FDA Approves Roche's PI3Kα Inhibitor

On October 10, the FDA approved Genentech's (a Roche subsidiary) oral small molecule therapy Inavolisib (Itovebi), in combination with CDK4/6 inhibitor palbociclib and fulvestrant, for adult patients with locally advanced or metastatic breast cancer who carry the PIK3CA mutation, are endocrine-resistant, hormone receptor (HR) positive, and human epidermal growth factor receptor 2 (HER2) negative.

Itovebi is a potential "best-in-class" PI3Kα inhibitor and had previously received FDA Breakthrough Therapy Designation. Inavolisib has high in vitro PI3Kα inhibitory potency and selectivity, specifically triggering the degradation of mutated PI3Kα proteins. Through this unique dual mechanism of action, inavolisib may offer well-tolerated, sustained disease control and potentially improved outcomes for patients with HR-positive/HER2-negative, PIK3CA-mutated advanced breast cancer.

This approval is based on the results of the pivotal Phase III INAVO120 trial. The primary efficacy endpoint was progression-free survival (PFS), as assessed by the investigator according to RECIST 1.1. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR). The study demonstrated a 57% reduction in the risk of disease progression or death compared to palbociclib and fulvestrant alone (15.0 months vs. 7.3 months; HR=0.43, 95% CI: 0.32-0.59, p<0.0001), showing both statistically and clinically meaningful benefits.

Key Results

• The median PFS in the inavolisib + palbociclib + fulvestrant group was 15.0 months (95% CI: 11.3, 20.5), compared to 7.3 months (95% CI: 5.6, 9.3) in the placebo + palbociclib + fulvestrant group (HR=0.43 [95% CI: 0.32, 0.59], p-value <0.0001).
• The ORR was 58% (95% CI: 50, 66) for the inavolisib group, compared to 25% (95% CI: 19, 32) in the placebo group.
• The median DOR for inavolisib was 18.4 months (95% CI: 10.4, 22.2), versus 9.6 months (95% CI: 7.4, 16.6) for the control group.
• While the interim analysis of OS did not reach statistical significance, inavolisib reduced the risk of death by 36% (HR=0.64, 95% CI: 0.43-0.97).

Common Adverse Reactions

The most common adverse reactions (≥20%) included laboratory abnormalities, such as neutropenia, decreased hemoglobin, increased fasting glucose, thrombocytopenia, lymphopenia, stomatitis, diarrhea, reduced calcium levels, fatigue, reduced potassium, elevated creatinine, increased ALT, nausea, reduced sodium, reduced magnesium, rash, decreased appetite, COVID-19 infection, and headache.

Dr. Komal Jhaveri, one of the lead investigators of the INAVO120 study, commented, "The PI3K pathway plays a critical role in disease progression and has been a challenging target. The Itovebi-based regimen has more than doubled progression-free survival while maintaining manageable safety and tolerability, adding a new standard of care for PIK3CA-mutated breast cancer."

Currently, Itovebi is being investigated in three Phase III clinical trials (INAVO120, INAVO121, INAVO122) for the treatment of locally advanced or metastatic breast cancer with PIK3CA mutations in combination with different therapeutic regimens.