Elsevier

The Lancet

Volume 395, Issue 10236, 16–22 May 2020, Pages 1547-1557
The Lancet

Articles
Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(20)30230-0Get rights and content

Summary

Background

Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.

Methods

In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.

Findings

Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.

Interpretation

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.

Funding

F Hoffmann-La Roche and Genentech.

Introduction

Cisplatin-based chemotherapy became the standard first-line treatment for metastatic urothelial carcinoma in the 1980s,1 with long-term remission possible in around 10% of patients. Although tolerability has improved,2 no further substantial improvements in efficacy have been reported.1, 2 Furthermore, around 50% of patients with metastatic urothelial carcinoma are ineligible for cisplatin treatment because of poor performance status, comorbidities, or impaired renal function.3, 4 These patients generally receive inferior carboplatin-based regimens.4 Programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) inhibitors are the first new systemic therapies for metastatic urothelial carcinoma, both for first-line treatment of cisplatin-ineligible patients and for patients with disease progression despite platinum-based chemotherapy.5, 6, 7, 8, 9, 10, 11, 12

Research in context

Evidence before this study

We searched PubMed and major international oncology and urology congresses for articles published in English pertaining to metastatic urothelial carcinoma between June 1, 2011, and June 1, 2016, with MeSH search terms “metastatic” AND “bladder cancer”, “urothelial carcinoma”, “urothelial cancer”, “programmed cell death 1”, “PD-1”, “programmed cell death ligand 1”, and “PD-L1”. This search identified an unmet clinical need for effective and tolerable therapies for metastatic urothelial carcinoma based on the paucity of positive data from randomised phase 3 studies. Platinum-based combination chemotherapy has been the preferred regimen in the first-line setting and single-agent chemotherapy is typically reserved for the second-line setting. However, 40–50% of patients with metastatic urothelial carcinoma are ineligible for cisplatin because of poor performance status, comorbidities, or impaired renal function, and these patients generally receive carboplatin-based regimens, an inferior option. Although tolerability has improved with new treatments over the past 30 years, efficacy has not. Checkpoint inhibitors that target programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) are the first new systemic therapies for metastatic urothelial carcinoma, both for first-line treatment of cisplatin-ineligible patients and for patients with disease progression despite platinum-based chemotherapy.

Added value of this study

To our knowledge, IMvigor130 is the first phase 3, randomised trial to report results for platinum-based chemotherapy plus PD-L1 or PD-1 blockade, or PD-L1 blockade alone or PD-1 blockade alone, versus standard platinum-based chemotherapy plus placebo as a first-line treatment for metastatic urothelial carcinoma. IMvigor130 met its co-primary progression-free survival endpoint, showing a significant improvement when atezolizumab was added to platinum-based chemotherapy versus platinum-based chemotherapy alone. At the interim analysis, the result for the co-primary endpoint of overall survival did not cross the interim efficacy boundary. The combination of atezolizumab plus platinum-based chemotherapy had a safety profile consistent with previous studies and with the safety profiles of each individual agent.

Implications of all the available evidence

The results of IMvigor130, to our knowledge the largest phase 3 trial reporting results from first-line treatment for metastatic urothelial cancer, included both cisplatin-eligible and cisplatin-ineligible patients. Preliminary results have already impacted clinical practice; recommendations from the US Food and Drug Administration and European Medicines Agency based on an unplanned early analysis by independent data monitoring committees of IMvigor130 led to revision of the prescribing label for atezolizumab for metastatic urothelial cancer in the first-line setting. Results from IMvigor130 support clinical activity of the atezolizumab plus chemotherapy combination as a potential first-line treatment option for metastatic urothelial carcinoma.

Regimens that combine platinum-based chemotherapy and PD-L1 and PD-1 inhibitors are appealing for several reasons. Platinum-based chemotherapy can induce immunomodulatory effects, thereby enhancing concomitant PD-L1 and PD-1 blockade.13, 14 This combination might also be beneficial because of the absence of clinical cross-resistance between these therapeutic classes, because a minority of patients receive treatment beyond first-line therapy.15, 16

IMvigor130, a phase 3, global, multicentre, randomised, partly-blinded trial evaluated the efficacy of atezolizumab alone or combined with platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in patients with untreated metastatic urothelial carcinoma. Preliminary results have already affected clinical practice. As of July, 2018, based on unplanned assessments by the independent data monitoring committees (IDMC) of both IMvigor130 and KEYNOTE-361, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) revised the labels for atezolizumab and pembrolizumab monotherapy in the first-line setting to limit treatment to PD-L1 biomarker-expressing tumours.17, 18, 19 Here, we report the primary progression-free survival and interim overall survival results from IMvigor130.

Section snippets

Study design and participants

We did a multicentre, phase 3, randomised trial at 221 sites in 35 countries (Australia, Belgium, Bosnia and Herzegovina, Brazil, Canada, Chile, China, Czech Republic, Estonia, Finland, Georgia, Greece, Hong Kong, Israel, Italy, Japan, South Korea, Malaysia, Mexico, Netherlands, Poland, Portugal, Romania, Russia, Serbia, Singapore, Slovenia, South Africa, Spain, Taiwan, Thailand, Turkey, Ukraine, the UK, and the USA). Eligible patients were aged 18 years or older with locally advanced or

Results

Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients (intention-to-treat population). 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C (figure 1). Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. Most baseline characteristics were similar between treatment groups (table 1). The proportions of cisplatin-ineligible patients in group A, group B, and group C were 58%, 53%, and 56%, respectively. The differences

Discussion

In this study, we report the final analysis of progression-free survival and the interim analysis of overall survival for IMvigor130, the first phase 3 trial to assess a PD-L1 and PD-1 inhibitor alone or in combination with platinum-based chemotherapy versus platinum-based chemotherapy alone in untreated metastatic urothelial carcinoma, and the first trial to include both cisplatin-ineligible and cisplatin-eligible patients. Addition of atezolizumab to platinum-based chemotherapy resulted in a

Data sharing

Qualified researchers can request access to individual patient-level data through the clinical study data request platform. Further details on Roche's criteria for eligible studies are available online. Further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available online.

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    *

    Current affiliation: Department of Urology, St Marianna University School of Medicine, Kawasaki, Japan

    Members are listed in the appendix

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