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Atezolizumab Plus Chemotherapy and Bevacizumab in First-Line Treatment of Metastatic Lung Cancer


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In late 2018, atezolizumab was approved for use in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberration.1,2

Supporting Efficacy Data

Approval was based on findings from the phase III open-label IMpower150 trial (ClinicalTrials.gov identifier NCT02366143).2,3 In the trial, 1,045 patients without EGFR or ALK tumor mutations (of a total of 1,202 patients) were randomly assigned to receive atezolizumab, carboplatin, paclitaxel, and bevacizumab (atezolizumab four-drug regimen, n = 359); atezolizumab, carboplatin, and paclitaxel (atezolizumab three-drug regimen, n = 349); or carboplatin, paclitaxel, and bevacizumab (control group, n = 337). After completion of 4 or 6 cycles of carboplatin and paclitaxel, patients continued to receive bevacizumab in the four-drug group and the control group and continued to receive atezolizumab in the four-drug and three-drug groups until disease progression or

OF NOTE

Atezolizumab carries warnings/precautions for immune-related pneumonitis, hepatitis, colitis, and endocrinopathies; infections; infusion-related reactions; and embryo-fetal toxicity.

unacceptable toxicity. Study drug doses follow: atezolizumab, 1,200 mg; bevacizumab, 15 mg/kg; paclitaxel, 175 mg/m2 (in Asian patients) or 200 mg/m2; and carboplatin AUC = 6 on day 1 of each 21-day cycle for a maximum of 4 or 6 cycles. The major efficacy measures were overall survival and progression-free survival.

On interim analysis for overall survival, median overall survival was 19.2 months in the atezolizumab four-drug group vs 14.7 months in the control group (hazard ratio [HR] = 0.78, P = .016). Estimated median progression-free survival was 8.5 months in the atezolizumab four-drug group vs 7.0 months in the control group (HR = 0.71, P = .0002). The overall response rate was 55% vs 42%, with a median duration of response of 10.8 vs 6.5 months.

No significant differences in overall survival (median = 19.4 months, P = .204) or progression-free survival (median = 6.7 months, P = .5219) were observed for the atezolizumab three-drug group vs the control group. The overall response rate was 43% in the atezolizumab three-drug group, with a median response duration of 9.5 months.

How It Works

Atezolizumab is a programmed cell death ligand 1 (PD-L1)-blocking monoclonal antibody that binds to PD-L1 and inhibits its interactions with PD-1 and B7.1 receptors. This action 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 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

In the first-line treatment of metastatic nonsquamous NSCLC, the recommended dosage of atezolizumab is 1,200 mg intravenously over 60 minutes followed by bevacizumab, paclitaxel, and carboplatin on day 1 of each 21-day cycle for a maximum of 4 to 6 cycles of chemotherapy. If the first atezolizumab infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. After completion of chemotherapy cycles, atezolizumab should be given followed by bevacizumab on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Prescribing information for bevacizumab, paclitaxel, and carboplatin should be consulted for recommended dosing information.

Infusion should be slowed or interrupted for grade 1 or 2 infusion reactions and permanently discontinued for grade 3 or 4 infusion reactions.

Atezolizumab Combination Therapy for Lung Cancer

  • Atezolizumab was approved for use in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer with no EGFR or ALK genomic tumor aberration.
  • The recommended dosage of atezolizumab is 1,200 mg intravenously over 60 minutes followed by bevacizumab, paclitaxel, and carboplatin on day 1 of each 21-day cycle for a maximum of 4 to 6 cycles of chemotherapy.

No dose reductions for atezolizumab are recommended. Atezolizumab should be withheld for the following: grade 2 pneumonitis; aspartate transaminase (AST) or alanine transaminase (ALT) > 3 and up to 8 times the upper limit of normal (ULN) or total bilirubin > 1.5 and up to 3 times ULN; grade 2 or 3 diarrhea or colitis; grade 2, 3, or 4 endocrinopathies; other grade 3 immune-mediated events involving a major organ; and grade 3 or 4 infection. Product labeling provides instructions regarding when treatment can be resumed, including after reduction to grade 1 or resolution and reduction in corticosteroid treatment for adverse events to a prednisone dose ≤ 10 mg/d (or equivalent) and after clinical stability on hormone replacement therapy has been achieved in the case of endocrinopathies.

Atezolizumab should be permanently discontinued for: grade 3 or 4 pneumonitis; AST or ALT > 8 times ULN or total bilirubin > 3 times ULN; grade 4 diarrhea or colitis; other grade 4 immune-mediated events involving a major organ; grade 2 or 3 adverse reactions that do not recover to grade 0 or 1 within 12 weeks of the last dose; inability to reduce corticosteroid treatment to prednisone ≤ 10 mg/d (or equivalent) within 12 weeks after the last dose; and recurrent grade 3 or 4 adverse reactions.

Development of Antibodies to Atezolizumab

Antibodies to atezolizumab (antidrug antibodies) have developed in 30% to 42% of patients across clinical studies supporting the approved indications. In patients receiving the atezolizumab four-drug regimen in the IMpower150 study, 36% had treatment-emergent antidrug antibodies, with 83% of these patients having antidrug antibodies prior to receiving the second atezolizumab dose. Patients who tested positive for treatment-emergent antidrug antibodies had lower systemic atezolizumab exposure than did those who tested negative to antidrug antibodies.

In an exploratory analysis, the hazard ratio for overall survival in the antidrug antibodies–positive subgroup (0.69, 95% confidence interval [CI] = 0.44–1.07) was similar to that in the antidrug antibodies–negative subgroup (0.64, 95% CI = 0.46–0.90). The presence of antidrug antibodies was not associated with an increased incidence or severity of adverse reactions. Given the high rate of antidrug antibodies, the manufacturer (Genentech) has agreed to conduct analyses across the atezolizumab development program to evaluate the effects of antidrug antibodies on efficacy, safety, and pharmacokinetics.

Safety Profile

In the IMpower150 study, the most common adverse events (≥ 20%) in patients receiving atezolizumab with bevacizumab, paclitaxel, and carboplatin were fatigue/asthenia (50%), alopecia (48%), nausea (39%), diarrhea (32%), constipation (30%), decreased appetite (29%), arthralgia (26%), hypertension (25%), and peripheral neuropathy (24%). The most common grade 3 or 4 adverse events in this group were hypertension (9%), fatigue/asthenia (6%), and diarrhea (6%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (31%), lymphopenia (17%), anemia (10%), and hyponatremia (10%).

REPORT ADVERSE EVENTS

Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Serious adverse events occurred in 44% of the group, with the most common (> 2%) being febrile neutropenia, pneumonia, diarrhea, and hemoptysis. Adverse events led to atezolizumab interruption in 48% of patients and to treatment discontinuation in 15% of patients, with the most common cause of treatment discontinuation being pneumonitis (1.8%). Fatal adverse events occurred in 6% of patients receiving atezolizumab, with causes including hemoptysis, febrile neutropenia, pulmonary embolism, pulmonary hemorrhage, cardiac arrest, cerebrovascular accident, pneumonia, aspiration pneumonia, chronic obstructive pulmonary disease, intracranial hemorrhage, intestinal angina, intestinal ischemia, intestinal obstruction, and aortic dissection.

Atezolizumab carries 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 advised not to breastfeed when receiving atezolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627874.htm. Accessed August 7, 2019.

2. Tecentriq (atezolizumab) prescribing information, December 2018, Genentech. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s009lbl.pdf. Accessed August 7, 2019.

3. Socinski MA, Jotte RM, Cappuzzo F, et al: Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378:2288-2301, 2018.


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