Inavolisib

Risk Summary

Inavolisib is used in combination with palbociclib and fulvestrant. Refer to the Full Prescribing Information of palbociclib and fulvestrant for pregnancy information.

Based on animal data and its mechanism of action, inavolisib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of inavolisib in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of inavolisib to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and alterations to growth at maternal exposures approximately equivalent to the human exposure at the recommended dose of 9 mg/day based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.

Data

Animal Data

In an embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis. Administration of doses ≥2 mg/kg/day resulted in decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations (including kyphosis of vertebral column, fused thoracic arch, microphthalmia) and variations (including dilated renal pelvis, short supernumerary rib, wavy rib). At a dose of 2 mg/kg/day, maternal exposures were 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC.

Inavolisib is used in combination with palbociclib and fulvestrant. Refer to the Full Prescribing Information of palbociclib and fulvestrant for lactation information.

There are no data on the presence of inavolisib or its metabolites in human milk, its effects on milk production or a breastfed child. Because of the potential for serious adverse reactions in a breastfed child, advise lactating women to not breastfeed during treatment with inavolisib and for 1 week after the last dose.

Females and Males of Reproductive Potential

Inavolisib is used in combination with palbociclib and fulvestrant. Refer to the Full Prescribing Information of palbociclib and fulvestrant for contraception and infertility information. Inavolisib can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating treatment with inavolisib.

Contraception

Females:

Advise females of reproductive potential to use effective non-hormonal contraception during treatment with inavolisib and for 1 week after the last dose.

Males:

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with inavolisib and for 1 week after the last dose.

Infertility

Based on animal studies, inavolisib may impair fertility in females and males of reproductive potential.

• Hyperglycemia
• Stomatitis
• Diarrhea

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Locally Advanced or Metastatic Breast Cancer

INAVO120

The safety of inavolisib was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

Patients received either inavolisib 9 mg (n=162) or placebo (n=162) with palbociclib and fulvestrant. The median duration of treatment with inavolisib was 9 months (range: 0 to 39 months) in the inavolisib with palbociclib and fulvestrant arm.

Serious adverse reactions occurred in 24% of patients who received inavolisib with palbociclib and fulvestrant. Serious adverse reactions in ≥1% of patients included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%).

Fatal adverse reactions occurred in 3.7% of patients who received inavolisib with palbociclib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrhage, cerebrovascular accident, COVID-19 infection, and gastrointestinal hemorrhage.

Permanent discontinuation of inavolisib due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of inavolisib included hyperglycemia (1.2%), and (0.6% each) stomatitis, gastric ulcer, intestinal perforation, anal abscess, increased ALT, decreased weight, bone pain, musculoskeletal pain, transitional cell carcinoma, and acute kidney injury.

Dosage interruptions of inavolisib due to an adverse reaction occurred in 69% of patients. Adverse reactions which required dosage interruption in ≥2% of patients included hyperglycemia (28%), neutropenia (23%), COVID-19 infection (16%), stomatitis (10%), diarrhea (7%), thrombocytopenia (4.9%), anemia (4.3%), upper respiratory tract infection (4.3%), decreased white blood cell count (3.7%), pyrexia (3.1%), nausea (2.5%), and fatigue (2.5%).

Dose reductions of inavolisib due to adverse reactions occurred in 14% of patients. Adverse reactions which required dose reduction of inavolisib in ≥2% of patients were stomatitis (3.7%) and hyperglycemia (2.5%).

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased hemoglobin, increased fasting glucose, decreased platelets, decreased lymphocytes, stomatitis, diarrhea, decreased calcium, fatigue, decreased potassium, increased creatinine, increased ALT, nausea, decreased sodium, decreased magnesium, rash, decreased appetite, COVID-19 infection, and headache.

Adverse reactions and laboratory abnormalities in INAVO120 are summarized in Table 1 and Table 2, respectively. Patient-reported symptoms are summarized in Table 3.

Table 1. Adverse Reactions (≥10% with ≥5% [All Grades] or ≥2% [Grade 3-4] Higher Incidence in the Inavolisib Arm) in INAVO120:

^* No Grade 4 adverse reactions were observed.
^a Includes aphthous ulcer, glossitis, glossodynia, lip ulceration, mouth ulceration, mucosal inflammation, and stomatitis.
^b Includes other related terms.
^c Includes dry skin, skin fissures, xerosis, and xeroderma.

Clinically relevant adverse reactions occurring in <10% of patients who received inavolisib in combination with palbociclib and fulvestrant included abdominal pain, dry eye, dysgeusia, and dyspepsia.

Table 2. Select Laboratory Abnormalities (≥10% with a ≥2% [All Grades or Grade 3-4] Higher Incidence in the Inavolisib Arm) in INAVO120:

ALT = alanine aminotransferase
^* No Grade 4 laboratory abnormalities were observed.
^a The denominator used to calculate the rate varied from 122 to 160 based on the number of patients with a baseline value and at least one post-treatment value.
^b The denominator used to calculate the rate varied from 131 to 161 based on the number of patients with a baseline value and at least one post-treatment value.
^c Grading according to CTCAE version 4.03.

In INAVO120, patient-reported symptomatic toxicities (i.e., diarrhea, nausea, vomiting, fatigue, mouth sores, decreased appetite, and rash) were assessed via the Patient-Reported Outcomes – Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline, every two weeks through Cycle 3 Day 15, and then Day 1 of every other 28-day cycle until treatment discontinuation.

Completion rates in both arms were >90% at baseline and >80% at subsequent time points where >50% of randomized patients were on treatment.

Table 3. Patient-Reported Symptoms Assessed by PRO-CTCAE in INAVO120:

Inavolisib+P+F = Inavolisib with palbociclib and fulvestrant arm; Placebo+P+F = placebo with palbociclib and fulvestrant arm.
^a The symptom attribute scoring is defined by amount/frequency/severity with a score of 0 = ‘not at all’/‘never’/‘none’; 1 = ‘a little bit’/‘rarely’/‘mild’; 2 = ‘somewhat’/‘occasionally’/‘moderate’; 3 = ‘quite a bit’/‘frequently’/‘severe’; 4 = ‘very much’/‘almost constantly’/‘very severe’.
^b The percentage of patients whose symptom score before treatment was 1-4.
^c The percentage of patients whose symptom score increased during treatment, with respect to their score before treatment.
^d The percentage of patients whose symptom score increased to 3 or 4 during treatment, with respect to their score before treatment.
^e The number of patients who provided a score before treatment and at least one on-treatment score.

Patient-reported overall side-effect impact was assessed using the Modified Bother Item (MBI). Patients provided a response to “I am bothered by side effects of treatment,” and at baseline the proportion of patients with MBI responses of “not at all” were 70% in the inavolisib with palbociclib and fulvestrant arm and 76% in the placebo with palbociclib and fulvestrant arm. At Cycle 2 Day 15, the proportion of patients with MBI responses of “not at all” were 25% in the inavolisib with palbociclib and fulvestrant arm and 53% in the placebo with palbociclib and fulvestrant arm. Through 31 cycles of treatment, patients in the inavolisib with palbociclib and fulvestrant arm reported more side effect bother compared to the placebo with palbociclib and fulvestrant arm.