De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma

Abstract

PurposeDespite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.MethodsThe Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome.ResultsOverall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30–0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20–0.89; MEL-IPI: HR 0.55, 95% CI 0.34–0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma.ConclusionsCollectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.

Mutational landscape and predictors of survival in head and neck mucosal melanoma

“…Recently, entrectinib and crizotinib, both RTK inhibitors, have been approved for treating ROS1‐positive solid tumors 7 . In cutaneous melanoma, de novo mutations in ROS1 has been shown to result in improved OS for patients treated with immunotherapy, along with having a higher TMB 8 . We also observed in our cohort that ROS1‐mutated cases had a higher TMB, likely contributing to their improved OS.…”

“…7 In cutaneous melanoma, de novo mutations in ROS1 has been shown to result in improved OS for patients treated with immunotherapy, along with having a higher TMB. 8 We also observed in our cohort that ROS1-mutated cases had a higher TMB, likely contributing to their improved OS. Furthermore, one case report describes complete response to crizotinib therapy in a HNMM patient harboring a ROS1 mutation.…”

HYDIN mutation status as a potential predictor of immune checkpoint inhibitor efficacy in melanoma

“…For example, Johnson et al demonstrated that melanoma patients with NRAS mutations had a higher response rate to first-line ICIs treatment with ipilimumab or anti-PD-L1 antibody than those with wild type [ 14 ]. It was also noted that melanoma patients with ROS1 mutations yielded longer OS from ICIs [ 15 ]. These results suggest that certain genetic mutations may be reliable predictive markers of ICIs efficacy in melanoma patients.…”

The association of ROS1 mutation with cancer immunity and its impact on the efficacy of pan-cancer immunotherapy

“…Indeed, evidences from both in vivo and in vitro studies revealed ROS1 could regulate the expression of PD-L1 and participate in immune escape through the activation of ROS1-SHP2 - and MEK-ERK -signaling pathways in lung cancer [ 2 ]. In melanoma, ROS1 mutation was associated with an enrichment of DNA-damage-response-related processes and DNA-repair-related molecules [ 3 ], which might lead to the enhanced immune surveillance. Here, we conducted a comprehensive bioinformatic and clinical analysis to study the characteristics of ROS1 mutation and its association with pan-cancer immunotherapy (Suppl.…”