Targeting specific genomic mutation in breast cancer improves outcomes, first study shows

October 22, 2018

Munich, Germany, 20 October 2018 - Targeting a common mutation in patients with hormone receptor positive (HR+) HER2 negative (HER2-) advanced breast cancer with the alpha-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib significantly improves progression-free survival, according to late-breaking results reported at ESMO 2018. (1)

"Alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients," said lead author Fabrice André, oncologist and Professor of Medical Oncology at the Institut Gustave Roussy, Villejuif, France. He explained: "We have had HER2-targeted drugs - targeting the HER2 protein - but, until now, the use of tumour genomics has not really entered the practical care of breast cancer, unlike melanoma or lung cancer."

About 40% of patients with HR+ breast cancer have PIK3CA mutations, activating the PI3 kinase pathway leading to cancer progression and resistance to endocrine therapy. Alpelisib (BYL719) is an oral PI3K inhibitor that is alpha specific. "The alpha isoform of PI3-kinase is the one that is mutated in breast cancer. Previous PI3K inhibitors targeted all four isoforms so there were a lot of toxicities," noted André. A previous phase 1 trial with alpelisib showed promising preliminary efficacy and manageable safety profile (2).

The SOLAR-1 trial randomised 572 postmenopausal women or men with HR+, HER2- advanced breast cancer; 341 had PIK3CA mutations when tumour tissue was tested. The patients had good performance status (Eastern Cooperative Oncology Group (ECOG) status of ?1) and had received one or more prior lines of hormonal therapy but no chemotherapy for advanced breast cancer. They had not previously received fulvestrant, or any PI3K, Akt or mTOR inhibitor, and were not on concurrent anticancer therapy.

Patients were randomised to oral alpelisib (300 mg/day) or placebo plus intramuscular fulvestrant (500 mg every 28 days and on days 1 and 15 of treatment cycle 1). The primary endpoint was locally assessed progression free survival (PFS) in patients with PIK3CA mutations, detected in tumor tissue.

Results showed the PFS was nearly twice as long in patients with PIK3CA mutations randomised to alpelisib compared to the placebo group. The median PFS was 11.0 months in the alpelisib arm compared to 5.7 months in the placebo group (hazard ratio 0.65, 95% confidence interval [CI] 0.50 to 1.25, p=0.00065) at a median follow-up of 20.0 months.

Just over one-third (36%) of patients with measurable PI3KCA-mutated advanced breast cancer (n=262) responded to alpelisib plus fulvestrant, while the overall response rate in the placebo/fulvestrant group was 16% (p=0.0002). The secondary endpoint of locally assessed PFS in patients without PI3KCA mutations did not meet the predefined proof of concept endpoint (HR0.85, 95% CI 0.58-1.25, median 7.4-5.6mo).

André said: "Alpelisib offers the potential for increased life expectancy in patients with HR+ HER2- advanced breast cancer with PI3KCA mutations." But he cautioned: "For now, the follow-up is short so we cannot say whether there is a long-term survival benefit. But alpelisib increased progression-free survival and that will hopefully translate to improvement in outcome."

Commenting on the study for ESMO, Prof. Angelo Di Leo, Head of the Department of Medical Oncology, Hospital of Prato, Italy, said: "This is the first trial to show a clinically relevant benefit with a PI3K inhibitor combined with endocrine therapy in patients with HR+ HER2- advanced breast cancer with PIK3CA mutations."

Di Leo added: "The next critical step will be to understand when, and how, this compound should be incorporated into the current treatment algorithm - upfront, in combination with endocrine therapy and a CDK4/6 inhibitor, or sequentially, after disease progression on the combination of endocrine therapy and a CDK4/6 inhibitor." He cautioned that a limitation of the study was that only a modest number of patients were pre-treated with CDK4/6 inhibitors, which have become a new standard of care in this setting.

The most frequent side-effects with alpelisib were hyperglycaemia, which André said could be managed with metformin, nausea, decreased appetite and rash. He said: "There is no life-threatening toxicity or major toxicity that would be expected to affect quality of life. This is good because alpelisib is a drug that is supposed to be given before chemotherapy."

Considering the wider implications, André said: "This study opens the door for clinical genomics for breast cancer as the first study to show that treatment based on a patient's tumour genomic profile - specifically PI3KCA mutation - can improve the outcome." He predicted: "These results will have a major impact for practice because we have to implement genomic testing for breast cancer."

Di Leo agreed: "If PI3K inhibitors become a treatment option for patients with advanced breast cancer, assessing PIK3CA mutations using plasma samples (liquid biopsies) will become standard of care, with the considerable advantage of this being a non-invasive procedure."
Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2018 Congress

Official Congress hashtag: #ESMO18


This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO or IASLC who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.


  1. Abstract LBA3_PR 'Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial' will be presented by Fabrice André during the Presidential Symposium 1 on Saturday 20 October, 16:30 to 18:20 (CEST) in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
  2. Mayer IA, Abramson VG, Formisano L et al. A phase Ib study of alpelisib (BYL719), a PI3Kα inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clinical Cancer Research 2017; 23;: 26-34.

About the European Society for Medical Oncology (ESMO)

ESMO is the leading professional organisation for medical oncology. With 18,000 members representing oncology professionals from over 150 countries worldwide, ESMO is the society of reference for oncology education and information. ESMO is committed to offer the best care to people with cancer, through fostering integrated cancer care, supporting oncologists in their professional development, and advocating for sustainable cancer care worldwide.Visit:

LBA3_PR - Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial

F. André1, E.M. Ciruelos2, G. Rubovszky3, M. Campone4, S. Loibl5, H.S. Rugo6, H. Iwata7, P. Conte8, I.A. Mayer9, B. Kaufman10, T. Yamashita11, Y.-S. Lu12, K. Inoue13, M. Takahashi14, Z. Pápai15, A.-S. Longin16, D. Mills17, C. Wilke17, S. Hirawat18, D. Juric19

1Breast Cancer Unit, Department of Medical Oncology, Gustave Roussy - Cancer Campus, Villejuif, France, 2Medical Oncology , Hospital Universitario 12 de Octubre, Madrid, Spain, 3Department of Medical Oncology and Clinical Pharmacology, National Institute of Oncology Hungary, Budapest, Hungary, 4Medical Oncology, ICO Institut de Cancerologie de l'Ouest René Gauducheau, Saint-Herblain, France, 5Department of Medicine and Research, German Breast Group (GBG) Forschungs GmbH, Neu-Isenburg, Germany, 6Breast Cancer Center, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, 7Nagoya City University Medical School, Aichi Cancer Center Hospital, Nagoya, Japan, 8Department of Surgery, Oncology and Gastroenterology, University of Padova, Istituto Oncologico Veneto IRCCS, Padova, Italy, 9Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 10Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel, 11Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan, 12Hematology/Oncology, National Taiwan University Hospital, Taipei, Taiwan, 13Medical Oncology, Saitama Cancer Center, Saitama, Japan, 14Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, 15Medical Oncology, Duna Medical Center, Budapest, Hungary, 16Oncology, Novartis Pharma S.A.S, Paris, France, 17Oncology, Novartis Pharma AG, Basel, Switzerland, 18Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 19Medical Oncology, Massachusetts General Hospital, Boston, MA, USA

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 SOLAR 1 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: NCT024373, 18 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 from Novartis during the conduct of the study; Grants from AstraZeneca, Pfizer, Eli Lilly, and Roche, outside of the submitted work.

G. Rubovszky: Fees paid to his institution by Novartis during the conduct of the study, and fees for advisory boards from 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 her institution for research funding: Abbvie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Teva, Vifor, outside of the submitted work.

H.S. Rugo: Grants to her 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 his institution: Roche, Novartis; Merck Serono; Travel & accommodation: Novartis; Celgene; AstraZeneca.

I.A. Mayer: Consulting/advisory relationship with Novartis, Genentech; Research funding: Novartis, Pfizer.

B. Kaufman: Participation in advisory boards for 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 by Novartis and ownership of stocks.

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.

European Society for Medical Oncology

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