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.