Atezolizumab showed durable activity and good tolerability in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy according to results of the single-arm, two-cohort, phase II trial, published online on 4 March 2016 in the Lancet. Increased levels of programmed death ligand 1 (PD-L1) expression on immune cells were associated with increased response.
Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, the investigators assessed treatment with atezolizumab, an engineered humanised monoclonal antibody that binds selectively to PD-L1, in this patient population.
In this study patients aged ≥18 years with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America.
Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections.
Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry: IC0 (<1 and="" but="" ic1="" ic2="" p="">
The co-primary endpoints were the independent review facility-assessed objective response rate (ORR) according to RECIST v1.1 and the investigator-assessed ORR according to immune-modified RECIST, analysed by intention to treat.
Between May 2014 and November 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received intravenous atezolizumab 1200 mg, given every 3 weeks (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug).
The primary analysis (data cut-off 5 May, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 ORR for each prespecified immune cell group (IC2/3: 27%, p<0 .0001="" 18="" all="" and="" ic1="" in="" p="0.0058).</p" patients="">
With longer follow-up (data cut-off 14 September, 2015), by independent review, ORRs were 26% in the IC2/3 group, 18% in the IC1/2/3 group, and 15% overall in all 310 patients. With a median follow-up of 11.7 months, ongoing responses were recorded in 38 (84%) of 45 responders.
Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab.
Grade 3–4 treatment-related adverse events, of which fatigue was the most common (2%), occurred in 16% of 310 treated patients. Grade 3–4 immune-mediated adverse events occurred in 5% of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.
The authors concluded that atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.