Biomarker combo forecasts improved survival with anti–PD-1/L1 agents in bladder cancer

Sangeeta Goswami, MD, PhD

The dual biomarker of ARID1A mutations and CXCL13 expression at baseline predicted improved overall survival (OS) in patients with advanced bladder cancer, according to a retrospective analysis published in Science Translational Medicine.^1,2

Researchers have struggled to develop predictive biomarkers for outcomes with immune checkpoint agents in patients with metastatic urothelial carcinoma. Single-biomarker research with PD-L1 level and tumor mutation burden (TMB) status have shown potential, but each has its pitfalls.

“Most biomarker studies have been limited to a single biomarker, such as tumor mutational burden or PD-L1 expression,” lead study author Sangeeta Goswami, MD, PhD, assistant professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, stated in a press release. “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.”

For the discovery component of their research, the investigators used tumor samples from 2 clinical trials (NCT02387996 and NCT01928394) obtained at MD Anderson Cancer Center. Using these samples in multiplatform analyses with mouse models, the researchers found strong clinical activity with checkpoint inhibitors in patients whose tumors cells had ARID1A mutations and enriched expression of CXCL13 in surrounding immune cells

The researchers followed this discovery by retrospectively assessing data from the IMvigor210 and CheckMate-275 trials to independently confirm the predictive value of the biomarkers. The single-arm phase 2 IMvigor210 study (NCT02108652) examined atezolizumab (Tecentriq) in patients with locally advanced or metastatic urothelial cancer. The IMvigor210 study supported the FDA accelerated approval of atezolizumab for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are cisplatin ineligible.

The phase 2 single-arm CheckMate-275 trial (NCT02387996) explored nivolumab (Opdivo) in patients with metastatic or unresectable bladder cancer who progressed or recurred after treatment with a platinum agent. The CheckMate-275 trial supported the FDA accelerated approval of nivolumab for use in this setting.

Analysis of the IMvigor210 data showed that the median OS was 7.2 months higher in patients with ARID1A mutations versus those without, at 15.4 versus 8.2 months, respectively. The median OS in patients with high versus low CXCL13 expression was 17.1 versus 8 months, respectively. The median OS was 17.8 months in patients who had both biomarkers. Among those without either ARID1A mutations or CXCL13 expression, the median OS was only 7.1 months.

Similar outcomes were observed in the CheckMate-275 trial data. The median OS was 11.4 versus 6 months in patients with and without ARID1A mutations, respectively. The median OS was improved by 7.8 months in patients with high versus low CXCL13 expression, at 13.5 versus 5.7 months, respectively. The median OS increased to 19.1 months in patients with both biomarkers. Patients without either biomarker had a median OS of just 5.3 months.

“We hope that our study will highlight the importance of developing combinatorial biomarkers that consider both tumor cells and immune cells,” corresponding author Padmanee Sharma, MD, PhD, professor of Genitourinary Medical Oncology and Immunology at MD Anderson, stated in the press release. “This approach may identify better biomarkers that can reliably predict response to immune checkpoint therapy across various tumor types.”

Regarding next steps the investigators plan to launch a prospective study to assess the dual biomarker in patients receiving immune checkpoint therapy.

References

1. Combination biomarker predicts response to immune checkpoint therapy in patients with advanced bladder cancer. Published June 18, 2020. https://bit.ly/2AGKzt8. Accessed June 18, 2020.

2. Goswami S, Chen Y, Anandhan S, et al. ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC. Sci Transl Med. 2020;12(548):eabc4220. doi: 10.1126/scitranslmed.abc4220