Summary Basis of Decision for Itovebi

Clinical Pharmacology

Inavolisib, the medicinal ingredient in Itovebi, is a selective inhibitor of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) with activity predominantly against the catalytic subunit alpha isoform protein (p110α), encoded by the PI3K catalytic subunit alpha (PIK3CA) gene. In vitro, inavolisib led to the degradation of mutated p110α, inhibited the activity of the downstream PI3K pathway target protein kinase B (AKT), reduced cellular proliferation, and induced apoptosis in PIK3CA-mutated breast cancer cell lines. In PIK3CA-mutated breast cancer xenograft models, inavolisib reduced tumour growth, which increased when combined with palbociclib (a cyclin-dependent kinase [CDK] 4/6 inhibitor) and fulvestrant (an endocrine therapy), as compared to any treatment alone or in doublet combinations.

The pharmacokinetics of inavolisib was characterized in patients with locally advanced or metastatic PIK3CA-mutated solid tumours, including breast cancer, and in healthy subjects. Patients with solid tumours were treated under an oral dosing regimen ranging from 3 mg to 12 mg daily, and healthy subjects were given a single 9 mg dose.

The pharmacokinetics of inavolisib is presented as a geometric mean (geometric coefficient of variation [geo CV]%) following administration of the approved recommended dosage unless otherwise specified. Determined through population pharmacokinetic modelling, the inavolisib steady-state exposure as measured by the area under the concentration-time curve (AUC) is 1,010 h*ng/mL (25%), and as measured by the peak plasma concentration (C_max) is 69 ng/mL (27%). Inavolisib exhibited dose-proportional pharmacokinetics (steady-state AUC from 0 to 24 h [AUC_0-24] is proportional with dose) in patients with locally advanced or metastatic breast cancer over a dose range of 6 mg to 12 mg (0.7 to 1.3 times the recommended dose). Steady-state concentrations are predicted to be attained by Day 5.

Based on findings from a population pharmacokinetic analysis, no clinically significant differences were observed in the pharmacokinetics of inavolisib based on age (27 to 85 years), sex, race (Asian or all others, with the majority Caucasian), body weight (39 kg to 159 kg), mild hepatic impairment, or mild renal impairment. No dose adjustment is recommended for patients with mild hepatic impairment or mild renal impairment.

The predominant metabolites of inavolisib are not mediated by cytochrome P450 (CYP) enzymes, suggesting a low likelihood of interaction between inavolisib and CYP inhibitors or inducers. Results of in vitro studies have indicated that inavolisib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6, and does not induce CYP1A2 at clinically relevant concentrations. Additionally, inavolisib did not appear to have the potential to inhibit any of the transporters tested (P-glycoprotein, breast cancer resistance protein [BCRP], organic anion transporting polypeptide [OATP] 1B1, OATP1B3, organic cation transporter [OCT] 1, OCT2, multidrug and toxin extrusion [MATE] 1, MATE2K, organic anion transporter [OAT] 1, or OAT3) at clinically relevant concentrations.

The effects of hepatic and renal impairment were evaluated through population pharmacokinetic analyses. Mild hepatic impairment was not found to be a significant covariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild hepatic impairment were similar to those in patients with normal hepatic function. The effect of moderate to severe hepatic impairment on the pharmacokinetics of inavolisib has not been studied. Mild renal impairment was also not found to be a significant covariate on inavolisib exposure. The pharmacokinetics of inavolisib in patients with mild renal impairment were similar to those in patients with normal renal function. The effect of moderate and severe renal impairment on the pharmacokinetics of Itovebi has not been established. The use of Itovebi is not recommended in patients with moderate or severe renal impairment.

Although the exposure-response relationship for the efficacy of inavolisib has not been fully characterized, higher systemic exposure of inavolisib was associated with higher incidence of anemia or hyperglycemia of Grade 2 severity or higher, and inavolisib dose modification due to adverse events.

The ability of inavolisib to prolong the QT interval was assessed in a pharmacokinetic-pharmacodynamic analysis which indicates that at the recommended dose, a mean increase in the QTc interval of greater than 20 ms is unlikely.

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

Clinical Efficacy

The clinical efficacy of Itovebi was established based on data from the Phase III INAVO120 study. It was designed to compare the efficacy and safety of the triplet combination of inavolisib, palbociclib, and fulvestrant to the triplet combination of placebo, palbociclib, and fulvestrant in patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer. These patients had disease which progressed during treatment or within 12 months of completing adjuvant endocrine therapy, and had not received prior systemic therapy for locally advanced or metastatic disease.

The primary endpoint of the study was progression-free survival (PFS). The key secondary endpoints were overall survival (OS), objective response rate (ORR), best response (BoR), duration of response (DoR), and clinical benefit rate (CBR). The PFS, ORR, BoR, DoR, and BCR were evaluated by investigators using the Response evaluation criteria in solid tumours (RECIST) version 1.1, which provided a standardized approach to solid tumour measurement throughout the study. Progression-free survival was also evaluated by blinded independent central review (BICR) for sensitivity analysis using RECIST version 1.1 criteria. Crossover between the treatment arms was not permitted after randomization.

The patient population enrolled in the INAVO120 study is mostly representative of the population targeted by the approved indication for Itovebi. Patients in pre- or perimenopause were included in the study. Patients that were not included in the study were those with Type 1 or Type 2 diabetes, severe organ dysfunction (assessed by signs and symptoms, laboratory studies, and rapid progression of disease), and central nervous system (CNS) involvement (known and untreated or active CNS metastasis) at the time of randomization.

The full analysis set (FAS; hereafter referred to as the FAS population) included 325 patients randomized in a 1:1 ratio to either the inavolisib, palbociclib, and fulvestrant group (the Itovebi group; 161 patients) or the placebo, palbociclib, and fulvestrant group (the placebo group; 164 patients). At the time of the first data cut-off, treatment was ongoing for 116 patients (67 patients in the Itovebi group and 49 patients in the placebo group). Demographic and baseline characteristics were generally balanced between the two groups. Most patients were diagnosed at an earlier stage of disease and had progressed to stage 4 breast cancer. Almost all patients had distant lesions (metastatic disease, no CNS involvement) at the time of randomization. Most patients had prior (neo)adjuvant chemotherapy (82.8%) and endocrine therapy (99.4%). Almost all patients were naïve to cyclin-dependent kinase (CDK) 4/6 inhibitors (98.8%).

The study met its primary endpoint. A statistically significant improvement in the median PFS was observed in the Itovebi group relative to the placebo group, as the risk of disease progression or death was reduced by 57% in patients with PIK3CA-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer (stratified hazard ratio [HR] = 0.43; 95% confidence interval [CI]: 0.32, 0.59; p<0.0001).

An improvement in the median PFS of 7.7 months was observed in the Itovebi group (15 months) compared to the placebo group (7.3 months). Progression-free survival was additionally analyzed by BICR in the FAS population, to address the possibility of investigator bias in the determination of disease progression. The results of this sensitivity analysis were consistent with those of the investigator-based analysis (HR = 0.50; 95% CI: 0.36, 0.68; p-value log-rank < 0.0001 stratified analysis), with a 9-month improvement in the median PFS in the Itovebi group compared to the placebo group. Other sensitivity analyses of PFS were performed to evaluate the impact of stratification, the evaluation of PIK3CA mutation-positive status by central test, missing data, and use of any non-protocol anti-cancer therapy prior to disease progression. A consistent improvement in PFS was observed in the Itovebi group compared to the placebo group in all sensitivity analyses. Primary endpoint findings across pre-specified subgroups were mostly consistent with findings in the FAS population and were supportive of a robust statistical and clinical finding for PFS in the FAS population.

At the planned interim analysis for overall survival, a key secondary endpoint, 97 events had occurred (63% of planned OS events). The stratified HR was 0.64 (95% CI: 0.43, 0.97; p = 0.0338), with 42 deaths in the Itovebi group and 55 deaths in the placebo group. Under the interim analysis stopping boundary (p£0.0098), statistical significance was not reached. However, the outcome of the interim OS analysis supports the primary endpoint.

Results from the evaluations of the other key secondary endpoints (ORR, BoR, DoR, and CBR) all favoured the Itovebi group over the placebo group.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Itovebi (inavolisib-film coated tablets), in combination with palbociclib and fulvestrant, is indicated for: the treatment of adult patients with 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.	Itovebi (inavolisib-film coated tablets), in combination with palbociclib and fulvestrant, is indicated for: the treatment of adult patients with endocrine-resistant PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer following recurrence on or after completing adjuvant endocrine treatment.

For more information, refer to the Product Monograph for Itovebi, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The most frequently reported adverse events in the INAVO120 study (reported in more than 20% of patients in the Itovebi group) were neutropenia, hyperglycemia, diarrhea, anemia, stomatitis, nausea, thrombocytopenia/decreased platelet count, decreased appetite, fatigue, coronavirus disease 2019 (COVID-19) infection, and headache.

Adverse events leading to death occurred for 6 patients in the Itovebi group and 2 patients in the placebo group. In the Itovebi group, the adverse events leading to death included cerebral hemorrhage, cerebrovascular accident, gastrointestinal hemorrhage, acute coronary syndrome, and COVID-19 infection. None were determined to be treatment-related by the investigators.

Adverse events classified as Grade 3 or higher were reported in 89.5% of patients in the Itovebi group and in 83.3% of patients in the placebo group. The adverse events classified as Grade 3 or 4 for which the incidence differed by more than 2% between treatment groups were decreased white blood cell count, decreased platelet count, anaemia, hyperglycemia, thrombocytopenia, increased alanine transaminase, diarrhea, decreased weight, stomatitis, and hypokalemia. Serious adverse events were reported in 24% of patients in the Itovebi group and 10.5% of patients in the placebo group. Adverse events reported more frequently in the Itovebi group than in the placebo group include COVID-19 infection, pneumonia, anemia, febrile neutropenia, urinary tract infection, diarrhea, pyrexia, and acute coronary syndrome. The respective incidences of adverse events leading to dose reduction and dose interruption were 14.2% and 69.1% of patients in the Itovebi group, and 3.1% and 34.6% of patients in the placebo group. Adverse events leading to withdrawal were reported in 6.2% of patients in the Itovebi group and 0.6% of patients in the placebo group.

Fourteen adverse events of special interest (AESIs) were identified for Itovebi based on the known safety profile of inavolisib and PI3K inhibitors: hyperglycemia, diarrhea, nausea, vomiting, colitis, stomatitis/mucosal inflammation, rash, ocular toxicities, pneumonitis, neutropenia, thrombocytopenia, aspartate transferase/alanine transaminase elevation, lymphopenia, and anemia. Of the AESI, hyperglycemia, stomatitis, and diarrhea have been reported more often and at a higher severity in the Itovebi group than in the placebo group. The remaining AESI were either confounded by the other drugs in the triplet combination (such as hematotoxicity associated with palbociclib), or by the extended exposure to the treatment resulting from the delay in progression of the disease in the Itovebi group compared to the placebo group. Most reported AESI were classified as Grade 1 or 2, with a few of the remaining AESI reported in the Itovebi group classified as Grade 4. No cases of colitis were reported in the Itovebi group.

Hyperglycemia was highlighted in a Serious Warnings and Precautions box in the Product Monograph for Itovebi, as severe cases of hyperglycemia have been reported. The safety of Itovebi has not been studied in patients with Type 1 or Type 2 diabetes mellitus requiring ongoing anti-hyperglycemic treatment. Metformin prophylaxis is recommended for patients with risk factors for hyperglycemia.

For more information, refer to the Product Monograph for Itovebi, approved by Health Canada and available through the Drug Product Database.

The non-clinical pharmacology studies indicated that inavolisib selectively inhibits the p110α subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) in vitro and inhibits tumour growth in vivo. Additionally, it was not found to have any significant off-target effects, and has a favourable pharmacokinetic profile consistent with a drug that can be delivered orally to achieve clinically relevant exposures.

The key effects observed in repeat-dose toxicity studies included hyperglycemia and body weight loss in rats and dogs; inflammation in dogs; bone marrow hypocellularity, atrophy of glandular and reproductive tissues, and eye lens degeneration in rats; and lymphoid depletion and lens fiber swelling and lens cortex vacuolation in the eye in dogs. The no-observed-adverse-effect levels (NOAELs) were 1.5 mg/kg/day in rats and 0.3 mg/kg/day in dogs, which correspond to 0.44 and 0.56 times the human exposure at a clinical dose of 9 mg.

Findings were generally dose-dependent and reversible, and could be clinically monitored and/or managed. At exposures at least 0.56 times higher than the human exposure (at a clinical dose of 9 mg), lens fiber swelling and lens vacuolation in dogs were reversible. At exposures at least 3.6 times higher than the human exposure, lens fiber degeneration in rats was considered irreversible.

No carcinogenicity studies have been conducted with inavolisib.

Inavolisib was not found to be mutagenic in the bacterial mutagenesis assay. Inavolisib showed clastogenicity in an in vitro assay in human lymphocytes, but no evidence was found that inavolisib induced in vivo genotoxicity in the micronucleus and comet study in rats.

In an embryo-fetal development study in Sprague-Dawley rats, the observed dose-dependent effects included decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, and teratogenicity. These effects were observed at exposures of at least 0.8 times the human exposure at a clinical dose of 9 mg. No dedicated fertility studies have been conducted with inavolisib.

The effects observed in male rats included dose-dependent atrophy of the prostate and seminal vesicle and decreased organ weights without microscopic correlate in the epididymis and testis (at exposures at least 0.4 times the human exposure at a clinical dose of 9 mg). In a 1-month toxicity study in dogs, focal inspissation of seminiferous tubule contents, multinucleated spermatids in the testis, and epithelial degeneration/necrosis in the epididymis were observed (at exposures at least 2 times the human exposure at a clinical dose of 9 mg). Multinucleated spermatids in the testis persisted through the 4-week recovery period. However, there were no inavolisib-related microscopic findings in the testes or epididymides or effects on sperm concentration, motility, or morphology in the 3-month dog toxicity study at similar exposures.

In the 4-week toxicity study, the effects observed in female rats included minimal to mild and reversible atrophy in the uterus and vagina and decreased ovarian follicles (at exposures at least 1.1 times the human exposure at a clinical dose of 9 mg). In the 3-month toxicity study in rats, findings suggesting an interruption/alteration of the estrus cycle were observed (at exposures at least 1.5 times the human exposure at a clinical dose of 9 mg).

Inavolisib did not show potential for phototoxicity in the in vitro BALB/c 3T3 mouse fibroblast assay.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Itovebi. Considering the intended use of Itovebi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Itovebi, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Itovebi has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.