Dr. Pal’s study found that given the proposed correlation between tumor mutation burden and immunotherapy response, results from their study may inform the utility of combination treatment strategies. Specifically, given the higher tumor mutation burden in patients with ERBB2/ERBB3 or PIK3CA alteration, combination studies exploring immunotherapy and targeted therapy directed at these molecular targets may be warranted. Dr. Grivas notes that although these are not practicing changing findings at the current time, these results can influence clinical trial design, provide insight into urothelial pathogenesis and clonal evolution, and provides evidence that cell free ctDNA may be considered as a complimentary to tumor tissue next-generation sequencing. The strengths of this study according to Dr. Grivas is the large sample size with both upper and lower tract tumors, reproducible technology, and the potential for serial assessment. He feels that the next steps include designing clinically relevant trails to test the rational hypotheses and assess the clinical utility or predictive biomarkers and treatment targets.
Dr. Galsky’s first discussed abstract found that in their exploratory analysis of CheckMate 275 (Nivolumab efficacy in a single-arm phase II study in patients with metastatic or surgically unresectable urothelial carcinoma) exploratory findings suggest that increased tumor mutation burden may enrich for response to nivolumab and may provide complementary prognostic/predictive information beyond PD-L1. Dr. Grivas notes that tumor mutation burden appears to be the most significant predictor of response to immune checkpoint inhibitors, but clinical utility needs to be prospectively validated. As such, this can certainly influence clinical trial design, eligibility and stratification. The caveat for assessing tumor mutation burden is that there is variability of assays/methodology, cut-off levels, and implications for assessing as a continuous vs categorical/ordinal variable in clinical trials.
Dr. Galsky’s second discussed abstract of the afternoon found that high EMT gene signature tumors are associated with a lower ORR to nivolumab and shorter PFS and OS. These findings substantiate EMT as a potential mechanism of immune escape and raise the possibility of co-targeting EMT and PD-1/PD-L1 in this at-risk subset of urothelial cancers. Dr. Grivas notes that this study confirms the critical role of the tumor microenvironment to the development and progression of urothelial carcinoma; ie. the “seed and soil” hypothesis. Furthermore, the dynamic interactions between epithelial cells and stroma may impact tumor growth, the natural history, and treatment response. In Dr. Grivas’ opinion, the impact of this study is that patient selection for immunotherapy should not be based only on urothelial carcinoma molecular subtypes and/or tumor infiltrating lymphocytes (“hot” vs “cold” tumors). He feels this opens the door for a potential role of stroma-related therapeutic targets (eg. IDO, adA2A).
Speaker: Petros Grivas, Cleveland Clinic, Cleveland, United States of America
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1. Pal SK, Agarwal N, Choueiri TK, et al. Comparison of tumor mutational burden in relevant molecular subsets of metastatic urothelial cancer. ESMO 2017 abstr 849.
2. Galsky MD, Saci A, Szabo PM, et al. Impact of Tumor Mutation Burden on Nivolumab Efficacy in Second-Line Urothelial Carcinoma Patients: Exploratory Analysis of the Phase II CheckMate 275 Study. ESMO 2017 abstr 848.
3. Galsky MD, Wang L, Saci A, et al. Epithelial-mesenchymal transition, T cell infiltration, and outcomes with nivolumab in urothelial cancer. ESMO 2017 abstr 850.