Elsevier

The Lancet Oncology

Volume 18, Issue 3, March 2017, Pages 312-322
The Lancet Oncology

Articles
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30065-7Get rights and content

Summary

Background

Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen.

Methods

In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing.

Findings

Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0–24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9–39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5–32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5–23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3–4 treatment-related adverse events occurred in 48 (18%) of 270 patients—most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure).

Interpretation

Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma.

Funding

Bristol-Myers Squibb.

Introduction

The prognosis for patients with metastatic or surgically unresectable urothelial carcinoma is poor—expected survival is generally less than 12 months.1 Standard first-line treatment for metastatic disease is cisplatin-based combination chemotherapy, and around half of patients respond to treatment.1, 2 However, response durations are short and disease progresses in most patients; median survival is approximately 15 months.1, 2 Furthermore, chemotherapy is associated with substantial toxicities and many patients receive inferior or no treatment because they are ineligible for cisplatin.3, 4 For patients whose metastatic urothelial carcinoma progresses despite first-line platinum-containing therapy, options are few. Around 10% of patients respond to second-line single-agent chemotherapy, but complete responses are rare and short-lived.5, 6

Urothelial carcinoma appears to be immunogenic, with high expression levels of PD-L1, suggesting tumour-associated immune tolerance and escape from immune surveillance. PD-L1 expression has been noted in approximately 20% (5% cutoff) and 30% (1% cutoff) of tumour tissue samples.7, 8, 9 PD-1 and PD-L1 immune checkpoint inhibitors have shown survival benefits in patients with disease progression on platinum-based therapy who received second-line chemotherapy or biologics.10 Atezolizumab (an anti-PD-L1 antibody) was approved in the USA to treat metastatic urothelial carcinoma in patients whose disease progressed during or after platinum-based chemotherapy, on the basis of a 15% response to treatment in a single-arm study.10

Research in context

Evidence before this study

We searched PubMed with the terms “metastatic urothelial carcinoma”, “surgically unresectable urothelial carcinoma”, “relapsed urothelial carcinoma”, “clinical trials”, “platinum based chemotherapy”, “immune response”, “immune checkpoint blockade”, “immunotherapy”, and “PD-L1 expression” for articles published in English between Sept 1, 2000, and Aug 31, 2016 (the date of our final search). The findings of this search suggested that patients with metastatic or surgically unresectable urothelial carcinoma have a poor prognosis, that first-line treatment with cisplatin-based chemotherapy has a response in only 50% of patients, and that this response is of short duration but is associated with considerable toxicities. Furthermore, patients whose disease progresses on cisplatin-based therapy have few treatment options. Objective responses to second-line single-agent chemotherapy are uncommon: they occur in approximately 10% of patients. No standard of care second-line therapy is available for these patients. Evidence suggests that urothelial carcinoma is an immunogenic disease, with high expression of PD-L1, and the presence of tumour-infiltrating lymphocytes in urothelial carcinoma specimens has been correlated with improved clinical outcomes. Immune checkpoint blockade is a promising new approach to activating therapeutic tumour immunity, as shown by the regulatory approval of an anti-PD-L1 agent to treat metastatic urothelial carcinoma in patients whose disease progressed during or after platinum-based chemotherapy. Furthermore, in an open-label, multicentre phase 1 and 2 expansion cohort study in patients with metastatic urothelial carcinoma, the PD-1 inhibitor nivolumab elicited a response in 24·4% of patients irrespective of tumour PD-L1 expression and with an acceptable safety profile, in patients who had received one or more previous lines of chemotherapy. These findings provided the rationale for further investigation of nivolumab in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy.

Added value of this study

No second-line treatments for metastatic urothelial carcinoma were approved until 2016. Our study is the largest to date to report the activity and safety of nivolumab, a PD-1 immune checkpoint inhibitor, in the second-line (or later) setting for the treatment of metastatic or surgically unresectable urothelial carcinoma. Nivolumab monotherapy provided a confirmed objective response and overall survival that was clinically meaningful, irrespective of tumour PD-L1 expression. These findings, taken together with those of a phase 2 study of atezolizumab (which has anti-PD-L1 activity), provide significant data showing that blockade of the PD-1–PD-L1 immune inhibitory pathway can elicit meaningful clinical responses in patients with metastatic urothelial carcinoma.

Implications of all the available evidence

Patients with metastatic or surgically unresectable locally advanced urothelial carcinoma that has progressed during or after one or more previous platinum-containing regimens have a poor prognosis, with few treatment options. Immune checkpoint inhibitors such as nivolumab have elicited significant improvements in outcomes across several tumour types, and increasing evidence suggests that these drugs could be an effective treatment option for patients with metastatic urothelial carcinoma. Findings from our study support further investigation of nivolumab in this setting.

Nivolumab is a fully human IgG4 PD-1 inhibitor antibody that selectively blocks interaction between PD-1 expressed on activated T cells and PD-L1 and PD-L2 expressed on tumour cells, restoring T-cell-driven anti-tumour response by disrupting PD-L1-mediated signalling. Nivolumab has shown anti-tumour activity and improved overall survival across several tumour types, and has an acceptable safety profile.11, 12, 13, 14, 15 In an open-label, multicentre phase 1 and 2 expansion cohort study16 in patients with metastatic urothelial carcinoma, nivolumab elicited an objective response of 24·4% (95% CI 15·3–35·4) with acceptable safety, irrespective of tumour expression of PD-L1, in patients who had received one or more previous lines of chemotherapy. In this Article, we report on CheckMate 275, a phase 2 study of the activity and safety of nivolumab in patients with metastatic or surgically unresectable urothelial carcinoma with progressive disease during or after platinum-based chemotherapy.

Section snippets

Study design and participants

CheckMate 275 was a multicentre, single-arm, phase 2 trial of nivolumab (Bristol-Myers Squibb, Lawrenceville, NJ, USA) monotherapy done at 63 sites in 11 countries (Australia, Belgium, Czech Republic, Finland, Germany, Italy, Japan, Poland, Spain, Sweden, and the USA; appendix pp 3–4). Eligible patients were aged 18 years or older and had histological evidence of metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease by CT or MRI (per Response Evaluation

Results

Between March 9, 2015, and Oct 16, 2015, 270 patients were enrolled and treated with nivolumab. The last patient's last visit date was April 15, 2016, providing a minimum of 6 months' follow-up at data cutoff. Demographic and safety data are presented for all treated patients; activity data are presented for 265 patients, because follow-up was insufficient for five patients (figure 1).

No patients had indeterminate PD-L1 expression. Tissue samples for PD-L1 expression analysis were collected

Discussion

In this phase 2 study, nivolumab monotherapy was associated with a clinically meaningful and sustained confirmed objective response of 19·6% (95% CI 15·0–24·9) in patients with metastatic or locally advanced urothelial carcinoma with disease progression after platinum-based chemotherapy. Objective responses in all treated patients and across PD-L1 subgroups compared favourably with the 10% historical objective response with second-line single-drug systemic chemotherapies in this setting.5, 6

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