Incorporating Biomarkers to Improve Statistical Power of Immunotherapeutic Neoadjuvant Clinical Trials in Patients with Triple-Negative Breast Cancer

Neoadjuvant (preoperative) approach to breast cancer treatment has become widely accepted. Traditionally, the primary objective of neoadjuvant treatment is to improve subsequent surgical intervention and the effectiveness is often evaluated by its ability to achieve complete pathological response (pCR) and the eradication of the malignant disease in the breast and axillary lymph nodes. More recently, neoadjuvant treatment has also become recognized as an in vivo, preoperative” window of opportunity” to explore the efficacy of novel agents such as immunotherapies where several tumor biomarkers are also routinely collected to quantify antitumor immunity. However, one challenge to combine the traditional pCR and efficacy biomarkers is that these tumor biomarkers are only partially available and cannot be measured in patients who have achieved pCR. In this article, a stepwise hypothesis testing procedure is proposed to combine a continuous tumor biomarker with the conventional binary endpoint in a two-arm randomized phase II superiority trial to improve statistical power. The operating characteristics of the proposed procedure are illustrated with a real-world example and the performance is also evaluated numerically.