Abstract 958: Signal transduction pathway activity of TGF-β and Hedgehog as possible response predictors to checkpoint inhibition in patients with advanced melanoma; a retrospective cohort study

Abstract

Abstract Introduction: Although immunotherapy is highly effective in patients with melanoma, not all patients respond equally well to immune checkpoint inhibition (ICI). Preclinical data indicate that TGF-β pathway activity mediates immune evasion by tumor T cell exclusion and may therefore be predictive for response. Recently, a new mRNA-based methodology has been developed to measure and quantify signal transduction pathway (STP) activities in tissue. This study was initiated to characterize the STPs in advanced melanoma samples to better understand the role of STPs in immune check point efficacy. Method: The OncoSIGNal pathway activity profiling PCR test (InnoSIGN) was used to measure the activity of 8 different STPs (AR, PI3K, MAPK, Hedgehog (HH), TGF-β, Notch, NFkB and JAK-STAT1/2) in biopsies (FFPE) from patients with advanced melanoma (n=34) and expressed on a scale from 0 -100. A biopsy of a metastatic site was obtained prior start of ICI therapy (nivolumab or pembrolizumab). These samples were analyzed for STP activity and related to progression-free survival (PFS). Also, STP activities were compared between responders (n=15; partial or complete response) and non-responders (n=19; defined as progression within 6 months). Results: The mean HH score of responders versus non-responders was 35.7 + 6.1 vs 41.6 + 8.7 (p=0.038), while TGF-β scores were 53.9 + 6.2 vs 56.8 + 8.2 (p=0.265), respectively. Cox regression analysis showed a hazard ratio of 1-1.1 for PFS of both HH and TGF-β (HH: p=0.032) (TGF-β: p=0.071). Kaplan Meier curves indicated a better PFS for lower HH activity at a threshold of 46 (p< 0.001) and lower MAPK activity at a threshold of 47.3 (p= 0.041). No relation with PFS was detected for TGF-β activity. No statistically significant differences were observed in STP activity between different metastatic locations ((sub)cutaneous, lymph node or visceral metastases). Conclusion: Signal transduction pathway activity of metastatic samples, taken prior start of ICI therapy, from patients with advanced melanoma, suggest that TGF-β did not correlate with response nor PFS but increased HH and MAPK STP activity may relate towards a worse PFS from ICI therapy. Citation Format: Stefan G. vanRavensteijn, Daniele V. Taurello, Avital Amir, Yvonne J. Wesseling, Anne G. vanBrussel, Diederick M. Keizer, Henk M. Verheul, Kalijn F. Bol. Signal transduction pathway activity of TGF-β and Hedgehog as possible response predictors to checkpoint inhibition in patients with advanced melanoma; a retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 958.