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ESMO 2018: SOLAR-1: Alpelisib in Patients With PIK3CA-Mutated HR-Positive, HER2-Negative Advanced Breast Cancer

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Key Points

  • Progression-free survival was nearly twice as long in patients with PIK3CA mutations randomly assigned to receive alpelisib compared to the placebo group. The median progression-free survival was 11.0 months in the alpelisib arm compared to 5.7 months in the placebo group.
  • Just over one-third (36%) of patients with measurable PIK3CA-mutated advanced breast cancer responded to alpelisib plus fulvestrant, whereas the overall response rate in the placebo/fulvestrant group was 16%.
  • The secondary endpoint of locally assessed progression-free survival in patients without PIK3CA mutations did not meet the predefined proof-of-concept endpoint.

Targeting a common mutation in patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with the alpha-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib improved progression-free survival, according to late-breaking results reported by André et al at the European Society for Medical Oncology (ESMO) 2018 Congress (Abstract LBA3_PR).

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

About 40% of patients with HR-positive breast cancer have PIK3CA mutations, activating the PI3K 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 PI3K is the one that is mutated in breast cancer. Previous PI3K inhibitors targeted all four isoforms, so there were a lot of toxicities,” noted Dr. André. A previous phase I trial with alpelisib published by Mayer et al in Clinical Cancer Research showed promising preliminary efficacy and manageable safety profile.

SOLAR-1 Trial

The SOLAR-1 trial randomly selected 572 postmenopausal women or men with HR-positive, HER2-negative advanced breast cancer; 341 had PIK3CA mutations when tumor tissue was tested. The patients had good Eastern Cooperative Oncology Group performance status (≤ 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 (Faslodex) or any PI3K, Akt, or mTOR inhibitor, and were not on concurrent anticancer therapy.

Patients were randomly assigned to receive oral alpelisib (300 mg/d) 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 in patients with PIK3CA mutations, detected in tumor tissue.

Results showed the PFS was nearly twice as long in patients with PIK3CA mutations randomly assigned to receive 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 (HR 0.65, 95% CI 0.50–1.25, P = .00065) at a median follow-up of 20.0 months.

Key Findings

Just over one-third (36%) of patients with measurable PIK3CA-mutated advanced breast cancer (n = 262) responded to alpelisib plus fulvestrant, whereas the overall response rate in the placebo/fulvestrant group was 16% (P = .0002). The secondary endpoint of locally assessed progression-free survival in patients without PIK3CA mutations did not meet the predefined proof of concept endpoint (hazard ratio = 0.85, 95% confidence interval = 0.58–1.25, median = 7.4 vs 5.6 months).

Dr. André said, “Alpelisib offers the potential for increased life expectancy in patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA 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.”

The most frequent side effects with alpelisib were hyperglycaemia (which Dr. André said could be managed with metformin), nausea, decreased appetite, and rash. Dr. André 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.”

Commentary

Commenting on the study, Angelo Di Leo, MD, PhD, Head of the Department of Medical Oncology, Hospital of Prato, Italy, said in a statement, “This is the first trial to show a clinically relevant benefit with a PI3K inhibitor combined with endocrine therapy in patients with HR-positive, HER2-negative advanced breast cancer with PIK3CA mutations.”

Dr. 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 [cyclin-dependent kinase (CDK)4/6] 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 pretreated with CDK4/6 inhibitors, which have become a standard of care in this setting.

Future Implications

Considering the wider implications, Dr. 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 tumor genomic profile … can improve the outcome.” He predicted, “These results will have a major impact on practice because we have to implement genomic testing for breast cancer.”

Dr. 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 noninvasive procedure.”

 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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