Inavolisib Receives FDA Approval for PIK3CA-Mutated Hormone-Positive Breast Cancer

On October 10, 2024, the US Food and Drug Administration (FDA) approved a treatment for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer: inavolisib (Itovebi, Genentech, Inc.), combined with palbociclib and fulvestrant. The approval covers patients whose PIK3CA mutation is detected by an FDA-approved test and whose disease recurs during or after adjuvant endocrine therapy.

The FDA also approved the FoundationOne Liquid CDx diagnostic test to identify patients eligible for inavolisib with palbociclib and fulvestrant.

Previously, in 2019, FDA approval for breast cancers carrying a PIK3CA mutation had been granted to Pimreva, containing alpelisib . Itovebi, containing inavolisib, has now received FDA approval for similar patients but differs from alpelisib in both efficacy and side effects.

What Is a PIK3CA Mutation and Why Does It Matter in Breast Cancer?

Among HR-positive, HER2-negative breast cancers, 40% carry a PIK3CA mutation in their genetic makeup.

This mutation is an important factor in cancer development and resistance to treatment. Before this approval, the only approved therapy targeting a PIK3CA mutation was alpelisib, a PI3K inhibitor.

PI3K inhibitors block the PI3K pathway, which plays a critical role in cellular energy production and growth. Mutations in PIK3CA overactivate this pathway, contributing to uncontrolled cancer cell growth and survival. By blocking it, PI3K inhibitors aim to stop cancer cell proliferation and destroy the cells.

Mutations in the PIK3CA gene cause different forms of PI3K proteins, called isoforms, to develop. PI3K has several isoforms, one of which is the alpha isoform. Alpelisib specifically targets this alpha isoform, thereby suppressing cancer cells. However, this targeting mechanism can cause serious side effects, particularly high blood sugar and severe skin reactions such as rashes and blisters.

Inavolisib targets not only the alpha isoform but also its mutant forms. Researchers believe it may cause less severe side effects than alpelisib.

FDA Approval Based on the INAVO120 Trial

Inavolisib's efficacy was evaluated in INAVO120, a randomized, double-blind, placebo-controlled, multicenter trial.

The study's key finding was that, compared with palbociclib plus fulvestrant alone, adding inavolisib extended progression-free survival (PFS), more than doubling its duration.

The study included 325 patients with endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. Their disease had progressed during adjuvant endocrine therapy or within 12 months of completing it, and they had not received systemic treatment for locally advanced or metastatic disease. Primary endocrine resistance was defined as recurrence within the first 2 years of adjuvant endocrine therapy (ET), while secondary resistance was defined as recurrence at least 2 years after adjuvant ET or within 12 months of treatment completion.

Patients were randomized 1:1 to inavolisib 9 mg or placebo. Both groups also received oral palbociclib 125 mg once daily for 21 days, followed by a 7-day break, forming a 28-day cycle. Fulvestrant 500 mg was also administered intramuscularly on days 1 and 15 of cycle 1 and then on day 1 of each 28-day cycle.

Patients received treatment until cancer growth or unacceptable side effects.

In addition to endocrine resistance, these 325 patients had the following high-risk characteristics:

• 48% were premenopausal.
• 80% had visceral metastases and 50% had liver involvement.

Other characteristics:

• 38% were Asian.
• 48% had received only adjuvant tamoxifen.

Results

The study's primary efficacy measure was progression-free survival (PFS) . Additional measures included overall survival (OS), investigator-assessed objective response rate (ORR) and duration of response (DOR).

Median follow-up was 21.3 months, meaning that half the participants were followed for longer and half for a shorter time.

At median follow-up, progression-free survival was more than twice as long in people receiving inavolisib, palbociclib and fulvestrant as in those receiving palbociclib and fulvestrant alone. Progression-free survival was:

• 15 months with inavolisib, palbociclib and fulvestrant
• 7.3 months with palbociclib and fulvestrant alone
• Stratified hazard ratio (95% CI): HR 0.43 (0.32, 0.59), p<0.0001
• At 6 months, PFS was 82.9% in the inavolisib group and 55.9% in the control group. At 12 months, the rates were 55.9% and 32.6%, respectively. At 18 months, they were 46.2% versus 21.2%.

Overall survival data—how long people lived whether or not the cancer grew—were not yet ready for analysis, although there was a trend toward better overall survival with inavolisib.

Inavolisib with palbociclib and fulvestrant may become a new standard treatment for patients with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer.

Side Effects of Inavolisib

The results suggest that researchers' hopes that inavolisib would cause less severe side effects than alpelisib were realized.

The most common side effects of inavolisib (more than 25%) were:

• Low white blood cell count
• Mouth sores
• Anemia
• High blood sugar
• Diarrhea
• Nausea
• Rash

Although mouth sores, high blood sugar, diarrhea and rash were common, they were not severe in most people:

• 5.6% had severe mouth sores
• 5.6% had severe high blood sugar
• 3.7% had severe diarrhea
• No one had a severe rash

Only approximately 7% of those receiving inavolisib, palbociclib and fulvestrant stopped treatment because of side effects.

The recommended dose of inavolisib is 9 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Refer to the relevant prescribing information for palbociclib and fulvestrant dosing.