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Atezolizumab With Chemotherapy for Metastatic Nonsquamous NSCLC Without EGFR/ALK Aberrations


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On December 3, 2019, atezolizumab in combination with nab-paclitaxel and carboplatin was approved for first-line treatment of metastatic nonsquamous non–small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumore aberrations.1,2

The approval was based on findings in the open-label phase III IMpower130 trial (ClinicalTrials.gov identifier NCT02367781),3 in which 724 patients were randomly assigned 2:1 to receive atezolizumab plus nab-paclitaxel/carboplatin or nab-paclitaxel/carboplatin; of these patients , 681 were in the wild-type EGFR/ALK subgroup, including 453 in the atezolizumab group and 232 in the control group. Patients in the atezolizumab group received atezolizumab at 1,200 mg on day 1, nab-paclitaxel 100 mg/m2 on days 1, 8, and 15, and carboplatin AUC = 6 mg/mL/min on day 1 of 21-day cycles for a maximum of 4 or 6 cycles followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity. Those in the control group received the same regimen of nab-paclitaxel plus carboplatin plus best supportive care or maintenance pemetrexed at investigator discretion.

OF NOTE

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

The primary efficacy outcome measures were progression-free survival on Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival in the intention-to-treat subpopulation of patients without EGFR/ALK aberrations. Median progression-free survival was 7.2 months (95% confidence interval [CI] = 6.7–8.3 months) in the atezolizumab group vs 6.5 months (95% CI = 5.6–7.4 months) in the control group (hazard ratio [HR] = 0.75, P = .0024). Median overall survival was 18.6 months (95% CI = 15.7–21.1 months) vs 13.9 months (95% CI = 12.0–18.7 months; HR = 0.80, P = .0384). Objective response was observed in 46% vs 32% of patients, including complete response in 5% vs 1%. The median duration of response was 10.8 vs 7.8 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 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.

How It Is Used

The recommended dosage of atezolizumab in the current indication is 1,200 mg via intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. If the first infusion is tolerated, all subsequent infusions can be given over 30 minutes. Prescribing information for nab-paclitaxel and carboplatin should be consulted for recommended dosage in combination with atezolizumab. When atezolizumab is administered on the same day as chemotherapy, atezolizumab should be given first.

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, endocrinopathies, 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 or alanine transaminase > eight times the upper limit of normal (ULN) or total bilirubin more than three 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 treatment to ≤ 10 mg/d or equivalent of prednisone within 12 weeks after the last dose; and recurrent grade 3 or 4 adverse reactions.

Safety Profile

The most common adverse events in clinical trials of atezolizumab in combination with other antineoplastic drugs in patients with NSCLC and small cell lung cancer have been fatigue/asthenia, nausea, alopecia, constipation, diarrhea, and decreased appetite. Among 705 patients in IMpower130, the most common adverse events of any grade in 473 patients treated with atezolizumab plus nab-paclitaxel/carboplatin vs 232 treated with nab-paclitaxel/carboplatin were fatigue/asthenia, nausea, diarrhea, myalgia/pain, constipation, neuropathy, dyspnea, alopecia, and decreased appetite. The most common grade 3 or 4 adverse events included fatigue, diarrhea, and dyspnea. The most common grade 3 or 4 laboratory abnormalities were neutropenia, anemia, lymphopenia, and thrombocytopenia.

Atezolizumab Plus Chemotherapy

  • Atezolizumab in combination with nab-paclitaxel and carboplatin was approved for first-line treatment of metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations.
  • The recommended dosage of atezolizumab in the current indication is 1,200 mg via intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.

Serious adverse events occurred in 51% of patients in the atezolizumab group, with the most frequent being pneumonia, diarrhea, lung infection, pulmonary embolism, chronic obstructive pulmonary disease exacerbation, dyspnea, and febrile neutropenia. Adverse events led to atezolizumab interruption in 62% of patients and to atezolizumab discontinuation in 13%; the most common causes of treatment discontinuation were pneumonia, pulmonary embolism, fatigue, dyspnea, pneumonitis, neutropenia, nausea, renal failure, cardiac arrest, and septic shock. Fatal adverse events occurred in 5.3% of patients, including pneumonia, septic shock, and hepatic cirrhosis.

Atezolizumab carries warnings/precautions for immune-related pneumonitis, hepatitis, colitis, and endocrinopathies; 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 receiving atezolizumab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves atezolizumab with nab-paclitaxel and carboplatin for metastatic NSCLC without EGFR/ALK aberrations. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-nab-paclitaxel-and-carboplatin-metastatic-nsclc-without-egfralk. Accessed January 8, 2020.

2. Tecentriq (atezolizumab) injection prescribing information, Genentech, Inc, revised June 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s010lbl.pdf. Accessed January 8, 2020.

3. West H, et al: Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130). Lancet Oncol 20:924-937, 2019.


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