Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer.

Abstract

4073 Background: In VOLTAGE-A1, after 5 cycles of nivolumab (240 mg q2 weeks) plus radical surgery following chemoradiotherapy (CRT; 50.4 Gy with capecitabine 1,650 mg/m2), a major pathologic response is observed in 38% (AJCC tumor regression grade 0-1) of 37 patients with microsatellite-stable locally advanced primary rectal cancer. Here, biomarkers for predicting the efficacy of this treatment were investigated. Methods: Serial tumor biopsies and blood collections were performed at 4 time points; before CRT, after CRT, after 3 cycles of nivolumab, and before surgery. Tumor-infiltrating lymphocytes (TILs) and DNA/RNA were extracted from tumor samples, and peripheral blood mononuclear cells (PBMCs) were extracted from blood samples. We analyzed the immune status of the patients by flow cytometry using the collected TILs and PBMCs. Whole exome and RNA sequencing analyses were conducted using the extracted DNA and RNA, respectively. The PD-L1 status of tumor samples was also evaluated by in vitro diagnostic immunohistochemistry staining. Results: Among the 24 patients whose samples were serially collected, 11 (46%) were AJCC grade 0-1 and 13 were 2-3. Before CRT, effector regulatory T (eTreg) cells in TILs were higher in patients with AJCC grade 2-3, and both the CD8+ T cell/eTreg cell ratio in TILs and PD-L1-positive tumor cells (≥1%) were higher in patients with AJCC grade 0-1 (p = 0.047, p = 0.083, respectively). Ki67 expression by CD8+ T cells in TILs was higher before CRT in patients with AJCC grade 0-1 (p = 0.037) and increased after CRT in all patients. Patients with consensus molecular subtype (CMS) 1 and CMS3 achieved AJCC grade 0-1 at rates of 100% (2/2) and 60% (4/6), respectively. In contrast, patients with CMS2 and CMS4 achieved AJCC grade 0-1 at rates of 43% (3/7) and 29% (2/7), respectively. The tumor mutation burden of pre-CRT samples was significantly higher in patients with AJCC grade 0-1 (median 1.45/MB) than in patients with AJCC grade 2-3 (0.84/MB) (p = 0.016). Conclusions: A higher CD8+ T cell/eTreg cell ratio, PD-L1-positive, Ki67 expression by CD8+ T cells in TILs, CMS1 or 3, and higher tumor mutation burden are good predictors of the efficacy of the sequential combination of CRT and nivolumab. Further results will be reported in the meeting. Clinical trial information: NCT02948348 .