Elsevier

The Lancet Oncology

Volume 18, Issue 11, November 2017, Pages 1483-1492
The Lancet Oncology

Articles
First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study

https://doi.org/10.1016/S1470-2045(17)30616-2Get rights and content

Summary

Background

More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer.

Methods

In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing.

Findings

Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20–29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0–8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29–48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).

Interpretation

First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424).

Funding

Merck & Co.

Introduction

First-line cisplatin-based combination chemotherapy improves survival in patients with advanced urothelial cancer.1 However, more than half of all patients are unable to receive cisplatin because of renal dysfunction, poor performance status, or other comorbidities, including hearing loss, neuropathy, or heart failure.2, 3 Alternative first-line chemotherapies, such as carboplatin-based regimens, are accepted standards4 but are associated with inferior outcomes compared with cisplatin-based treatments in patients who can tolerate cisplatin.5 Substantial toxic effects have also been reported with first-line carboplatin-based regimens in cisplatin-ineligible patients.6 Gemcitabine plus carboplatin, the most common drug regimen for cisplatin-ineligible patients, is associated with a 9 month median overall survival and a 21% treatment discontinuation frequency because of toxic effects.6 About 50% of patients with advanced urothelial cancer do not receive any chemotherapy because of concerns with toxic effects, underscoring the need for effective and tolerable first-line treatments that can be given broadly in this population.7, 8

Research in context

Evidence before this study

We searched PubMed using the search strings (no search restrictions): “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR lambrolizumab OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND urothelial cancer” OR “PD-1 OR PD-L1 OR pembrolizumab OR MK-3475 OR lambrolizumab OR nivolumab OR BMS-936558 OR MPDL3280A OR atezolizumab OR BMS-936559 OR MEDI4736 OR durvalumab OR avelumab AND bladder cancer”. We identified five reports describing results of phase 1 or 2 clinical studies of the anti-PD-L1 antibodies atezolizumab, durvalumab, and avelumab and the anti-PD-1 antibody nivolumab in patients with recurrent, advanced urothelial cancer. We also identified a phase 2 study of atezolizumab in cisplatin-ineligible patients with advanced urothelial cancer and a phase 3 study of pembrolizumab versus chemotherapy in patients whose disease progressed after platinum-based chemotherapy. Use of a PD-1 inhibitor as first-line treatment for advanced urothelial cancer has not been reported.

Added value of this study

To our knowledge, this is the first report of the activity and safety of an anti-PD-1 antibody used as first-line treatment in patients with advanced urothelial cancer. We included patients who were ineligible to receive standard first-line therapy with cisplatin, including a large proportion of elderly patients and those with comorbidities and poor performance status. In the first-line setting, pembrolizumab had antitumour activity and was well tolerated in this patient population. Patients responded to pembrolizumab irrespective of reason for cisplatin ineligibility, comorbidities, primary or metastatic tumour site, or age. Although some differences in response to pembrolizumab correlated with PD-L1 expression levels in tumour biopsies, responses were observed in patients with all PD-L1 expression levels.

Implications of all the available evidence

About 50% of patients with advanced urothelial carcinoma are unable to receive standard first-line treatment with cisplatin-based chemotherapy because of comorbidities or poor functional status, so there is a large need for alternative first-line therapies. The clinical benefit and acceptable safety profile observed in KEYNOTE-052 suggest that targeting the PD-1 pathway with pembrolizumab could be an effective first-line treatment option for patients who cannot benefit from standard therapy.

The PD-1 receptor is a therapeutic target in bladder cancer and other cancer types.9, 10, 11, 12, 13, 14 PD-1 and its ligands, PD-L1 and PD-L2, are expressed in a variety of solid tumours,15 where their interaction inhibits effector T-cell function and permits immune system evasion.9, 15, 16 Drugs targeting the PD-1 pathway have been effective in the treatment of recurrent advanced urothelial cancer.10, 11, 12, 13

Pembrolizumab is an anti-PD-1 antibody with robust antitumour activity in multiple tumour types and a favourable safety profile. Pembrolizumab is approved for at least one advanced malignancy in more than 60 countries.17, 18, 19, 20, 21, 22, 23 In the phase 1 KEYNOTE-012 study,12 26% of patients with PD-L1-positive advanced urothelial cancer responded to pembrolizumab. In the phase 3 KEYNOTE-045 trial, second-line pembrolizumab improved overall survival compared with chemotherapy (10 months vs 7 months; p=0·0022) in patients with recurrent, advanced urothelial cancer.14 Nivolumab (a PD-1 inhibitor) and atezolizumab (a PD-L1 inhibitor) also have activity in advanced urothelial cancer.10, 24

KEYNOTE-052 is an ongoing phase 2 study to investigate the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra.

Section snippets

Study design and participants

KEYNOTE-052 is a single-arm, phase 2 trial done in 91 academic medical centres in 20 countries (appendix pp 4–6). Eligible participants were aged 18 years or older; had histologically or cytologically confirmed locally advanced and unresectable or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (including transitional cell and mixed transitional or non-transitional cell histologies); were ineligible for cisplatin-based therapy (defined as meeting at least one of

Results

Between Feb 24, 2015, and Aug 8, 2016, we screened 541 patients. 374 patients were enrolled, and 370 patients received at least one dose of pembrolizumab (figure 1). The most common reason for screen failure was not meeting eligibility criteria (n=166). Baseline characteristics of the 370 patients who received treatment are in table 1.

As of Sept 1, 2016 (data cutoff), 233 (63%) patients had discontinued treatment and 137 (37%) patients were still receiving pembrolizumab (figure 1). The median

Discussion

In this study, we show that first-line pembrolizumab elicits antitumour activity in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer. 24% of patients achieved a complete or partial response, and 23% of patients had stable disease as their best response. The response was slightly higher (27%) when the analysis was restricted to patients who had been enrolled long enough to have had at least two post-baseline imaging assessments (ie, enrolled

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