Alpelisib Nearly Doubles PFS in PIK3-Mutated Breast Cancer

Investigational agent alpelisib (Novartis), combined with fulvestrant (Faslodex, AstaZeneca), nearly doubled progression-free survival compared with fulvestrant alone in patients with PIK3CA-mutated breast cancer, according to the results of a large phase 3 trial.

For patients with hormone receptor (HR)–positive/HER2-negative advanced breast cancer who also have a PIK3CA mutation, the median progression-free survival was 11.0 months in the alpelisib group vs 5.7 months in the control group.

The results were initially presented at the European Society for Medical Oncology (ESMO) Congress in October 2018 and were reported by Medscape Medical News at that time. The full study was published May 16 in the New England Journal of Medicine.

Alpelisib is an alpha-specific PI3K inhibitor and blocks only the alpha isoform of the enzyme, which is the one that is mutated in breast cancer. Previous PI3K inhibitors targeted all four isoforms, which in turn increased the amount of drug-related toxicity.

This is the first trial to show a clinically relevant benefit with a PI3K inhibitor combined with endocrine therapy in this subset of breast cancer patients. These results suggest that genomic testing for the PIK3CA mutation would be needed to select patients for this therapy, commented lead author Fabrice André, MD, PhD, professor of medical oncology at the Institut Gustave Roussy, Villejuif, France.

"If the drug is approved and reimbursed, we must implement sequencing of tumor in patients with metastatic breast cancer," he told Medscape Medical News. "The current standard method is PCR [polymerase chain reaction], but it could be that multigene sequencing will be useful to assess it in a near future, when other genes will have been validated."

The current treatment algorithm calls for alpelisib to be given after resistance to CDK46 inhibitors and endocrine therapy, André pointed out. "Alpelisib would be given after CDK46 inhibitors, and there are ongoing trials that will validate this strategy," he said.

**Improvement in PIK3CA-Mutated Disease**

PIK3CA-mutated cancers have been found to be sensitive to alpelisib in preclinical and phase 1 trials, and the combination of alpelisib with fulvestrant has shown synergistic antitumor activity compared with either agent alone in PIK3CA-mutated, estrogen receptor–positive xenograft models.

In the current SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1) study, André and colleagues compared alpelisib 300 mg per day plus fulvestrant 500 mg every 28 days and once on day 15 with placebo plus fulvestrant in a cohort of 572 pretreated patients with HR-positive, HER2-negative advanced breast cancer.

Patients were divided into two cohorts on the basis of tumor-tissue PIK3CA mutation status (341 patients had confirmed PIK3CA mutations). The primary endpoint was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer. Progression-free survival was also assessed in patients without the mutation. Secondary endpoints included overall response and safety.

At a median follow-up of 20 months, progression-free survival among patients with PIK3CA-mutated cancer was 11.0 months in the alpelisib–fulvestrant group vs 5.7 months in the placebo–fulvestrant group (hazard ratio for progression or death, 0.65; P < .001).

Among patients without the PIK3CA mutation, the hazard ratio was 0.85 (posterior probability of hazard ratio <1.00, 79.4%).

At 12 months, 46.3% of the patients who were treated with alpelisib achieved progression-free survival, compared to 32.9% in the placebo–fulvestrant group.

The overall response for all the patients in this cohort was greater with alpelisib–fulvestrant vs placebo–fulvestrant (26.6% vs 12.8%), as was the clinical benefit (61.5% vs 45.3%).

However, the proof-of-concept criteria were not met in the cohort who did not have the PIK3CA mutation. The median progression-free survival was 7.4 months in the alpelisib–fulvestrant group vs 5.6 months for the placebo group (hazard ratio for progression or death, 0.85; posterior probability of true hazard ratio <1.00, 79.4%). At 12 months, 28.4% of the patients in the alpelisib–fulvestrant group achieved progression-free survival, compared to 22.2% for control patients.

Safety

The most frequent side effect of alpelisib was hyperglycemia, which occurred in almost two thirds of patients (63.7%) who received alpelisib–fulvestrant and in 9.8% of those in the placebo group. Other common side effects were diarrhea (57.7% and 15.7%, respectively), nausea (44.7% and 22.3%), decreased appetite (35.6% and 10.5%), and rash (35.6% and 5.9%) or maculopapular rash (14.1% and 1.7%).

The most common grade 3/4 events were hyperglycemia (36.6% vs 0.7%), rash (9.9% vs 0.3%), maculopapular rash (8.8% vs 0.3%), and diarrhea (6.7% vs 0.3%).

Alpelisib was discontinued in 25% of the cohort because of adverse events. Treatment was stopped in 4.2% of the placebo group because of toxicity.

"There are three ways to decrease toxicity and therefore improve compliance," explained André. "First, patients must be well selected, and as an example, it has been shown that patients with uncontrolled diabetes should not receive the drug."

Second, he noted that early intervention with diabetes could prevent complications and high-grade toxicity. "To address this point, a visit at day 8 has been implemented in SOLAR1 and was probably one key for the success of the trial," André said. "Finally, there will be a learning curve for each oncologist to become comfortable with the management of hyperglycemia."

The Beginning of Gene Sequencing

If approved, alpelisib would offer another treatment option for this patient subgroup. "It will probably be used in the second-line setting for patients who have progressed after endocrine therapy and CDK46 inhibitors," commented Debu Tripathy, MD, professor and chairman, Department of Breast Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston.

This will also be the first treatment for which patient selection will be based on next-generation sequencing. "This will be a change in our process, as we typically don't do gene sequencing as part of the standard of care breast cancer, as treatments aren't based on genome testing," he said. "Up until now, most of the drugs we use aren't based on gene testing. We do use targeted HER2 therapy, for example, but we don't use gene sequencing for that."

If approved, gene testing will be needed. Such testing can be undertaken while patients are receiving their first line of therapy, which would allow the patient's status to be determined ahead of time. "I suspect that's what most of us will be doing," said Tripathy. "Breast cancer is a little further behind with this than in some other cancers when it comes to gene sequencing, but this is the beginning."

He pointed out that a few drugs have been approved for patients with mismatch repair — another aberration that can be found by genomic testing — but few breast cancer patients have mismatch repair. "It's maybe 1% or 2% at most," he said. "But PIK3 mutations, especially in patients with hormone-positive disease, can be as high as 40%."

The toxicity observed with alpelisib may be a problem. "The drug has more side effects than the CDK inhibitors, so the discontinuation rate was pretty high," Tripathy explained. "Its only about 10% with the CDK inhibitors but about 30% with this drug.

"While the side effects are manageable, it really requires screening and early treatment, and vigilance, especially in patients with mild diabetes or at a higher risk," he added,

Statistically, there was an improvement in progression-free survival with alpelisib. "It wasn’t a huge improvement in terms of additional months, but for second-line therapy, that's about what we see for the CDK inhibitors," he said. "We're looking at the median, so some patients could have a larger benefit."

The study was funded by Novartis, manufacturer of alpelisib. André received grants from Novartis during the conduct of the study, as well as grants from AstraZeneca, Pfizer, Eli Lilly, and Roche outside the submitted work. Other authors have also disclosed relevant financial relationships, as listed in the original article. Tripathy is the principal investigator for an open Novartis trial, and the institution receives support for research costs; he is also a paid consultant.

N Engl J Med. 2019;380:1929-40. Abstract

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