1. Goodwin, Peter M.

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MUNICH-A combination of the phosphoinositide 3-kinase (PI3K) inhibitor alpelisib plus fulvestrant significantly extended progression-free survival (PFS) compared to placebo plus fulvestrant in patients with HR+/HER2- advanced breast cancer in the randomized phase III SOLAR-1 trial reported at the 2018 ESMO Annual Congress.

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Precision Medicine

"This study opens the door for precision medicine in metastatic breast cancer," said lead investigator Fabrice Andre, MD, PhD, Associate Professor in the Department of Medical Oncology at Institut Gustave Roussy in Villejuif, France.


This had been the first study to show statistically significant clinically meaningful PFS improvement with an alpha isoform-specific PI3K inhibitor in patients with HR+/HER2- advanced breast cancer and mutated oncogene PIK3CA, he said, and the drug had a "manageable toxicity profile.

Fabrice Andr, MD, Ph... - Click to enlarge in new windowFabrice Andre, MD, PhD. Fabrice Andre, MD, PhD

"[This] alpha selective PI3-kinase inhibitor improves progression-free survival in a clinically meaningful way in patients who present [with] mutational PI3 kinase," Andre said. He noted that SOLAR-1 had been the first study to show a benefit from a targeted therapy driven by genomics. "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."


Andre said that previous PI3K inhibitors had targeted all four isoforms so there were a lot of toxicities. A previous phase I trial with alpelisib had shown that targeting the alpha isoform of PI3 kinase-the one commonly mutated in breast cancer-had promising preliminary efficacy and safety.


"What we know is that 40 percent of patients who present with HR+/HER2- metastatic breast cancer have an activating mutation on PI3 kinase," he said, also noting that the treatment was active because this particular mutation was on the P3CA gene that encoded specifically for the alpha isoform of PI3 kinase.


The SOLAR-1 study tested whether alpelisib-that is selective for the alpha isoform of PI3 kinase-could improve outcome of patients who are resistant to endocrine therapy. "What we observed is that by giving the PI3-kinase inhibitor we improve progression-free survival by more than 5 months and the hazard ratio is 0.65 with a p value below the pre-defined threshold," he said.


Study Details

Patients were recruited to the study if they had previously been treated with an aromatase inhibitor and had an identified PIK3CA status. The hypothesis of the trial to be tested was that the targeted therapy worked only in patients with the mutation.


SOLAR-1 randomized 572 postmenopausal women or men with HR+/HER2- advanced breast cancer. A total of 341 had PIK3CA mutations in their tumor tissue samples. All patients had good performance status and had received one or more prior lines of hormonal therapy but no chemotherapy. They had not previously received fulvestrant or any molecularly targeted therapy.


PFS was nearly twice as long in patients with PIK3CA mutations randomized to alpelisib compared to the placebo group-11.0 months in the alpelisib arm compared to 5.7 months in the placebo group. The hazard ratio was 0.65, with a p-value of 0.00065 at a median follow-up of 20.0 months.


Andre said the safety profile indicated that there was "some hyperglycemia-grade 3-4 in more than 30 percent of patients"-and that about 10 percent of patients had grade 3 rash. He noted that although there had been "some side effects" the drug had been tolerable in general and the efficacy finding had been highly statistically significant. "The magnitude of benefit is high-beyond statistical significance there is a real benefit for the patient."


According to Andre, the data were not sufficiently mature to assess benefit in overall survival, but he was optimistic. "We are going to even amplify this benefit by better understanding which patients derive the most benefit [and] by learning how to use the drug."


Alpelisib was one more drug that could contribute to disease control in these patients, he said. "We have incremental benefit and this drug is going to contribute to make the disease even more chronic.


"What we all must do as a community is first learn how to use this drug in order to increase duration of treatment and then include our patients in the follow-up trials that will come after this one that will aim at increasing the benefit that we already observe," he noted.


Commenting on the study for ESMO Angelo Di Leo, MD, PhD, Head of Sandro Pitigliani Medical Oncology Unit in the Hospital of Prato Istituto Toscani Tumori in Prato, Italy, said that the next critical step was to understand when and how this compound should be incorporated into the current treatment algorithm.


"Upfront in combination with endocrine therapy and a CDK4/6 inhibitor or sequentially after disease progression on the combination of endocrine therapy and a CDK4/6 inhibitor?" But he said a limitation of the study was that only a modest number of patients were pre-treated with CDK4/6 inhibitors-which had become a new standard of care in this setting.


Peter M. Goodwin is a contributing writer.