Atezolizumab and Its Many Uses

Atezolizumab is an immune-checkpoint inhibitor, which has been approved by the US Food and Drug Administration (FDA) in various combinations for a number of cancer types in recent years. Here is a closer look at atezolizumab and its expanding uses.

History of FDA Approvals

On March 18, 2019, the FDA approved the use of atezolizumab (Tecentriq) in combination with carboplatin and etoposide for first-line treatment of patients with extensive-stage small-cell lung cancer. Results were based on the IMpower133 trial (n = 403). Median overall survival was 12.3 months (10.8, 15.9) for patients receiving atezolizumab with chemotherapy as compared to 10.3 months (9.3, 11.3) for those receiving placebo with chemotherapy (hazard ratio [HR] 0.70; 95% CI, 0.54, 0.91; P = .0069). Negative side effects reported in 20% or more of the patient sample included fatigue, nausea, alopecia, constipation, and decreased appetite.[1]

On March 8, 2019, the FDA granted atezolizumab accelerated approval in combination with paxlitaxel protein-bound for the treatment of patients with unresectable or metastatic triple-negative breast cancer with programmed death ligand 1 (PD-L1) tumors. The FDA also approved an accompanying diagnostic assay to identify patients with triple-negative breast cancer.[2]

Approval was based on results of the IMpassion130 trial, which showed that in patients whose tumors express PD-L1, median progression-free survival (PFS) was 7.4 months (6.6, 9.2) for patients administered atezolizumab with paclitaxel protein-bound as compared to 4.8 months (3.8, 5.5) for those administered placebo with paclitaxel protein-bound.[2]

On December 6, 2018, the FDA approved a new combination of atezolizumab for the treatment of metastatic nonsquamous, non–small-cell lung cancer (NSCLC) that lacks epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. Specifically, this immune checkpoint inhibitor was approved in combination with a standard regimen of bevacizumab, paclitaxel, and carboplatin.[3]

Atezolizumab plus pembrolizumab and pemetrexed is also FDA approved as first-line treatment for patients with metastatic nonsquamous NSCLC whose tumors lack EGFR or ALK mutations. Importantly, patients with NSCLC without EGFR and ALK mutations-who harbor high PD-L1 levels-have another treatment option: pembrolizumab alone. It remains to be elucidated which option is better because the efficacies of both biologics have not been directly compared in clinical trials. This makes choosing difficult for providers according to the FDA.[4]

On May 18, 2016, atezolizumab was approved by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease has progressed during or following platinum-containing chemotherapy or within 12 months of receiving platinum-containing chemotherapy, either before or after surgical treatment.[5]

The approval was based on clinical trial data regarding safety and efficacy (n = 310). In total, 14.8% of participants had at least a partial shrinkage of their tumors. In patients positive for PD-L1 expression, there was a 26% tumor response compared to that of 9.5% in participants who were classified as negative for PD-L1. Of note, common adverse effects were fatigue, decreased appetite, nausea, urinary tract infection, fever, and constipation.

At the time, FDA’s Richard Pazdur, MD, remarked that, “Tecentriq provides these patients with a new therapy targeting the PD-L1 pathway. Products that block PD-1/PD-L1 interactions are part of an evolving story about the relationship between the body’s immune system and its interaction with cancer cells.”[5]

Importantly, on July 5, 2016, the FDA walked back some of this guidance on atezolizumab:

“The Agency took this action on June 19, 2018, due to decreased survival associated with the use of Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as single therapy (monotherapy) compared to platinum-based chemotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the protein programmed death ligand 1 (PD-L1).”[6]

Mechanism of Action

Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor that selectively binds to PD-L1 to stop the interaction between PD-1 and B7.1 (ie, CD80 receptors). The antibody still allows interaction between PD-L2 and PD-1.

Of note, PD-L1 is an immune checkpoint protein expressed on tumor cells and tumor infiltrating cells that downregulates antitumor T-cell function by binding to PD-1 and B7.1. Blocking PD-1 and B7.1 interactions returns antitumor T-cell function.[7]

Immune-Mediated Warnings and Precautions

As a biologic agent, atezolizumab can cause a number of immune-mediated complications.

Adrenal insufficiency has been reported with the drug both alone and in combination with other antineoplastic agents. The median time to onset was 5.7 months, and about 25% of patients experienced resolution. With grade 2 or higher adrenal insufficiency, the agent should be withheld and the patient given systemic steroids.

Myocarditis has been reported in case reports and may be immune mediated. This cardiotoxicity may require treatments or discontinuation of steroids or other immunosuppressive therapies.

Type 1 diabetes has occurred as a result of treatment. Patients should be monitored for hyperglycemia, as well as signs and symptoms of the diabetes, and insulin treatment can be initiated. For grade 2 or higher hyperglycemia, treatment with atezolizumab should be withheld.

Hepatotoxicity in the form of immune-mediated hepatitis-by definition, requiring systemic corticosteroids-has occurred with atezolizumab. The median time to onset was 1.4 months, and the median duration of hepatitis was 24 days. Treatment consists of systemic corticosteroids, and patients with grade 3 or 4 immune-mediated hepatitis must discontinue the drug permanently.

Infections commonly occur in patients receiving the agent. Grade 3 and higher infections can transpire, with urinary tract infection most common in those with urothelial cancer and pneumonia most common in non–small-cell lung cancer.

Cases of pulmonary toxicity in the form of immune-mediated pneumonitis and insterstitial lung disease have been observed in those receiving the agent. These cases include grades 3 and 4 disease, which require discontinuation of the drug. Lower grades can be treated with steroids.

Ocular toxicity in the form of uveitis and iritis have been reported in the literature. If uveitis occurs in the presence of other immune-mediated adverse reactions, a Vogt-Koyanagi-Harada-like syndrome should be considered, which may require systemic corticosteroids to decrease the risk of permanent vision loss.

Finally, hypothyroidism, hyperthyroidism, and rarely, acute thyroiditis can arise secondary to the administration of atezolizumab. Thyroid function should be monitored during treatment, and thyroid replacement hormone should be given as needed. With grade 2 or higher hyperthyroidism, one should withhold the agent and administer antithyroid medications.[7]

Financial Disclosure: Dr. Saleh and Dr. Copur have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Disclosures:

References:

1. U.S. Food and Drug Administration. FDA approves atezolizumab for extensive-stage small cell lung cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer. Accessed July 28, 2019.

2. U.S. Food and Drug Administration. FDA approves atezolizumab for PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-pd-l1-positive-unresectable-locally-advanced-or-metastatic-triple-negative. Accessed July 28, 2019.

3. U.S. Food and Drug Administration. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. Available at: https://www.fda.gov/drugs/fda-approves-atezolizumab-chemotherapy-and-bevacizumab-first-line-treatment-metastatic-non-squamous. Accessed July 28, 2019.

4. National Cancer Institute. Atezolizumab approved for initial treatment of metastatic lung cancer. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2019/atezolizumab-lung-cancer-first-line. Accessed July 28, 2019.

5. U.S. Food and Drug Administration. FDA approves new, targeted treatment for bladder cancer. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-targeted-treatment-bladder-cancer. Accessed July 28, 2019.

6. U.S. Food and Drug Administration. FDA limits the use of Tecentriq and Keytruda for some urothelial cancer patients. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-limits-use-tecentriq-and-keytruda-some-urothelial-cancer-patients. Accessed July 28, 2019.

7. Drug Monograph taken from Accessmedicine. Available at: https://accessmedicine-mhmedical-com.proxygw.wrlc.org/drugs.aspx?gbosID=423740#monoNumber=423740&sectionID=222845233&tab=tab0. Accessed July 28, 2019.