FDA Approves Alpelisib for Breast Cancer

The FDA has approved the PI3K inhibitor alpelisib (Piqray) for use in combination with fulvestrant as a treatment for postmenopausal women, and men, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.

The approval was based on data from the phase III SOLAR-1 trial. Among a subset of patients in the trial with PIK3CA mutations, the median progression-free survival (PFS) by local assessment was 11.0 months (95% CI, 7.5-14.5) for those who received the alpelisib combination compared with 5.7 months (95% CI, 3.7-7.4) for those who received placebo plus fulvestrant. Those results, assessed after a median follow-up of 20 months, translated into a 35% reduction in the risk of progression or death, with a hazard ratio of 0.65 in favor of alpelisib (95% CI, 0.50-0.85; P = .00065). There was no advantage to alpelisib on median PFS in patients without a PIK3CA mutation.

Alpelisib is the first PI3K inhibitor approved by the FDA for breast cancer. The therascreen PIK3CA RGQ PCR Kit was simultaneously approved as a companion diagnostic test to detect the PIK3CA mutation in a tissue and/or a liquid biopsy.

"Piqray is the first PI3K inhibitor to demonstrate a clinically meaningful benefit in treating patients with this type of breast cancer. The ability to target treatment to a patient's specific genetic mutation or biomarker is becoming increasingly common in cancer treatment, and companion diagnostic tests assist oncologists in selecting patients who may benefit from these targeted treatments," Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a press release.

In SOLAR-1, 572 postmenopausal women or men with HR-positive, HER2-negative advanced breast cancer were randomized 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). A total of 341 patients had PIK3CA mutations when tumor tissue was tested, with 169 receiving the alpelisib combination and 172 taking fulvestrant alone.

Participants had received 1 or more prior lines of hormonal therapy but no chemotherapy for advanced breast cancer. Patients could have received endocrine therapy in the neoadjuvant or adjuvant setting and then relapsed, followed by endocrine therapy for advanced disease until progression, or received endocrine therapy after diagnosis for advanced disease and then experienced disease progression.

Patients who received (neo)adjuvant endocrine therapy and relapsed >1 year were later excluded after a protocol amendment. Participants had not previously received fulvestrant, or any PI3K, AKT, or mTOR inhibitor, and were not on concurrent anticancer therapy. The primary endpoint was locally assessed PFS progression in patients with PIK3CA mutations.

About half of the patients in each arm had lung or liver metastases and approximately 6% had received prior CDK4/6 therapy.

When PFS was assessed by a blinded independent review committee, the median PFS was 11.1 months (95% CI, 7.3-16.8) in the alpelisib arm versus 3.7 months (95% CI, 2.1-5.6) in the placebo arm, for a 7.4-month improvement with the addition of alpelisib to fulvestrant (HR, 0.48; 95% CI, 0.32-0.71).

PFS was analyzed in the nonmutant cohort as a proof of concept. No clinically relevant effect was observed in patients with PIK3CA-nonmutant tumors, with a median PFS of 7.4 months and 5.6 months in the alpelisib and placebo arms, respectively (HR, 0.85; 95% CI 0.58-1.25).

The overall response rate (ORR) in the PIK3CA-mutant cohort was 26.6% in the alpelisib/fulvestrant arm compared with 12.8% in the placebo/fulvestrant arm (P = .0006). In the PIK3CA-mutant patients with measurable disease, the ORRs were 35.7% and 16.2%, respectively (P = .0002).

For the entire study population, the rate of grade ≥3 adverse events was 64.4% in the alpelisib/fulvestrant arm compared with 30.3% in the placebo/fulvestrant arm. Grade ≥3 hyperglycemia occurred in 32.7% of patients receiving alpelisib versus 0.3% receiving placebo.

Grade 3 rash developed in 9.9% of patients randomized to alpelisib and 0.3% randomized to placebo. The discontinuation rate of alpelisib/fulvestrant due to AEs was 5% versus 1% for fulvestrant alone.

"Today's approval is expected to change the way we practice medicine in advanced breast cancer. For the first time, physicians can test for PIK3CA biomarkers and develop a treatment plan based on the genomic profile of a patient's cancer," global SOLAR-1 principal investigator Fabrice André, MD, PhD, research director and head of INSERM Unit U981, professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France, said in a statement. "In the SOLAR-1 Phase III trial, alpelisib plus fulvestrant nearly doubled median PFS and more than doubled overall response rate in patients with a PIK3CA mutation, offering them new hope for longer life without progression."

André F, Ciruelos EM, Rubovszky G, et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase 3 SOLAR-1 trial. Presented at: 2018 ESMO Congress; October 19-23; Munich, Germany. Abstract LBA3.

"For this approval, we employed some of our newer regulatory tools to streamline reviews without compromising the quality of our assessment. This drug is the first novel drug approved under the Real-Time Oncology Review pilot program. We also used the updated Assessment Aid, a multidisciplinary review template that helps focus our written review on critical thinking and consistency and reduces time spent on administrative tasks," added Pazdur.