ASCO Connection

July 2017

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NSCLC The safety of TECENTRIQ was evaluated in Study 3, a multicenter, international, randomized, open- label trial in patients with metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD–L1 expression [see Clinical Studies (14.2)]. Patients received 1200 mg of TECENTRIQ (n=142) administered intravenously every 3 weeks until unacceptable toxicity or either radiographic or clinical progression or docetaxel (n=135) administered intravenously at 75 mg/m 2 every 3 weeks until unacceptable toxicity or disease progression. The median duration of exposure was 3.7 months (range: 0–19 months) in TECENTRIQ-treated patients and 2.1 months (range: 0–17 months) in docetaxel-treated patients. The most common adverse reactions (≥ 20%) in patients receiving TECENTRIQ were fatigue (46%), decreased appetite (35%), dyspnea (32%), cough (30%), nausea (22%), musculoskeletal pain (22%), and constipation (20%). The most common Grade 3-4 adverse reactions (≥2%) were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, AST increase, ALT increase, dysphagia, and arthralgia. Nine patients (6.3%) who were treated with TECENTRIQ experienced either pulmonary embolism (2), pneumonia (2), pneumothorax, ulcer hemorrhage, cachexia secondary to dysphagia, myocardial infarction, or large intestinal perforation which led to death. TECENTRIQ was discontinued due to adverse reactions in 4% (6/142) of patients. Adverse reactions leading to interruption of TECENTRIQ occurred in 24% of patients; the most common (>1%) were pneumonia, liver function test abnormality, upper respiratory tract infection, pneumonitis, acute kidney injury, hypoxia, hypothyroidism, dyspnea, anemia, and fatigue. Serious adverse reactions occurred in 37% of patients. The most frequent serious adverse reactions (> 2%) were pneumonia, dyspnea, pleural effusion, pyrexia, and venous thromboembolism. Table 5 summarizes adverse reactions that occurred in at least 10% of TECENTRIQ-treated patients and at a higher incidence than in the docetaxel arm. Table 6 summarizes selected laboratory abnormalities worsening from baseline that occurred in ≥10% of TECENTRIQ-treated patients and at a higher incidence than in the docetaxel arm. Table 5: Adverse Reactions Occurring in ≥10% of TECENTRIQ-Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3–4]) (Study 3) TECENTRIQ (n=142) Docetaxel (n=135) Adverse Reaction All grades Grade 3–4 All grades Grade 3–4 Percentage (%) of Patients General Disorders Pyrexia 18 0 13 0 Infections Pneumonia 18 6 4 2 Metabolism and nutrition disorders Decreased appetite 35 1 22 0 Musculoskeletal and connective tissue disorders Arthralgia 16 2 9 2 Back pain 14 1 9 1 Psychiatric Disorders Insomnia 14 0 8 2 Respiratory, thoracic and mediastinal disorders Dyspnea 32 7 24 2 Cough 30 1 25 0 Table 6: Selected Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of TECENTRIQ-Treated Patients with NSCLC and at a Higher Incidence than in the Docetaxel Arm (Between Arm Difference of ≥5% [All Grades] or ≥2% [Grades 3–4]) (Study 3) Percentage of Patients with Worsening Laboratory Test from Baseline TECENTRIQ Docetaxel Test All grades % Grade 3–4 % All grades % Grade 3–4 % Hyponatremia 48 13 28 8 Hypoalbuminemia 48 5 49 1 Alkaline Phosphatase increased 42 2 24 1 Aspartate aminotransferase increased 33 2 15 0 Alanine aminotransferase increased 31 2 9 1 Creatinine increased 19 1 14 2 Hypokalemia 18 2 11 4 Hypercalcemia 13 0 5 0 Total Bilirubin increased 11 0 5 1 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 275 patients in Study 1, 114 patients (41.5%) tested positive for treatment-emergent (treatment-induced or treatment-enhanced) anti-therapeutic antibodies (ATA) at one or more post-dose time points. Among 135 patients in Study 3, 73 patients (54.1%) tested positive for treatment-emergent ATAs at one or more post-dose time points. Among 111 patients in Study 4, 53 patients (47.7%) tested positive for treatment-emergent ATAs at one or more post-dose time points. In Study 1, Study 3, and Study 4, the presence of ATAs did not appear to have a clinically signicant impact on pharmacokinetics, safety or efcacy. Immunogenicity assay results are highly dependent on several factors, including assay sensitivity and specicity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of ATAs to TECENTRIQ with the incidence of antibodies to other products may be misleading. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of TECENTRIQ in pregnant women. Animal studies have demonstrated that inhibition of the PD–L1/PD–1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. 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. Data Animal Data Animal reproduction studies have not been conducted with TECENTRIQ to evaluate its effect on reproduction and fetal development. A literature-based assessment of the effects on reproduction demonstrated that a central function of the PD–L1/PD–1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to a fetus. Blockage of PD–L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to a fetus and to result in an increase in fetal loss; therefore, potential risks of administering TECENTRIQ during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD–L1/PD–1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD–1 and PD–L1 knockout mice. Based on its mechanism of action, fetal exposure to atezolizumab may increase the risk of developing immune-mediated disorders or altering the normal immune response. 8.2 Lactation Risk Summary There is no information regarding the presence of atezolizumab in human milk, the effects on the breastfed infant, or the effects on milk production. As human IgG is excreted in human milk, the potential for absorption and harm to the infant is unknown. Because of the potential for serious adverse reactions in breastfed infants from TECENTRIQ, advise a lactating woman not to breastfeed during treatment and for at least 5 months after the last dose. 8.3 Females and Males of Reproductive Potential Contraception Females Based on its mechanism of action, TECENTRIQ can cause fetal harm when administered to a pregnant woman [see Use in Specic Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TECENTRIQ and for at least 5 months following the last dose. Infertility Females Based on animal studies, TECENTRIQ may impair fertility in females of reproductive potential while receiving treatment [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of TECENTRIQ have not been established in pediatric patients. 8.5 Geriatric Use Of the 310 previously-treated patients with urothelial carcinoma treated with TECENTRIQ in Study 1, 59% were 65 years or older. Of the 142 patients with NSCLC treated with TECENTRIQ in Study 3, 39% were 65 years or older. No overall differences in safety or efcacy were observed between patients ≥ 65 years of age and younger patients. Of the 119 cisplatin-ineligible patients with urothelial carcinoma treated with TECENTRIQ in Study 4, 83% were 65 years or older and 41% were 75 years or older. The overall response rate in patients 65 years or older was 23% (23/99) and in patients 75 years or older was 29% (14/49). Grade 3 or 4 adverse reactions occurred in 53% (52/99) of patients 65 years or older and 51% (25/49) of patients 75 years or older. No overall differences in safety or efcacy were observed between patients ≥ 75 years of age and younger patients. 8.6 Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment of TECENTRIQ is recommended for patients with mild hepatic impairment. TECENTRIQ has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdose with TECENTRIQ. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-related adverse reactions that may require corticosteroid treatment and interruption or discontinuation of TECENTRIQ, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions (5.2)]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.3)]. • Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, hyperthyroidism, hypothyroidism, adrenal insufciency, or type 1 diabetes mellitus, including diabetic ketoacidosis [see Warnings and Precautions (5.4)]. • Meningoencephalitis, Myasthenic syndrome/Myasthenia Gravis, and Guillain-Barré syndrome: Advise patients to contact their healthcare provider immediately for signs or symptoms of meningitis, myasthenic syndrome/myasthenia gravis, or Guillain-Barré syndrome [see Warnings and Precautions (5.5)]. • Ocular Inflammatory Toxicity: Advise patients to contact their healthcare provider immediately for signs or symptoms of ocular inflammatory toxicity [see Warnings and Precautions (5.5)]. • Pancreatitis: Advise patients to contact their healthcare provider immediately for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)]. • Infection: Advise patients to contact their healthcare provider immediately for signs or symptoms of infection [see Warnings and Precautions (5.6)]. • Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)]. • Rash: Advise patients to contact their healthcare provider immediately for signs or symptoms of rash [see Dosage and Administration (2.2)]. Embryo-Fetal Toxicity Advise female patients that TECENTRIQ can cause fetal harm. Instruct females of reproductive potential to use effective contraception during treatment and for at least 5 months after the last dose of TECENTRIQ [see Use in Specic Populations (8.1, 8.3)]. Lactation Advise female patients not to breastfeed while taking TECENTRIQ and for at least 5 months after the last dose [see Use in Specic Populations (8.2)]. TECENTRIQ ® (atezolizumab) Manufactured by: PDL/080916/0193(1) Genentech, Inc. Initial U.S. Approval: May 2016 A Member of the Roche Group Code Revision Date: April 2017 1 DNA Way TECENTRIQ is a registered trademark of Genentech, Inc. South San Francisco, CA 94080-4990 © 2017 Genentech, Inc. U.S. License No. 1048

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