Linking T-cell receptor dynamics to outcomes in neoadjuvant-treated melanoma.

Abstract

9573 Background: Clinical Stage III (cSIII) melanoma patients are at high risk of recurrence following therapeutic lymph node dissection (TLND) and adjuvant therapy. Neoadjuvant immunotherapy based regimens have shown promising results in this setting, with pathological response being the best predictor of recurrence free survival (RFS) and distant metastases free survival (DMFS). T-cell Receptor (TCR) abundance and clonality are being explored as biomarkers. Methods: In the phase II NeoACTIVATE (NCT03554083) trial, patients were treated based on BRAF status with 12 weeks of neoadjuvant atezolizumab, vemurafenib and cobimetinib (Arm A, BRAF-mutated) or atezolizumab and cobimetinib (Arm B, BRAF wildtype), followed by TLND and 6 months adjuvant atezolizumab. TCR sequencing (n=23) was performed on the pretreatment involved lymph node (iLN) and on the same node, along with an adjacent uninvolved node (uiLN) after TLND. The fraction productive of T cells (fpTC) was defined as the percentage of in-frame TCR sequences (capable of encoding a functional expressed receptor protein) of all TCR sequences identified. Simpson Clonality Index (SCI) was used to measure relative abundance of specific clones, with a higher score indicating a more monoclonal repertoire. Comparisons were made using the Wilcoxon Rank Sum test. Results: 30 patients were enrolled, 15 in each arm. 2 patients were not operated on, and one did not receive adjuvant treatment, leaving 27 patients for outcome analysis. 3-year RFS was 55.6% (95% CI 9.5%-77.8%), median of 62.2 months (95% CI 19-NR); DMFS was 64.3% (95% CI 48%-86.3%), median 62.2 months (95% CI 33.9-NR). The fpTC was higher in the pretreatment iLN for those without an RFS event (p=0.04) with a trend in the uiLN as well (p=0.06). Patients without a DMFS event had a higher fpTC in the uiLN (p=0.03) but not in the iLN. The SCI was significantly higher only in the post treatment iLN for patients without an RFS event (p=0.03) and was not significantly different when compared based on DMFS status. When performing pairwise comparisons of nodes based on recurrence status, we found that patients who did not suffer an RFS event had a significantly higher SCI in the post treatment iLN compared to the uiLN (p=0.02). Conclusions: Neoadjuvant immunotherapy and targeted therapy for cSIII melanoma can lead to durable RFS. Higher pretreatment fpTC as well as higher post-treatment iLN TCR clonality were both associated with improved RFS. These data indicate that TCR repertoire characteristics within iLN and uiLN may reflect differential immune responses to neoadjuvant therapy and could inform future studies evaluating biomarkers to stratify risk of recurrence and allow personalization of therapy. Clinical trial information: NCT03554083 . fpTC Simpson Clonality Index RFS event DMFS event RFS event DMFS event Pretreatment iLN 0.04 0.12 0.43 0.11 Posttreatment iLN 0.09 0.09 0.03 0.12 uiLN 0.06 0.03 0.79 0.48 Δ iLN (post-pre) 0.79 0.37 0.07 0.41 Δ posttreatment iLN – uiLN 0.21 0.21 0.02 0.08