Gedatolisib

Gedatolisib is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information for fulvestrant and palbociclib for pregnancy information. When used in combination with gedatolisib, advise patients to use effective contraception during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

Based on its mechanism of action, gedatolisib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug- associated risk. Animal reproductive toxicity studies have not been conducted with gedatolisib. Inhibition of PI3K and mTOR pathways have been associated with adverse embryo-fetal growth and lethality in animals.

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

Gedatolisib is used in combination with fulvestrant, with or without palbociclib. Refer to the Prescribing Information for fulvestrant and palbociclib for lactation information. When used in combination with gedatolisib, advise patients to not breastfeed during treatment and for the longest post-treatment duration recommended in the Prescribing Information of any of the individual products.

There are no data on the presence of gedatolisib 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 gedatolisib and for 2 weeks after the last dose.

Carcinogenesis

Carcinogenicity studies have not been conducted with gedatolisib.

Mutagenesis

Gedatolisib was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay. Gedatolisib was not genotoxic in an in vivo rat bone marrow micronucleus assay.

Impairment of fertility

Fertility studies with gedatolisib have not been conducted. In repeated-dose toxicity studies, gedatolisib was administered intravenously once weekly on a 3 weeks on/1 week off schedule for 3 months in rats and dogs. Degeneration/atrophy of seminiferous tubules in testes was observed in male rats and dogs at ≥5 mg/kg and 0.5 mg/kg, respectively, and atrophy of prostate was observed in male rats at ≥1 mg/kg. In female rats, atrophy in the vagina and uterus was observed at ≥5 mg/kg. All findings occurred at exposures ≤0.2 times the human AUC at the recommended dose. Findings in males and females were reversible following a 12-week recovery period.

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.

The safety of gedatolisib was evaluated in 383 adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer without a detectable PIK3CA mutation in Study 1 of VIKTORIA-1.

Patients received either Arm A: gedatolisib 180 mg intravenously once weekly for 3 weeks on followed by 1 week off (Days 1, 8, 15 for each 28-day cycle) in combination with fulvestrant 500 mg intramuscularly on cycle 1 Days 1 and 15, and then at Day 1 of each subsequent 28-day cycle and palbociclib 125 mg orally once daily for 21 days followed by 7 days off treatment for each 28-day cycle (n=130); or Arm B: gedatolisib in combination with fulvestrant (n=130); or Arm C: fulvestrant alone (n=123). The dose, route of administration, and frequency of each drug in Arms B and C were the same as Arm A. The median duration of exposure for gedatolisib plus fulvestrant and palbociclib was 6.2 months (range: 0.5 to 25 months) and 5.7 months (range: 0 to 26 months) for gedatolisib plus fulvestrant.

Gedatolisib in Combination with Fulvestrant and Palbociclib

Serious adverse reactions occurred in 25% of patients who received gedatolisib in combination with fulvestrant and palbociclib. Serious adverse reactions in ≥1% of patients included pneumonia (3.8%), thrombosis (3.8%), and stomatitis (1.5%). Fatal adverse reactions occurred in 2.3% of patients who received gedatolisib in combination with fulvestrant and palbociclib, including (0.8% each) pneumonia, multiorgan failure, and hepatic failure.

Permanent discontinuation of gedatolisib due to an adverse reaction occurred in 12% of patients receiving gedatolisib in combination with fulvestrant and palbociclib. Adverse reactions that resulted in permanent discontinuation of gedatolisib were stomatitis, nausea, rash, pneumonitis, diplopia, hypertension, vomiting, breast ulceration, and squamous cell carcinoma of the lung.

Dosage interruptions of gedatolisib due to an adverse reaction occurred in 64% of patients receiving gedatolisib in combination with fulvestrant and palbociclib. Adverse reactions which required dosage interruption of gedatolisib in ≥2% of patients included neutropenia, stomatitis, decreased neutrophil count, fatigue, anemia, leukopenia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), pyrexia, rash, thrombosis, pneumonia, diarrhea, hyperglycemia, thrombocytopenia, upper respiratory tract infection, pruritus, and urinary tract infection.

Dose reductions of gedatolisib due to an adverse reaction occurred in 41% of patients receiving gedatolisib in combination with fulvestrant and palbociclib. Adverse reactions which required dose reduction of gedatolisib in ≥2% of patients included stomatitis, neutropenia, rash, nausea, increased AST, and increased ALT.

The most common (≥20%) adverse reactions, including laboratory abnormalities, in the gedatolisib in combination with fulvestrant and palbociclib arm were decreased white blood cell, decreased neutrophils, decreased hemoglobin, decreased lymphocytes, stomatitis, nausea, decreased platelets, increased fasting glucose, fatigue, vomiting, rash, constipation, diarrhea, increased ALT, increased AST, musculoskeletal pain, decreased sodium, and increased eosinophils.

Gedatolisib in Combination with Fulvestrant

Serious adverse reactions occurred in 19% of patients who received gedatolisib in combination with fulvestrant. Serious adverse reactions in ≥1% of patients included pneumonia (3.8%), thrombosis (2.3%), pleural effusion (1.5%), and pneumonitis (1.5%). Fatal adverse reactions occurred in 2.3% of patients who received gedatolisib in combination with fulvestrant, including (0.8% each) acute respiratory failure, bronchopulmonary hemorrhage, and cardiac arrest.

Permanent discontinuation of gedatolisib due to an adverse reaction occurred in 9% of patients receiving gedatolisib in combination with fulvestrant. Adverse reactions that resulted in permanent discontinuation of gedatolisib were stomatitis, nausea, rash, pneumonitis, acute respiratory failure, myocarditis, angina pectoris, fatigue, infusion-related reaction, peripheral neuropathy, and oral pain.

Dosage interruptions of gedatolisib due to an adverse reaction occurred in 37% of patients receiving gedatolisib in combination with fulvestrant. Adverse reactions which required dosage interruption of gedatolisib in ≥2% of patients included fatigue, increased AST, increased ALT, stomatitis, pneumonia, pyrexia, and diarrhea.

Dose reductions of gedatolisib due to an adverse reaction occurred in 22% of patients receiving gedatolisib in combination with fulvestrant. Adverse reactions which required dose reduction of gedatolisib in ≥2% of patients included stomatitis, rash, and nausea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, in the gedatolisib in combination with fulvestrant arm were stomatitis, increased fasting glucose, increased eosinophils, decreased hemoglobin, nausea, rash, increased ALT, fatigue, musculoskeletal pain, decreased lymphocytes, vomiting, increased AST, pruritus, and diarrhea.

Tables 1 and 2 summarize the adverse reactions and laboratory abnormalities in Study 1 of VIKTORIA-1, respectively.

Table 1. Adverse Reactions (≥10%) in Patients Who Received Gedatolisib plus Fulvestrant and Palbociclib in Study 1 of VIKTORIA-1:

Grading according to CTCAE 5.0.
N=number of patients.
^a Includes multiple related terms.
^b No Grade 4 events were reported.

Table 2. Select Laboratory Abnormalities (≥10%) in Patients Who Received Gedatolisib plus Fulvestrant and Palbociclib in Study 1 of VIKTORIA-1:

N = number of patients; WBC = white blood cells; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatine phosphokinase; ALP = alkaline phosphatase.
^a Glucose results were graded per CTCAE v4.03.
^b No Grade 4 events were reported.