Alpelisib Combo Nearly Doubles PFS in PIK3CA-Mutant Breast Cancer

The addition of the PI3K inhibitor alpelisib to fulvestrant nearly doubled median progression-free survival compared with the endocrine therapy alone in patients with HR-positive/HER2-negative advanced breast cancer who have a PIK3CA mutation.

Fabrice André, MD, PhD

The addition of the PI3K inhibitor alpelisib (BLY719) to fulvestrant (Faslodex) nearly doubled median progression-free survival (PFS) compared with the endocrine therapy alone in patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer who have a PIK3CA mutation, according to study findings that are expected to open the door for genomic testing in the malignancy.

The outcomes from the phase III SOLAR-1 trial represent the first study findings to show a benefit in a genomic subgroup of patients with breast cancer, lead investigator Fabrice André, MD, PhD, said in reporting the results during a press conference at ESMO 2018. The results will have a major impact on practice because genomic testing for breast cancer will have to be implemented for optimal use of alpelisib, predicted André, a professor of medical oncology at the Institut Gustave Roussy, Villejuif, France.

In the subset of patients in SOLAR-1 with PIK3CA mutations, the median 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.1

The finding could affect a significant proportion of patients with breast cancer. Overall, approximately 70% of breast cancers are classified as HR-positive/HER2-negative, André said. About 40% of patients who present with this type of breast cancer harbor an activating mutation of PIK3CA, the gene that encodes the alpha isoform of PI3K. “PI3K pathway hyperactivation is implicated in malignant transformation, cancer progression, and endocrine therapy resistance,” said André.

First-line treatment for HR-positive/HER2-negative advanced breast cancer is endocrine therapy with or without a CDK4/6 inhibitor. Only 39% of patients remain free of progression on treatment 2.2 years after initiating therapy with both endocrine therapy and a CDK4/6 inhibitor,2 André noted.

Alpelisib specifically targets the alpha isoform of PIK3CA, said André. “PI3K has 4 different isoforms. The 4 isoforms are important for normal cells,” he said. “Alpelisib is selective to the isoform that presents with the mutation. When you spare the other isoforms, then you can give the drug for a longer duration.”

Pan-PI3K inhibitors target multiple isoforms of PI3K, leading to excess toxicities and marginal efficacy. For example, the phase III SANDPIPER trial that tested the PI3K inhibitor taselisib in combination with fulvestrant provided only a 2-month benefit in median PFS compared with fulvestrant alone in patients with estrogen receptor—positive, PIK3CA-mutant locally advanced or metastatic breast cancer. Those results were reported at the 2018 ASCO Annual Meeting.3

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,” André said, 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.

This study “is going to lead us into the era of precision medicine,” observed Nadia Harbeck, MD, PhD, head of the Breast Center and Oncology Day Clinic, Women's Hospital of the University of Munich, Germany, who was not involved in the study.

“We’ve had numerous phase III trials with a PIK3CA inhibitor where we saw marginal benefit; hence, the drugs weren’t usable in clinical practice because their tolerability was so bad,” she said. “This is now the first phase III data proving that if you have a targeted drug and the tumor has the target, you can actually almost double PFS, and I think this will change the way we practice in HR-positive breast cancer because we now have to define the targets and then treat accordingly.”


  1. 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.
  2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547. doi: 10.1093/annonc/mdy155.
  3. Baselga J, Dent SF, Cortés J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. J Clin Oncol. 2018;36(suppl; abstr LBA1006).

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