Atezolizumab in Patients With Advanced Urothelial Carcinoma Who Are Ineligible for Cisplatin


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On April 17, 2017, the programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab (Tecentriq) was granted accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy.1 Atezolizumab was approved in May 2016 for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Supporting Efficacy Data

The current approval is based on durable responses observed in a cohort of a single-arm phase II study (IMvigor210) including 119 patients who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy.1,2 Patients were included regardless of PD-L1 expression status. Patients were considered cisplatin-ineligible if they met any one of the following criteria at study entry: impaired renal function (creatinine clearance of > 30 but < 60 mL/min), Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2, hearing loss of ≥ 25 dB at two contiguous frequencies, or ≥ grade 2 peripheral neuropathy. Treatment consisted of atezolizumab at 1,200 mg every 3 weeks until unacceptable toxicity or disease progression.

PD-L1 Inhibitor in Advanced Urothelial Carcinoma

  • Atezolizumab (Tecentriq) was granted accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy.
  • The recommended dose of atezolizumab is 1,200 mg via intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.

Patients had a median age of 73 years, 81% were male, 91% were white, 35% had nonbladder urothelial carcinoma, 66% had visceral metastases, 80% had an ECOG performance status of 0 or 1, and 20% had disease progression after platinum-containing neoadjuvant or adjuvant chemotherapy. Overall, 27% of patients were classified as having PD-L1 expression ≥ 5% (stained tumor-infiltrating immune cells covering ≥ 5% of the tumor area), with the remaining 73% classified with PD-L1 expression < 5%.

Among all patients, the objective response rate was 23.5%, including complete response in 6.7%. Response rates were 21.8% (6.9% complete response) in patients with PD-L1 expression < 5% and 28.1% (6.3% complete response) in those with PD-L1 expression ≥ 5%. Median duration of response was not reached among all responders or according to PD-L1 expression status. Response durations ranged from 3.7 to 16.6+ months in all responders and in those with PD-L1 expression < 5% and from 8.1 to 15.6+ months in those with PD-L1 expression ≥ 5%.

How It Works

Atezolizumab is a 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 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

The recommended dose of atezolizumab 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. No dose reductions of atezolizumab are recommended.

OF NOTE

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

Atezolizumab should be withheld for grade 2 pneumonitis; aspartate transaminase (AST) or alanine transaminase (ALT) > 3 and up to 5 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; symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, or grade 3 or 4 hyperglycemia; grade 2 ocular inflammatory toxicity; grade 2 or 3 pancreatitis, or grade 3 or 4 increases in amylase or lipase level (> 2.0 times ULN); grade 3 or 4 infection; grade 2 infusion-related reactions; and grade 3 rash. Treatment may be resumed with recovery of adverse reactions to grade 0 or 1.

Atezolizumab should be permanently discontinued for grade 3 or 4 pneumonitis; AST or ALT > 5 times ULN or total bilirubin > 3 times ULN; grade 4 diarrhea or colitis; grade 4 hypophysitis; any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré, or meningoencephalitis; grade 3 or 4 ocular inflammatory toxicity; grade 4 pancreatitis or any grade recurrent pancreatitis; grade 3 or 4 infusion-related reactions; and grade 4 rash.

Safety Profile

The median duration of exposure to atezolizumab was 15 weeks in the phase II study. The most common adverse events of any grade were fatigue (52%), decreased appetite (24%), diarrhea (24%), and nausea (22%). The most common grade 3 or 4 adverse events were fatigue (8%), urinary tract infection (5%), and diarrhea (5%). The most common grade 3 or 4 laboratory abnormalities were hyponatremia (15%), hyperglycemia (10%), lymphopenia (9%), anemia (7%), and increased alkaline phosphatase (7%).

Serious adverse events occurred in 37% of patients, with the most frequent (≥ 2%) being diarrhea, intestinal obstruction, sepsis, acute kidney injury, and renal failure. Immune-related adverse events requiring systemic corticosteroids (12.6%) or hormone replacement therapy (6.7%) occurred in 19.3% of patients.

Adverse events led to interruption of treatment in 35% of patients and to treatment discontinuation in 4.2%. Five patients (4.2%) had adverse events leading to death, with these events consisting of sepsis, cardiac arrest, myocardial infarction, respiratory failure, or respiratory distress. 

Atezolizumab carries warnings/precautions for immune-related pneumonitis, hepatitis, colitis, endocrinopathies, myasthenic syndrome/myasthenia gravis, and pancreatitis; Guillain-Barré or meningoencephalitis; ocular inflammatory toxicity; infection; infusion reaction; and embryofetal toxicity. ■

REFERENCES

1. Tecentriq (atezolizumab) injection prescribing information, Genentech, Inc, April 2017. Available at https://www.tecentriq.com/hcp.html. Accessed June 6, 2017.

2. Balar AV, Galsky MD, Rosenberg JE, et al: Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma. Lancet 389:67-76, 2017.



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