Advertisement

Biomarker Combination May Help Predict Response to Immunotherapy in Patients With Metastatic Urothelial Carcinoma


Advertisement
Get Permission

In patients with metastatic urothelial carcinoma, a novel combination of biomarkers from baseline tumor tissues was predictive of improved clinical responses and prolonged survival following treatment with immune checkpoint inhibitors, according to findings published by Goswami et al in Science Translational Medicine.

The study used multiplatform analyses of tumor samples to discover that ARID1A mutations in tumor cells and expression of the immune signaling protein CXCL13 in surrounding immune cells were enriched in patients who responded to checkpoint inhibition. Retrospective analyses of two phase II clinical trials confirmed that each of these biomarkers was associated with improved overall survival, but a combination of these biomarkers was predictive of better overall survival compared to either biomarker alone. Patients with ARID1A mutations and high CXCL13 expression had a median overall survival of more than 17 months in both trials, compared to fewer than 8 months in patients with no mutations and low CXCL13 expression.

“Combination of the two biomarkers in baseline tumor tissues suggested improved overall survival compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving immune checkpoint therapy.”
— Goswami et al

Tweet this quote

“Most biomarker studies have been limited to a single biomarker, such as tumor mutational burden or PD-L1 expression,” said lead study author Sangeeta Goswami, MD, PhD, Assistant Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. “Our study indicates that combinatorial biomarkers that reflect both the tumor mutational status and immune response will improve predictive capability of the biomarker and may enable better patient selection for treatment with immune checkpoint therapy.”

Study Background

Five-year overall survival rates for patients with metastatic urothelial cancers are roughly 5%. The approval of immune checkpoint therapy as an option for these patients has improved outcomes, explained Dr. Goswami, but only 15% to 20% of patients will see a benefit.

Currently, there are no clinically useful biomarkers to predict responses. Therefore, the research team performed immune and genomic profiling of baseline tumor tissues from MD Anderson patients participating in ongoing clinical trials to identify novel markers associated with responses to checkpoint inhibitors.

Results

Following discovery of the biomarkers, reverse translational studies in mouse models confirmed that ARID1A knockdown increased sensitivity to checkpoint blockade, whereas loss of CXCL13 expression rendered mice resistant to checkpoint inhibitors.

The researchers next sought to confirm the predictive capability of these biomarkers in additional cohorts from the phase II CheckMate 275 and IMvigor210 trials, which evaluated the efficacy of nivolumab or atezolizumab in patients with advanced urothelial cancers.

In the CheckMate 275 trial, ARID1A mutations were associated with a median overall survival of 11.4 months compared to 6.0 months in patients without mutations. High CXCL13 expression was associated with median overall survival of 13.5 months compared to 5.7 months in those with the lowest CXCL13 expression. Patients with both markers had a median overall survival of 19.1 months compared to 5.3 months in patients with neither marker.

The IMvigor210 trial showed similar results. Patients with ARID1A mutations had a median overall survival of 15.4 months compared to 8.2 months in those without. Median overall survival was 17.1 months and 8.0 months in patients with high and low CXCL13 expression, respectively. Patients with both biomarkers had a median overall survival of 17.8 months, while those without either biomarker had a median overall survival of 7.1 months.

As this was a retrospective study, the researchers currently are planning a clinical trial to prospectively evaluate outcomes for patients who are positive for the combination biomarker following treatment with anti–PD-1 therapy.

The study authors concluded, “Combination of the two biomarkers in baseline tumor tissues suggested improved overall survival compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving immune checkpoint therapy.”

Disclosure: For full disclosures of the study authors, visit stm.sciencemag.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
Advertisement

Advertisement




Advertisement