ASCO 2020: Emerging Biomarkers of Checkpoint Inhibitors-Based Combinations in Urothelial Cancer

( In the past four years, the immune checkpoint blockade (ICB) agents atezolizumab, pembrolizumab, and nivolumab have been improved for the treatment of metastatic urothelial cancer. Clinical trial efforts are underway to explore the utility of combination ICB and standard chemotherapy in this disease, including the IMvigor130 trial that has suggested at least a progression-free survival benefit from the combination of atezolizumab with platinum-based chemotherapy for first-line therapy in advanced bladder cancer. Given varied treatment responses to these agents, biomarkers to better understand treatment outcomes and appropriate patient selection for therapy are critical. In this presentation, Dr. Joshua Lang discusses biomarkers in general as well as emerging biomarkers of these combination therapies in urothelial carcinoma based on Abstract 5011 (biomarker analysis of IMvigor130) and Abstract 5012 (DUTRENEO study). 

He first described the major classes of oncology biomarkers:
  • Diagnostic – to identify the presence of malignancy
  • Prognostic – baseline characteristic associated with survival
  • Predictive – to identify patients most likely to benefit from a specific intervention
  • Pharmacodynamic – to monitor response to a specific intervention
  • Surrogate – to serve as an intermediate endpoint for survival

Multiple biomarkers have been explored in metastatic urothelial cancer, described below.

biomarkers in metastatic urothelial cancer

For combination ICB and chemotherapy, analysis of pretreatment biopsies from the IMVigor210 trial showed that response to atezolizumab was associated with PD-L1 expression on tumor cells, a CD8+ T-effector phenotype RNA expression signature in tumors, and higher tumor mutational burden. Conversely, TGF-b gene signaling in the tumor stroma and exclusion of immune cells (immune excluded or immune desert) were associated with a lack of response. In the presentation from IMvigor130, certain biomarkers (biomarker exploratory group or BEP shown below) were significantly associated with treatment response in either the combination ICB/chemotherapy arm (APOBEC mutational signature) or ICB alone (PD-L1 high expression, APOBEC signature, fibroblast TGF-b gene signaling).

pre treatment biopsies from the IMVigor210 trial

As opposed to the IMVigor130 trial, which explored biomarkers for treatment in advanced urothelial cancer, the DUTRENEO neoadjuvant muscle-invasive bladder cancer study utilized a tumor inflammation score (TIS) to stratify patients and then randomize those with a high TIS score to either standard neoadjuvant chemotherapy or immunotherapy. This study primarily explored the rate of pathologic complete response of combination anti-PD-L1 therapy with durvalumab and anti-CTLA4 therapy with tremelimumab.

Though the combination immunotherapy could induce pathologic complete responses, the TIS did not predict which patients receiving neoadjuvant immunotherapy.

distribution of pathological responses by TIS score

The results from the DUTRENEO study emphasize that a biomarker-based neoadjuvant clinical trial design is feasible in urothelial cancer, and should be pursued in subsequent neoadjuvant studies, though work is required to identify the appropriate biomarker to use in this context.

Together, these two abstracts suggest that a biomarker-based approach may be able to predict patients that respond to specific therapeutic strategies, thus improving the management of patients with urothelial cancer.

Presented by: Joshua Michael Lang, MD, MS, Associate Professor, UW Carbone Cancer Center, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020

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