On May 18, 2020, atezolizumab was approved for the first-line treatment of adult patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression and no EGFR or ALK genomic tumor aberrations. High PD-L1 expression is defined as PD-L1 staining of at least 50% of tumor cells (TC ≥ 50%) or PD-L1–stained tumor-infiltrating immune cells (IC) covering at least 10% of the tumor area (IC ≥ 10%).1,2 The U.S. Food and Drug Administration (FDA) simultaneously approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting patients with NSCLC for treatment with atezolizumab.
Supporting Efficacy Data
Approval was based on findings in the international open-label phase III IMpower110 study (ClinicalTrials.gov identifier NCT02409342).2,3 In the trial, 549 patients with stage IV NSCLC who had PD-L1 expression of TC ≥ 1% or IC ≥ 1%, including those with EGFR or ALK genomic tumor aberrations, were randomly assigned to receive atezolizumab at 1,200 mg every 3 weeks (n = 286) or platinum-based chemotherapy (n = 263) consisting of carboplatin or cisplatin with either pemetrexed (nonsquamous histology) or gemcitabine (squamous histology) for a maximum of four to six cycles. Patients receiving pemetrexed continued to receive maintenance doses of the drug until disease progression or unacceptable toxicity.
The efficacy analysis supporting the current approval was performed in a prespecified subgroup of 205 patients with high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), excluding those with EGFR or ALK aberrations, consisting of 107 patients in the atezolizumab group and 98 in the chemotherapy group. The main efficacy outcome measure was overall survival.
Among the 205 patients, median age was 65.0 years (range = 33–87 years). Overall, 70% were male, 82% were white, and 17% were Asian. Eastern Cooperative Oncology Group performance status was 0 (36%) or 1 (64%), 88% were current or former smokers, 76% had nonsquamous disease, and 24% had squamous disease.
Atezolizumab has warnings/precautions for immune-related pneumonitis, immune-related hepatitis, immune-related colitis, immune-related endocrinopathies, infections, infusion-related reactions, and embryofetal toxicity.
At interim analysis, median overall survival was 20.2 months (95% confidence interval [CI] = 16.5 months to not estimable) in the atezolizumab group vs 13.1 months (95% CI = 7.4–16.5 months) in the chemotherapy group (hazard ratio [HR] = 0.59, 95% CI = 0.40–0.89, P = .0106). No statistically significant differences in overall survival between treatments were observed for the other prespecified subgroups with PD-L1 expression of TC ≥ 5% or IC ≥ 5% or TC ≥ 1% or IC ≥ 1% at the interim or final analyses.
On investigator assessment, median progression-free survival was 8.1 months (95% CI = 6.8–11.0 months) vs 5 months (95% CI = 4.2–5.7 months; HR = 0.63, 95% CI = 0.45–0.88), and confirmed overall response rates were 38% vs 29%.
How It Works
Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors. This activity releases the PD-L1/programmed cell death protein 1 (PD-1)-mediated inhibition of immune response, including activation of antitumor immune response without inducing antibody-dependent cellular cytotoxicity.
PD-L1 may be expressed on tumor cells or tumor-infiltrating immune cells and can contribute to the inhibition of antitumor immune response in the tumor microenvironment. Binding of PD-L1 to PD-1 and B7.1 receptors on T cells and antigen-presenting cells results in suppression of cytotoxic T-cell activity, T-cell proliferation, and cytokine production. In syngeneic mouse tumor models, blocking PD-L1 activity resulted in decreased tumor growth.
How It Is Used
For the current indication, patients must be selected for atezolizumab treatment based on the presence of high PD-L1 expression (TC ≥ 50% or IC ≥ 10%), as determined by an FDA-approved test, and have no EGFR or ALK genomic tumor aberrations.
The recommended dosage of atezolizumab for treatment of NSCLC is 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks, administered intravenously over 60 minutes. If the first infusion is tolerated, all subsequent infusions can be given over 30 minutes.
No dose reductions for atezolizumab are recommended. Infusion should be slowed or interrupted for grade 1 or 2 infusion reactions and permanently discontinued for grade 3 or 4 infusion reactions.
Product labeling provides instructions for atezolizumab interruption or discontinuation for adverse reactions, including pneumonitis, hepatitis, colitis or diarrhea, and endocrinopathies including but not limited to hypophysitis, adrenal insufficiency, hyperthyroidism, and type 1 diabetes, as well as other immune-mediated adverse reactions involving a major organ, infections, infusion-related reactions, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies), inability to taper corticosteroid treatment, and recurrent grade 3 or 4 adverse reactions.
Atezolizumab should be permanently discontinued for grade 3 or 4 pneumonitis, hepatitis with aspartate transaminase (AST) or alanine transaminase (ALT) > 8 times the upper limit of normal (ULN) or total bilirubin > 3 times ULN, grade 4 diarrhea or colitis, other grade 4 immune-mediated events involving a major organ, persistent grade 2 or 3 adverse reactions (excluding endocrinopathies) that do not recover to grade 0 or 1 within 12 weeks of last dose, inability to reduce corticosteroid treatment to ≤ 10 mg/d prednisone or equivalent within 12 weeks after last dose, and recurrent grade 3 or 4 adverse reactions.
The most common adverse events of any grade (at least 20% of patients) observed in clinical trials of atezolizumab monotherapy have been fatigue/asthenia, nausea, cough, dyspnea, and decreased appetite.
Among all 286 patients receiving atezolizumab in the IMpower110 study, the median duration of exposure to treatment was 5.3 months (0–33 months). The most common adverse events of any grade occurring in at least 15% of patients were fatigue/asthenia (25% vs 34% in the chemotherapy group) and decreased appetite (15% vs 19%). The most common grade 3 or 4 adverse events were fatigue/asthenia (1.4% vs 4.2%) and constipation (1.0% vs 0.8%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (9% vs 17%), hyperkalemia (3.9% vs 2.7%), and hypophosphatemia (3.6% vs 2.0%).
Serious adverse events occurred in 28% of patients receiving atezolizu-mab, the most common being pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%), and pneumonitis (2.1%). Adverse events led to interruption of treatment in 26%, most commonly attributable to increased ALT (2.1%), increased AST (2.1%), pneumonitis (2.1%), pyrexia (1.4%), pneumonia (1.4%), and upper respiratory tract infection (1.4%). Treatment was discontinued due to adverse events in 6% of patients, with the most common causes (at least two patients) being peripheral neuropathy and pneumonitis. Adverse events led to death in 3.8% of patients; causes included mortality reported as unexplained death and death of unknown cause, aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infraction, and device occlusion (one patient each).
Atezolizumab has warnings/precautions for immune-related pneumonitis, immune-related hepatitis, immune-related colitis, immune-related endocrinopathies (including hypophysitis, thyroid disorders, adrenal insufficiency, and type 1 diabetes), infections, infusion-related reactions, and embryofetal toxicity. Patients should be monitored for changes in liver function and changes in thyroid function. Patients should be advised not to breastfeed while taking atezolizumab.
1. U.S. Food and Drug Administration: FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-first-line-treatment-metastatic-nsclc-high-pd-l1-expression. Accessed May 26, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Tecentriq (atezolizumab) injections. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761034s027lbl.pdf. Accessed May 26, 2020.
3. Spigel D, De Marinis F, Giaccone G, et al: IMpower110: Interim overall survival analysis of a phase III study of atezolizumab vs platinum-based chemotherapy as first-line treatment in PD-L1 selected NSCLC. 2019 ESMO Annual Meeting. Abstract LBA78. Presented September 27, 2020.