Clinical significance of the CGRP pathway gene expression in advanced solid tumors: A sub-analysis of MONSTAR-SCREEN-2.

Abstract

2629 Background: Calcitonin gene-related peptide (CGRP), a neuropeptide associated with pain perception, has emerged as a therapeutic target for migraine. Recent studies have reported that the CGRP pathway is associated with suppression of anti-tumor immunity and poor prognosis in patients (pts) with solid tumors via induction of CD8+ T cell exhaustion by sensory nerves. However, clinical significance of the CGRP pathway genes in oncology including the impact for the efficacy of immune checkpoint inhibitors (ICIs) remains elusive. Herein, we evaluated the landscape of the CGRP pathway gene expression and their association with efficacy of ICIs by mRNA expression level of the CGRP pathway genes in advanced solid tumors from the SCRUM-Japan MONSTAR-SCREEN-2, a nationwide molecular profiling project. Methods: Pts with advanced solid tumors were enrolled; tumor tissues were profiled using whole exome/transcriptome sequencing (MI Profile, Caris Life Sciences, Phoenix, AZ, USA). The association between the expression profiles of the CGRP pathway genes ( CALCA encoding CGRP, CALCRL and RAMP1 encoding CGRP receptors) and the efficacy of ICI monotherapy was analyzed. Results: Among 2,768 pts enrolled as of March 2024, mRNA expression data of baseline tissue samples were available in 1,475 pts across 36 cancer subtypes: most common subtypes were colorectal adenocarcinoma (n = 352) and esophagogastric adenocarcinoma (EGAC, n = 192). mRNA expression of the CGRP pathway genes were observed across diverse cancer types. One hundred and fifty-eight pts were treated with ICI monotherapies: most common subtypes were urothelial carcinoma (UC, n = 41), EGAC (n = 30) and head and neck squamous cell carcinoma (HNSCC, n = 30). The low RAMP 1 mRNA expression group tended to have a better objective response rate (ORR) and significantly better progression-free survival (PFS) than the high mRNA expression group (ORR: 29.3% vs 15.2%, P = 0.056, PFS: 5.1 vs 2.7 months, hazard ratio [HR]: 0.68, 95% CI: 0.47-0.98, P = 0.04). Among the patients with UC and HNSCC, the low RAMP1 mRNA expression group tended to have a better PFS than the high mRNA expression group (UC: 3.5 vs 6.0 months, HR: 0.69, 95% CI: 0.34-1.39, P = 0.3, HNSCC: 1.5 vs 6.0 months, HR: 0.67, 95% CI: 0.30-1.51, P = 0.3). Conclusions: High RAMP1 mRNA levels were associated with worse therapeutic efficacy of ICI, highlighting the potential of CGRP pathway as a resistance mechanism and a treatment target. Clinical trial information: UMIN000043899 .