneca, Eli Lilly, Pfizer, Novartis, Kyowa Hakko Kirin, AbbVie, and Odonate; uncompensated member of the steering committee for the SOLAR-1 trial; and member of the steering committee of DS-8201 registration study. HSR reports research funding paid to institution from Pfizer, Merck, Novartis, Eli Lilly, Genentech, OBI, Odonate, Sermonix, Daiichi Sankyo, Eisai, Seattle Genetics, MacroGenics and Immunomedics; travel, accommodations, and expenses from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and MacroGenics; one-time consulting for Samsung; and advisory boards for Puma. ZP has declared no conflicts of interest.

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