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First-Line Atezolizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone in Advanced Urothelial Cancer


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As reported in The Lancet by Matthew D. Galsky, MD, of Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, and colleagues, the phase III IMvigor130 trial has shown prolonged progression-free survival with first-line atezolizumab plus platinum-based chemotherapy vs platinum-based chemotherapy alone in patients with locally advanced or metastatic urothelial cancer.1 No significant difference was observed between the two groups in overall survival, a co-primary endpoint, on interim analysis. (The overall survival endpoint is being carried forward to the final analysis.) No formal statistical analysis of overall survival for atezolizumab monotherapy vs chemotherapy, an additional co-primary endpoint, was yet performed due to the lack of significant difference between the atezolizumab/chemotherapy group vs chemotherapy group.

Study Details

The trial initially enrolled and randomly assigned patients to an atezolizumab/chemotherapy arm and a placebo/chemotherapy arm; a subsequent protocol amendment added an atezolizu-mab-monotherapy arm.

An unplanned independent data monitoring committee review of early survival data in the trial found that patients with programmed cell death ligand 1 (PD-L1) tumor-infiltrating cell expression of up to 5% treated with atezolizumab monotherapy had poorer survival than did those receiving chemotherapy. The independent data monitoring committee recommended closure of the monotherapy group to further accrual of patients with low PD-L1 expression. No other changes were recommended, including no change in therapy for patients who had already been randomly assigned to the monotherapy arm.


These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.
— Matthew D. Galsky, MD

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The authors commented: “Due to these events [ie, the finding of poorer survival], and because of analogous findings with pembrolizumab in the KEYNOTE-361 trial in June 2018, the U.S. Food and Drug Administration and European Medicines Agency revised both labels to limit PD-L1 and PD-1 [programmed cell death protein 1] blockade therapies in the first-line metastatic urothelial carcinoma setting to patients who are cisplatin ineligible with increased tumor PD-L1 expression or ineligible for any platinum-based chemotherapy (United States only).”

In the placebo-controlled, partly blinded trial, 1,213 patients with locally advanced or metastatic (88%–92% of patients) disease from sites in 35 countries were randomly assigned between July 2016 and July 2018 to receive atezolizumab (blinded) plus platinum-based chemotherapy (n = 451, 37%), atezolizumab alone (open-label; n = 362, 30%), or placebo plus chemotherapy (n = 400, 33%). The choice of using carboplatin or cisplatin along with gemcitabine in the chemotherapy regimens was made by investigators prior to randomization. Randomization was stratified by PD-L1 immune cell expression status of < 1% vs ≥ 1% and < 5% vs ≥ 5%, Bajorin risk factor score (comprising Karnofsky performance status < 80% vs ≥ 80% and the presence of visceral metastases [0 vs 1 vs 2 or liver metastases]), and choice of
platinum-based chemotherapy.

Treatment consisted of 21-day cycles of gemcitabine at 1,000 mg/m2 on days 1 and 8 of each cycle plus either carboplatin at AUC of 4.5 mg/mL/min or cisplatin at 70 mg/m2 on day 1 of each cycle plus either atezolizumab at 1,200 mg or placebo on day 1 of each 21-day cycle; the monotherapy group received atezolizumab at 1,200 mg on day 1 of each 21-day cycle.

The co-primary endpoints, all in the intention-to-treat population, were investigator-assessed progression-free survival on Response Evaluation in Solid Tumors criteria, version 1.1, and overall survival for the atezolizumab/chemotherapy group vs chemotherapy group and overall survival for the atezolizumab-alone group vs the chemotherapy group; the latter was to be formally tested only if atezolizumab/chemotherapy showed an overall survival benefit vs chemotherapy.

Progression-Free and Overall Survival

Median follow-up for survival was 11.8 months for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 2019), median progression-free survival was 8.2 months (95% confidence interval [CI] = 6.5–8.3 months) in the atezolizumab/chemotherapy group vs 6.3 months (95% CI = 6.2–7.0 months) in the chemotherapy group (stratified hazard ratio [HR] = 0.82, P = .007). Median overall survival was 16.0 months (95% CI = 13.9–18.9 months) vs 13.4 months (95% CI = 12.0–15.2 months), with a stratified hazard ratio of 0.83 and a P value of .027, which did not meet the prespecified interim efficacy boundary for statistical significance of P = .007.

KEY POINTS

  • Atezolizumab plus platinum-based chemotherapy significantly improved progression-free survival vs chemotherapy alone in the first-line treatment of metastatic urothelial carcinoma.
  • No significant difference in overall survival was observed on interim analysis.

The progression-free survival benefit of atezolizumab plus chemotherapy was consistent across stratification subgroups and other subgroups examined. Median progression-free survival for the atezolizumab/chemotherapy group vs chemotherapy group according to PD-L1 expression level was 6.5 vs 6.2 months (HR = 0.79, 95% CI = 0.61–1.03) among 278 patients with PD-L1 expression < 0%, 8.1 vs 6.7 months (HR = 0.89, 95% CI = 0.70–1.13) among 374 patients with PD-L1 expression ≥ 1% and < 5%, and 8.6 vs 6.3 months (HR = 0.68, 95% CI = 0.49–0.95) among 199 patients with PD-L1 expression ≥ 5%. Median overall survival durations according to the respective PD-L1 expression levels were 14.2 vs 12.8 months (HR = 0.82, 95% CI = 0.60–1.12), 14.9 vs 13.4 months (HR = 0.87, 95% CI = 0.66–1.15), and 23.6 vs 15.9 months (HR = 0.74, 95% CI = 0.49–1.12).

Efficacy comparisons for the atezolizumab-monotherapy group vs the chemotherapy group included only the predefined subset of patients (n = 359) in the chemotherapy group enrolled after the protocol amendment, adding the atezolizumab-monotherapy group and before the amendment to limit enrollment in the monotherapy group to patients with PD-L1 expression of at least 5%. Median overall survival was 15.7 months (95% CI = 13.1–17.8 months) in the atezolizumab-monotherapy group vs 13.1 months (95% CI = 11.7–15.1 months) in the chemotherapy group (stratified HR = 1.02, 95% CI = 0.83–1.24). Among 88 vs 85 patients with tumors that had PD-L1 expression ≥ 5%, median overall—survival was not reached vs 17.8 months (HR = 0.68, 95% CI = 0.43–1.08). Among the 272 vs 274 patients with tumors that had PD-L1 expression < 1% or ≥ 1% and < 5%, median overall survival was 13.5 vs 12.9 months (HR = 1.07, 95% CI = 0.86–1.33).

Confirmed objective response was seen in 47% of the atezolizumab/chemotherapy group (including complete response in 13%), 23% of the atezolizumab-alone group (complete response in 6%), and 44% of the chemotherapy group (complete response in 7%). Median response durations were 8.5 months, not estimable, and 7.6 months, respectively.

Adverse Events

Grade 3 or 4 adverse events occurred in 85% of patients in the atezolizumab/chemotherapy group, 42% of the atezolizu-mab-monotherapy group, and 86% of the chemotherapy group; they were considered to be related to treatment in 81%, 15%, and 81%. Serious adverse events occurred in 52%, 43%, and 49% of patients and were considered to be related to treatment in 32%, 12%, and 26%.

Withdrawal of any agent due to adverse events occurred in 34% of patients in the atezolizumab/chemotherapy group (atezolizumab in 11%), 6% of the atezolizumab-monotherapy group, and 34% of the chemotherapy group (placebo in 7%). Adverse events led to death in 6%, 8%, and 5% of patients, respectively, with death in 2%, 1%, and 1% of patients considered related to treatment.

Potentially immune-related adverse events of any grade occurred in 50%, 37%, and 35% of patients, and they were grade 3 or 4 in 8%, 8%, and 4%. Six patients died of potentially immune-related adverse events, including three patients in the atezolizumab/chemotherapy group (due to hepatic failure, hepatitis, and pneumonitis), two patients in the atezolizumab-monotherapy group (hepatic failure and interstitial lung disease), and one patient in the chemotherapy group (hepatitis).

The investigators concluded: “Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.” 

DISCLOSURE: Dr. Galsky has served as a consultant or advisor for BioMotiv, Janssen, Dendreon, Merck, Glaxo Smith Kline, Lilly, Astellas, Genentech, Bristol-Myers Squibb, Novartis, Pfizer, EMD Serono, Astra Zeneca, Seattle Genetics, Incyte, Aileron, Dracen, Inovio, NuMab, and Dragonfly Therapeutics; and has received research funding from Janssen, Dendreon, Novartis, Bristol-Myers Squibb, Merck, Astra Zeneca, -Genentech/Roche. For full disclosures of the study authors, visit the lancet.com.

REFERENCE

1. Galsky MD, Arija JAA, Bamias A, et al: Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase III trial. Lancet 395:1547-1557, 2020.


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