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Atezolizumab Combined With Chemotherapy in First-Line Extensive-Stage Small Cell Lung Cancer


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On March 18, 2019, atezolizumab was approved for use in combination with carboplatin and etoposide in the first-line treatment of adult patients with extensive-stage small cell lung cance (SCLC).1,2

Supporting Efficacy Data

Approval was based on findings in the phase III double-blind IMpower133 trial (ClinicalTrials.gov identifier NCT02763579).2,3 IMpower133 enrolled 403 patients with extensive-stage SCLC who had received no prior chemotherapy for extensive-stage disease and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned to receive atezolizumab at 1,200 mg and carboplatin at AUC 5 on day 1 and etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for a maximum of four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity (n = 201) or placebo and carboplatin at AUC 5 on day 1 and etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for a maximum of four cycles, followed by placebo once every 3 weeks until disease progression or unacceptable toxicity (n = 203).

OF NOTE

Atezolizumab carries warnings/precautions for immune-related pneumonitis, hepatitis, colitis, and endocrinopathies, as well as infusion-related reactions and embryofetal toxicity.

Patients had a median age of 64 years (range = 26–90 years), 65% were male, 80% were white and 17% were Asian, ECOG performance status was 0 in 35% and 1 in 65%, 9% had a history of brain metastasis, and 97% were current or previous smokers. Major efficacy measures were investigator-assessed overall survival and progression-free survival.

Median overall survival was 12.3 months (95% confidence interval [CI] = 10.8–15.9 months) in the atezolizumab-plus-chemotherapy group vs 10.3 months (95% CI = 9.3–11.3 months) in the chemotherapy group (hazard ratio [HR] = 0.70, P = .0069). Median progression-free survival on Response Evaluation Criteria in Solid Tumors, version 1.1, was 5.2 months (95% CI = 4.4–5.6 months) vs 4.3 months (95% CI = 4.2–4.5 months; HR = 0.77, P = .0170). Objective response rates were 60% vs 64%, and median durations of response were 4.2 vs 3.9 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 programmed cell death protein 1 (PD-1) and B7.1 receptors. This action releases the PD-L1/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 the 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 patients with SCLC, the recommended dosage of atezolizumab is 1,200 mg given intravenously over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes. Atezolizumab should be given prior to chemotherapy when given on the same day. Prescribing information for the chemotherapy agents administered in combination with atezolizumab should be consulted for recommended dosing information.

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.

ATEZOLIZUMAB COMBINATION IN SMALL CELL LUNG CANCER

  • Atezolizumab was approved for use in combination with carboplatin and etoposide in the first-line treatment of adult patients with extensive-stage small cell lung cancer.
  • In patients with SCLC, the recommended dosage of atezolizumab is 1,200 mg given intravenously over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.

Product labeling provides instructions for the management of immune-mediated adverse reactions to atezolizumab. Atezolizu-mab should be withheld for grade 2 pneumonitis; hepatitis with 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; hepatitis with 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; persistent grade 2 or 3 adverse reactions (excluding endocrinopathies) that do not recover to grade 0 or 1 within 12 weeks of the last dose; inability to reduce corticosteroid (prednisone) treatment to ≤ 10 mg/d (or equivalent) within 12 weeks after the last dose; and recurrent grade 3 or 4 adverse reactions.

Safety Profile

The most common adverse events of any grade (≥ 20% of patients) in clinical trials with atezolizumab in combination with other antineoplastic drugs in patients with non–small cell lung cancer and SCLC have been fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite.

In IMpower133, the most common (≥ 20%) adverse events of any grade in patients in the atezolizumab-plus-chemotherapy group were fatigue/asthenia (39% vs 33% in chemotherapy group), nausea, alopecia, constipation, decreased appetite, and vomiting. The most common (≥ 2%) grade 3 or 4 adverse events in the atezolizumab-plus-chemotherapy group were fatigue/asthenia, febrile neutropenia, pneumonia, asthenia, diarrhea, and infusion-related reaction.

Serious adverse events occurred in 37% of patients in the atezolizumab group, with the most common being pneumonia, neutropenia, febrile neutropenia, and thrombocytopenia. Adverse events led to interruption of atezolizumab in 59% of patients. Atezolizumab was discontinued due to adverse events in 11% of patients. Fatal adverse events occurred in four patients receiving atezolizumab.

Atezolizumab carries warnings/precautions for immune-related pneumonitis, immune-related hepatitis, immune-related colitis, immune-related endocrinopathies, infections, infusion-related reactions, and embryofetal toxicity. Patients should be monitored for liver function. Patients should be advised not to breastfeed during atezolizumab therapy. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab for extensive-stage small cell lung cancer. Available at www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer. Accessed July 23, 2019.

2. Tecentriq (atezolizumab) injection prescribing information. Genentech, March 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s019lbl.pdf. Accessed July 23, 2019.

3. Horn L, Mansfield AS, Szczęsna A, et al: N Engl J Med 379:2220-2229, 2018.


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