(UroToday.com) Responses to immune checkpoint blockade in cancer therapy are heterogeneous, with a minority of patients experiencing sustained responses to therapy. The identification of predictive biomarkers for immunotherapy response is an area of intense research interest. In this presentation, Srikala Sridhar, MD, presented an assessment of potential biomarkers for response within the JAVELIN Bladder 100 trial, previously presented at ASCO 2020. This trial showed a significantly longer overall survival in patients who received standard platinum-based chemotherapy for advanced urothelial carcinoma followed by avelumab maintenance therapy. The schema and key results from the trial are shown below.
The assays and thresholds for exploratory analysis comparing biomarkers to overall survival are listed in the table below. Important, p-values were not corrected for multiple hypothesis testing.
PD-L1 expression in greater than 25% of either tumor cells or immune cells were associated with higher overall survival with avelumab maintenance.
Patients with PD-L1 positivity and TMB higher than median were more likely to derive survival benefit from avelumab maintenance therapy, but neither TMB or PD-L1 status alone could completely separate patients by survival benefit.
Certain DNA mutational signatures and gene mutations were associated with survival benefit from avelumab maintenance, specifically mutational signatures enriched in C > T base pair alterations.
The differential expression of immune-related genes such as LAG3, TIGIT and CXCL9 were associated with survival benefit from avelumab.
Interestingly, the presence of cell types expressing Fc gamma receptor variants may also identify patients that derive survival benefit from avelumab.
When previously derived gene expression signatures were applied to expression data from JAVELIN Bladder, higher expression of the JAVELIN-Immuno and T cell-inflamed signatures was associated with higher overall survival with avelumab. Patients with a high JAVELIN-immuno signature score had enrichment in multiple signaling pathways including Notch and TGF-beta.
In conclusion, tumor mutational burden and PD-L1 expression on either tumor or immune cells do not fully identify tumors more likely to derive benefit from avelumab maintenance. This work generated multiple hypotheses that warrant further investigation including (1) the presence of variants in Fc gamma receptors may be implicated in anti-tumor mechanisms and (2) the prospective application of previously published immune response gene expression signatures may ultimately identify patients more likely to derive benefit from avelumab maintenance therapy.
Presented by: Srikala Sridhar, MD, Medical Oncologist and Assistant Professor of Medicine at the Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept – 21 Sept 2020.