Washington, DC (UroToday.com): Elizabeth Plimack, MD., MS from Fox Chase Cancer Center presented an overview of checkpoint blockade therapies with a potential role in upper tract urothelial carcinoma. She emphasizes that currently there is no data and no role specific to upper tract, but we can generate hypothesis from early trials in urothelial carcinoma of the bladder.
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Programmed cell death receptor 1 (PD-1) is a negative co-stimulatory receptor expressed on several activated T cells. Binding of PD-1 to its ligands PD-L1 and PD-L2 inhibits effector T-cell function. Tumor cells can express PD-L1 and suppress immune surveillance. PD-1/PDL1 interaction can be blocked via several antibodies. Nivolumab and Pembrolizumab are PD-1 antibodies while Atezolizumab, Durvalumab, Avelumab are all PD-L1 antibodies.
Dr. Plimack presented Phase I trials utilizing Pembrolizumab and Atezolizumab for urothelial cancer (which also included some metastatic upper tract urothelial tumors). Data suggest significantly reduced target lesions in those being treated. Additionally, there is a benefit in progression-free survival and overall survival. However, unlike many chemotherapy trials, progression free survival and overall survival curves with PD-1 blockade do not match. Many patients progress even before first surveillance imaging but have a significantly prolonged overall survival. While Pembrolizumab had median PFS of 2 months, median overall is about 12.7 months. Study on Atezolizumab suggests similar benefit in overall survival as well as a decrease in size of target lesion. However, response is dependent on PD-L1 status of tumors where tumors expressing higher level of PD-L1 show better response.
Dr. Plimack emphasizes that immunotherapy is not without its own toxicity. While majority are asymptomatic, about 8-15% may experience Grade 3-4 toxicities including endocrinopathies, pneumonitis, colitis, rash, myositis, and neurotoxicities.
Recent data in UTUC suggest that UTUC may have higher mutational burden than urothelial bladder carcinoma. Moreover, UTUC subsets may have a mutator phenotype. Dr. Plimack presented a recent NEJM article on PD-1 blockade in tumors with mismatch repair deficiency (Le et al, NEJM 2015). Mismatch repair deficient colorectal tumors responded better to pembrolizumab than mismatch repair proficient tumors. Additionally, in lung cancer, higher mutation burden correlates with longer progression free survival (Rizvi et al, Science 2015). If it is true that UTUC may have a higher mutational burden, than it is possible that UTUC may respond better to immunotherapy.
Further data and trials are needed to evaluate this benefit. Currently, metastatic UTUC is included in most clinical trials launched so far. Subset clinical trial data on response is not yet available.
Elizabeth Plimack, MD
Fox Chase Cancer Center