Pembrolizumab is a humanized antibody that exerts dual blockade of the immune checkpoint receptor programmed death-1 (PD-1). It has demonstrated robust antitumor activity and acceptable tolerability in several tumors, including melanoma and lung cancer. The KEYNOTE-012 trial is an ongoing, multicohort, open-label, phase 1b clinical trial that is evaluating the safety, tolerability, and antitumor activity of pembrolizumab in patients with PD-1 ligand 1 (PD-L1)-positive advanced solid tumors, including recurrent and metastatic urothelial cancer. The results of this trial were reported at ESMO 2014 (Pilmack A, et al. ESMO 2014: Abstract LBA23). Before study entry, tumor samples were screened for PD-L1 expression using a prototype immunohistochemistry assay, with positivity defined by PD-L1 expression staining in stroma or ?1% of tumor cells. Eligible patients received pembrolizumab 10 mg/kg every 2 weeks until complete response, progression, or unacceptable toxicity. Any patients deriving benefit could remain on pembrolizumab beyond the initial progression. The primary efficacy end point was overall response rate (ORR). A total of 33 patients were enrolled in the trial; 22 (67%) patients received ?3 doses of pembrolizumab. By central review of the 29 evaluable patients using the RECIST 1.1 criteria, the ORR was 24%, including complete responses in 3 (10%) patients. Overall, 64% of the patients experienced a decrease in target lesions. At a median follow-up of 11 months, the median time to response was 8 weeks, and the duration of response was 16 weeks to 40+ weeks (median not yet reached), with 6 of the 7 responses ongoing. The median progression-free survival (PFS) was 8.6 weeks (6-month PFS rate, 23.1%), and the median overall survival (OS) was 9.3 months (6-month OS rate, 58%). Of the 33 evaluable patients for safety, 61% reported treatment-related adverse events of any grade; common events included fatigue, peripheral edema, and nausea. Grade 3 or 4 treatment-related adverse events were reported in 4 (12%) patients, including 1 case each of dehydration, neuromyopathy, maculopapular rash, pruritic rash, rhabdomyolysis, and thrombocytopenia. These results indicate that pembrolizumab is associated with an acceptable safety and tolerability profile and produces durable responses in patients with advanced urothelial cancer.
