Regulatory Decision Summary for Itovebi

The purpose of this New Drug Submission (NDS) was to obtain market authorization for Itovebi (inavolisib) in combination with fulvestrant and palbociclib for the treatment of adult patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following recurrence on or within 12 months of completing adjuvant endocrine treatment.

To better reflect the study design, the indication was revised to:

Itovebi (inavolisib film-coated tablets), in combination with palbociclib and fulvestrant, is indicated for the treatment of adult patients with endocrine-resistant PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine treatment.

The purpose of this New Drug Submission (NDS) was to obtain market authorization for Itovebi (inavolisib) in combination with fulvestrant and palbociclib for the treatment of adult patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following recurrence on or within 12 months of completing adjuvant endocrine treatment.

This submission was supported by the INAVO120 study, a Phase III, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of inavolisib plus palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in patients with PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer.

Pre/perimenopausal patients and men were included in the study but were required to receive luteinizing hormone-releasing hormone (LHRH) agonist therapy. Although few men were enrolled, they were included in the indication for Itovebi.

The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS), objective response rate (ORR), best overall response (BoR), duration of response (DoR), and clinical benefit rate (CBR). Crossover between treatment arms was not permitted. A total of 325 patients were randomized 1:1 to receive either Itovebi (inavolisib + palbociclib + fulvestrant; n=161) or placebo + palbociclib + fulvestrant (n=164). At interim analysis, 116 patients remained on treatment (67 in the Itovebi arm and 49 in the placebo arm).

The study met its primary endpoint. Itovebi demonstrated a statistically significant 57% reduction in the risk of disease progression or death compared with placebo (HR = 0.43; 95% confidence interval [CI]: 0.32, 0.59; p<0.0001). Median PFS was 15 months in the Itovebi arm versus 7.3 months in the placebo arm, an improvement of 7.7 months.

For OS, the stratified HR was 0.64 (95% CI: 0.43, 0.97; p = 0.0338), but statistical significance was not reached. Kaplan-Meier curves separated early and remained separated throughout the study. Other secondary endpoints (ORR, BoR, DoR, CBR) favored Itovebi over placebo.

The most frequently reported adverse events (>20% in the Itovebi group) included neutropenia, hyperglycemia, diarrhea, anemia, stomatitis, nausea, thrombocytopenia, decreased appetite, fatigue, COVID-19, and headache. Grade ≥3 adverse events occurred in 89.5% of patients in the Itovebi arm versus 83.3% in the placebo arm. Serious adverse events (SAEs) occurred in 24% of Itovebi-treated patients compared to 10.5% in the placebo group. Adverse events leading to dose reduction and interruption were more frequent in the Itovebi arm (14.2% and 69.1%, respectively) than in the placebo arm (3.1% and 34.6%). Withdrawal due to adverse events occurred in 6.2% of Itovebi patients versus 0.6% in placebo.

Adverse events of special interest (AESIs) included hyperglycemia, diarrhea, stomatitis, rash, ocular toxicities, pneumonitis, and hematologic abnormalities. Hyperglycemia, stomatitis, and diarrhea were more frequent and severe in the Itovebi arm. Despite risk mitigation strategies, over 50% of patients experienced hyperglycemia, including Grade 3 events. Metformin prophylaxis was recommended for at-risk patients. The effect of Itovebi in patients with pre-existing hyperglycemia is unknown, as these patients were excluded from the study.

Overall, INAVO120 demonstrated a clinically meaningful improvement in PFS and favorable trends in secondary endpoints. The safety profile of Itovebi was consistent with other PI3K inhibitors marketed in Canada. Most adverse events were manageable with dose modifications or supportive care. The Risk Management Plan was considered acceptable. Therefore, the benefit-harm-uncertainty profile was deemed favorable.

To better reflect the study design, the indication was revised to:

Itovebi (inavolisib film-coated tablets), in combination with palbociclib and fulvestrant, is indicated for the treatment of adult patients with endocrine-resistant PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine treatment.

For further details about Itovebi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.