Journal Article

Avelumab first‐line maintenance in advanced urothelial carcinoma: Complete screening for prognostic and predictive factors using machine learning in the JAVELIN Bladder 100 phase 3 trial

Gerhold‐Ay, Aslihan, Kieslich, Pascal, Manitz, Juliane, Tyroller, Karin, Shah, Parantu, Mrowiec, Thomas

2024

Overview

Background Avelumab first‐line (1 L) maintenance is a standard of care for advanced urothelial carcinoma (aUC) based on the JAVELIN Bladder 100 phase 3 trial, which showed that avelumab 1 L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression‐free survival (PFS) vs BSC alone in patients who were progression free after receiving 1 L platinum‐containing chemotherapy. Here, we comprehensively screened JAVELIN Bladder 100 trial datasets to identify prognostic factors that define subpopulations of patients with longer or shorter OS irrespective of treatment, and predictive factors that select patients who could obtain a greater OS benefit from avelumab 1 L maintenance treatment. Methods We performed machine learning analyses to screen a large set of baseline covariates, including patient demographics, disease characteristics, laboratory values, molecular biomarkers, and patient‐reported outcomes. Covariates were identified from previously reported analyses and established prognostic and predictive markers. Variables selected from random survival forest models were processed further in univariate Cox models with treatment interaction and visually inspected using correlation analysis and Kaplan–Meier curves. Results were summarized in a multivariable Cox model. Results Prognostic baseline covariates associated with OS included in the final model were assignment to avelumab 1 L maintenance treatment, Eastern Cooperative Oncology Group performance status, site of metastasis, sum of longest target lesion diameters, levels of C‐reactive protein and alkaline phosphatase in blood, lymphocyte proportion in intratumoral stroma, tumor mutational burden, and tumor CD8+ T‐cell infiltration. Potential predictive factors included site of metastasis, tumor mutation burden, and tumor CD8+ T‐cell infiltration. An analysis in patients with PD‐L1+ tumors had similar findings to those in the overall population. Conclusions Machine learning analyses of data from the JAVELIN Bladder 100 trial identified potential prognostic and predictive factors for avelumab 1 L maintenance treatment in patients with aUC, which warrant further evaluation in other clinical datasets.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Aged / Alkaline phosphatase / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Agents, Immunological - therapeutic use / Biomarkers / Biomarkers, Tumor / Bladder / Blood levels / C-reactive protein / Cancer therapies / Carcinoma, Transitional Cell - drug therapy / Carcinoma, Transitional Cell - mortality / Carcinoma, Transitional Cell - pathology / CD8 antigen / Chemotherapy / clinical cancer research / Clinical decision making / Clinical outcomes / clinical trials / Correlation analysis / Datasets / Female / Humans / Immunotherapy / Infiltration / Kinases / Learning algorithms / Lymphocytes / Lymphocytes T / Machine Learning / Maintenance Chemotherapy - methods / Male / Medical prognosis / Metastases / Metastasis / Middle Aged / Missing data / Monoclonal antibodies / Oncology / Patients / PD-L1 protein / Population / Prognosis / prognostic factor / Progression-Free Survival / Stroma / Targeted cancer therapy / Tumors / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - mortality / Urinary Bladder Neoplasms - pathology / Urological cancer / urothelial / Urothelial carcinoma / Variables