Alpelisib, a New Genomic Mutation-Targeted Drug for Treatment-Resistant Breast Cancer, Receives FDA Approval

The United States Food and Drug Administration (FDA), on 24 May 2019, for postmenopausal patients with hormone receptor-positive, HER2 -negative advanced or metastatic breast cancer with a PIK3CA mutation, approved the use of a drug with the hormonal treatment medicine fulvestrant in combination with alpelisib (Piqray tablets). For this patient group, alpelisib together with fulvestrant may be used if the patient's cancer has progressed during or after hormonal therapy.

A new genetic target has been identified in patients with hormone receptor-positive (HR +), HER2-negative (HER2-), advanced breast cancer: alpha-specific phosphatidylinositol-3-kinase (PI3K) inhibiting its mutation, alpelisib was shown to significantly reduce tumor growth (increase progression-free survival) in patients with hormone-positive, HER2-negative breast cancer, in results at ESMO 2018from the phase-3 clinical trial called SOLAR-1.

The first effective drug targeting a "genetic subgroup" in breast cancer

According to the study's lead author, Professor of Medical Oncology Fabrice André, "Alpelisib is the first drug to show a benefit in a specific genomic subgroup of breast cancer patients."

Previously, targeting the HER2 protein, HER2-targeted drugs were available—but until now, unlike in skin cancer, malignant melanoma or lung cancer , a drug directed at a tumor's genetic characteristics had not been applicable to breast cancer.

Approximately % 40 of patients with hormone-positive breast cancer have PIK3CA mutations;these activate one of the mechanisms responsible for cancer progression and resistance to hormone-suppressing treatment, the PI3 kinase pathway.

- Related topic: Reasons for the Development of Treatment Resistance in Breast Cancer (Detailed)

Alpelisibis an alpha-specific oral (taken as a pill by mouth) PI3K inhibitor (suppressor). The alpha isoform of PI3-kinase is the one mutated in breast cancer.

Study details

SOLAR-1 clinical trialincluded patients with hormone-positive, HER2-negative, stage 4 breast cancer, a total of 572 postmenopausal female and male patients.

In 341 patients, tumor tissue testing identified PIK3CA mutations. Patients had previously received one or more lines of hormonal therapy but no chemotherapy for advanced breast cancer. They also had not previously received fulvestrant (Faslodex) or any PI3K, Akt or mTOR inhibitor.

Patients were randomized to two arms; one received oral alpelisib (300 mg / day) + fulvestrant, while the control arm received placebo + fulvestrant. The study's primary endpoint was the time disease was kept under control with treatment (progression-free survival) in patients whose tumor tissue was positive for PIK3CA mutations.

Study results

• Patients were followed for a median of 20 months. 
• Compared with the fulvestrant + placebo group, fulvestrant + alpelisib treatment in patients with PIK3CA mutation-positive breast cancer produced a median progression-free survival that was twice as long (11 versus 5.7 months).
• In patients with PI3KCA mutation-positive advanced breast cancer, a group of 262 patients, more than one-third (% 36) responded to alpelisib plus fulvestrant, compared with an overall response rate of % 16 in the placebo + fulvestrant group. 
• No significant difference in treatment response was obtained in patients without PI3KCA mutations (median 7.4 versus 5.6 months).
• The most common alpelisib side effects, metformin -controllable hyperglycemia (high blood sugar), nausea, decreased appetite and rash, were observed. Hyperglycemia occurred in %64 of those receiving alpelisib versus %10 receiving placebo. However, no serious side effects expected to affect quality of life or to be life-threatening were reported. The lack of severe side effects suggests that alpelisib may be a drug that should be given before chemotherapy.

In conclusion, alpelisib offers the potential for longer life expectancy in patients with hormone-positive, HER2-negative advanced breast cancer and PI3KCA mutations, but follow-up is currently short and overall survival has not yet been reached. Therefore, long-term results will be awaited before this genetically targeted drug receives approval for use.

The SOLAR-1 study is the first trial to demonstrate a clinically meaningful benefit from a PI3K inhibitor together with hormonal therapy, opening the door to genomic testing for breast cancer. Studies to detect PI3KCA mutations using liquid (blood-based, fluid) biopsy have already begun.

Just as, in recent years, immunotherapies have significantly changed treatment pathways and provided great benefits to patients, particularly in melanoma, lung cancer and bladder cancer, the remarkable advances in breast cancer that began with drugs acting on the cell division cycle, CDK4 / 6 inhibitors (palbociclib, ribociclib and abemaciclib), appear set to continue with PI3K inhibitors. All these developments are major steps for oncology and offer hope to our patients. One important next step will be determining the sequence and combinations in which hormonal drugs, CDK4/6 and PI3K inhibitors should be used in hormone-positive advanced breast cancer.