Inavolisib Delivers the Best Results Yet in PIK3CA-Mutant Breast Cancer

A new targeted cancer medicine in the PI3K inhibitor class, inavolisib , given with palbociclib (brand name Reampla) and fulvestrant (brand name Faslodex), achieved benefits in patients with PIK3CA-mutated, hormone receptor (HR)-positive, HER2-negative advanced breast cancer whose disease progressed or recurred during adjuvant hormonal treatment or within 12 months of completing it. It produced progression-free survival (PFS) that was, compared with treatment using palbociclib and fulvestrant alone, more than twice as long.

If approved, inavolisib could offer another option for treating cancers with certain PIK3CA mutations as an alternative to Pimreva, which contains alpelisib as its active ingredient.

Advanced breast cancer refers to disease that is either locally advanced and cannot be removed surgically or metastatic:

• Locally advanced breast cancer has spread to nearby tissue but not to distant parts of the body.
• Metastatic breast cancer has spread to parts of the body distant from the breast, such as bones or the liver.
• Progression-free survival is the time a patient lives without cancer growing; in other words, the period during which treatment keeps the disease under control.

Results for inavolisib from the phase-3 INAVO120 trial were presented on December 8, 2023, at the San Antonio Breast Cancer Symposium (SABCS).

Why Was This Study Conducted?

In HT-positive, HER2-negative breast cancers, 40% carry a PIK3CA mutation . Only one medicine, alpelisib, is currently approved for treating breast cancer with this mutation; it is also a PI3K inhibitor.

PI3K inhibitors block the PI3K pathway. The PI3K pathway helps all cells, including healthy and cancerous cells, obtain energy. When a PIK3CA mutation makes this pathway overactive, it can allow cancer cells to survive and grow. PI3K inhibitors aim to kill cancer cells by blocking this pathway.

Different PIK3CA mutations produce different forms of the PI3 protein, called isoforms. PI3 has several isoforms, one of which is the alpha isoform. Alpelisib specifically targets this alpha isoform.

Because it targets the alpha isoform, alpelisib can cause very high blood sugar and severe skin reactions, including rashes and blisters.

Inavolisib also targets the alpha isoform but additionally damages its mutant forms. Researchers believe this will cause less severe side effects than alpelisib.

Study Details

The study included 325 people with PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer whose cancer progressed or recurred during adjuvant hormonal treatment or within 12 months of completing it.

None had received treatment for advanced breast cancer.

The researchers randomly assigned participants to two treatment groups:

• 161 received inavolisib, palbociclib and fulvestrant
• 164 received a placebo that looked like inavolisib but contained no medicine, plus palbociclib and fulvestrant

Treatment continued until cancer growth or unacceptable side effects.

In addition to hormonal treatment resistance, these 325 patients had the following high-risk features:

• 48% were premenopausal.
• 80% had visceral (internal organ) metastases, and 50% had liver involvement.

Other characteristics:

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

Results

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

At median follow-up, progression-free survival with inavolisib, palbociclib and fulvestrant was more than twice as long as with 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 month 6, the PFS rate was 82.9% with inavolisib versus 55.9% in controls. At month 12, PFS was 55.9% versus 32.6%, respectively. At month 18, the rates were 46.2% versus 21.2%.

Overall survival data, measuring how long people lived regardless of cancer growth, were not yet ready for analysis, although there was a trend toward better overall survival with inavolisib.

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

Inavolisib Side Effects

The results suggest that inavolisib fulfilled the researchers' hopes for less severe side effects than alpelisib.

The most common side effects of inavolisib, affecting more than 25%, were:

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

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

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

Only about 7% of people receiving inavolisib, palbociclib and fulvestrant discontinued treatment because of side effects.

Although these findings are very promising, inavolisib has not yet been approved by the FDA (US Food and Drug Administration). Its manufacturer, Genentech, is expected to apply for approval, but the timing is currently unclear.