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Experimental Alpelisib May Help Treat Advanced-Stage, Hormone-Receptor-Positive, HER2-Negative Breast Cancer With Specific Mutation

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The experimental medicine alpelisib combined with the hormonal therapy medicine Faslodex (chemical name: fulvestrant) improved progression-free survival more than Faslodex alone in people diagnosed with advanced-stage, hormone-receptor-positive, HER2-negative breast cancer with a PIK3CA mutation.

The research was presented on Oct. 22, 2018, at the European Society for Medical Oncology 2018 Congress. Read the abstract of "Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): results of the Phase 3 SOLAR-1 trial.”

About alpelisib and Faslodex

Alpelisib is an experimental targeted therapy medicine that inhibits the PI3K pathway. The PI3K pathway helps all cells -- both healthy and cancer cells -- get the energy they need. When this pathway is overactivated because of a mutation in the PIK3CA gene, it can allow cancer cells to survive and grow. PI3K inhibitors block this pathway, with the goal of killing cancer cells.

Alpelisib is a pill taken by mouth.

Different mutations in the PIK3CA gene make different forms of the PI3 protein, called isoforms by researchers. There are several isoforms of PI3; one of them is the alpha isoform. Alpelisib specifically targets the alpha isoform.

2016 research on experimental buparlisib, another PI3K inhibitor, found that buparlisib combined with Faslodex also increased progression-free survival in postmenopausal women diagnosed with advanced-stage, hormone-receptor-positive, HER-negative breast cancer. Buparlisib targeted four isoforms of PI3, and researchers believe this is why buparlisib caused a number of severe, unacceptable side effects, including mood disorders and suicide attempts. So research on buparlisib was stopped.

Because alpelisib targets only the alpha isoform of PI3, the researchers hypothesized that its side effects would be tolerable.

Faslodex is an estrogen receptor downregulator. Faslodex sits in the estrogen receptor in breast cells so the cell can’t receive estrogen’s signals to grow and multiply. Faslodex also reduces the number of estrogen receptors and changes the shape of breast cell estrogen receptors so they don’t work as well. Faslodex is a liquid that is given once a month as an injection into a muscle.

Advanced-stage breast cancer is breast cancer that has spread to tissue near the breast or to parts of the body away from the breast, such as the bones or liver.

Progression-free survival is how long a person lives without the cancer growing.

The SOLAR-1 trial

The SOLAR-1 trial included 572 people diagnosed with advanced-stage, hormone-receptor-positive, HER2-negative breast cancer that had previously been treated with hormonal therapy; 341 of the cancers had a PIK3CA mutation. The people in the study were either postmenopausal women or men.

The people were randomly split into two treatment groups:

  • alpelisib plus Faslodex
  • placebo (a sugar pill that looked just like alpelisib) plus Faslodex

Median follow-up was 20 months. This means that half the people were followed for a longer time and half the people were followed for a shorter time.

The results showed that progression-free survival was nearly twice as long in people diagnosed with breast cancer with a PIK3CA mutation treated with alpelisib and Faslodex compared to those treated with Faslodex alone.

For people diagnosed with advanced-stage, hormone-receptor-positive, HER2-negative breast cancer with a PIK3CA mutation, progression-free survival was:

  • 11 months in the alpelisib-Faslodex group
  • 5.7 months in the Faslodex alone group

Only people diagnosed with cancers with a PIK3CA mutation got benefits from alpelisib.

"Alpelisib is the first drug to show a benefit in a genomic subgroup of breast cancer patients," said lead author Fabrice André, oncologist and professor of medical oncology at the Institut Gustave Roussy, Villejuif, France. "We have had HER2-targeted drugs…but, until now, the use of tumor genomics has not really entered the practical care of breast cancer, unlike melanoma or lung cancer.

"This study opens the door for clinical genomics for breast cancer as the first study to show that treatment based on a patient's tumor genomic profile -- specifically, PIK3CA mutation -- can improve the outcome," he continued. "These results will have a major impact for practice, because we have to implement genomic testing for breast cancer."

The most common side effects of any severity caused by alpelisib in the study were:

  • high blood sugar
  • diarrhea
  • nausea
  • decreased appetite
  • rash

The most common severe side effects were:

  • high blood sugar
  • rash
  • diarrhea

Overall, 5% of people treated with alpelisib and 1% of people treated with Faslodex alone stopped treatment because of side effects.

Alpelisib is still experimental

While the results of this study are promising, it’s important to know that these are early results. The follow-up time was very short, fewer than 2 years, and it’s not clear if the better progression-free survival will translate to better outcomes in the long term.

If you’re being treated for advanced-stage, hormone-receptor-positive, HER2-negative breast cancer, you and your doctor may be considering a number of treatment options. If the cancer has a PIK3CA mutation and you’re willing to participate in a clinical trial, you may have even more options, possibly including an experimental treatment such as a PI3K pathway inhibitor. Talk to your doctor about clinical trials that might be a good fit for you and your unique situation. Visit the Clinical Trials pages for more information.

And stay tuned to for more news about how PI3K pathway inhibitors are being used to treat advanced-stage breast cancer.

Editor’s Note: On May 24, 2019, the U.S. Food and Drug Administration approved Piqray (chemical name: alpelisib) in combination with Faslodex to treat metastatic and advanced-stage, hormone-receptor-positive, HER2-negative breast cancer with a PIK3CA mutation that has grown after hormonal therapy treatment in postmenopausal women and men.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser

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