ROS1 Gene Rearrangements Are Associated With an Elevated Risk of Peridiagnosis Thromboembolic Events

Abstract

Introduction: This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1þ NSCLC) has a higher than expected thromboembolic event (TEE) rate.Methods: Venous and arterial TEEs within ±365 days of diagnosis of ROS1þ, ALKþ, EGFRþ, or KRASþ advanced NSCLC at five academic centers in the United States and China were captured (October 2002-April 2018). The primary endpoint was incidence of TEE in ROS1þ compared to anaplastic lymphoma kinase (ALK)þ, EGFRþ, and KRASþ NSCLC within ±90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers.Results: Eligible data from 95 ROS1þ, 193 ALKþ, 300 EGFRþ, and 152 KRASþ NSCLC patients were analyzed. The incidence rate of TEE was 34.7% (n ¼ 33), 22.3% (n ¼ 43), 13.7% (n ¼ 41), and 18.4% (n ¼ 28), respectively. In univariate analysis, the odds of a TEE in ROS1þ NSCLC were higher than ALKþ, EGFRþ, and KRASþ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1þ compared to EGFRþ and KRASþ cohorts, the odds ratio (OR) was 2.44, with a 95% confidence interval of 1.31-4.57 (p ¼ 0.005), and OR: 2.62, with a 95% confidence interval of 1.26-5.46 (p ¼ 0.01), respectively.Although numerically superior, the odds for a TEE with ROS1þ compared to ALKþ was not statistically significant (OR: 1.45, p ¼ 0.229). Overall survival was not significantly

Impact of ALK Rearrangement on Venous and Arterial Thrombotic Risk in NSCLC

“…overall and were the focus of this study). 24 This study concluded that the ROS1-mutant group had statistically significant, higher thrombotic event risk than the EGFR group (OR 2.44, 95% CI: 1.31-4.57, p ¼ 0.005) and KRAS group (OR 2.62, 95% CI: 1.26-5.46, p ¼ 0.01), but not the ALK group, which had similar risk (OR 1.45, 95% CI: 0.79-2.64, p ¼ 0.229).…”

“…In addition, although this rate was relatively high, it was similar to the rates observed in other large studies evaluating thromboembolic events in unresectable or metastatic NSCLC. 24 Finally, there are numerous different molecular subtypes of NSCLC with varying biologic activity, and our control group was heterogenous, comprising all non-ALK molecular subtypes. Although this was sufficient for our goal of identifying whether ALK-rearranged tumors had a higher thrombotic risk than the general NSCLC population, it is likely that each molecular subtype imparts a distinct risk.…”

“…Evidence for increased thrombotic risk in NSCLC attributable to specific molecular aberrations is not limited to the ALK rearrangement; such an increased risk has also been suggested in a large cohort of patients with ROS1-rearranged NSCLC. 24 Therefore, this study aimed to define the risk of both venous and arterial thrombosis in ALK-rearranged NSCLC versus NSCLC without the ALK rearrangement by analyzing large cohorts of patients with advanced-stage NSCLC with and without the ALK rearrangement, employing time-to-event analyses accounting for covariates and confounders relevant to thrombosis risk.…”

Is There an Interplay between Immune Checkpoint Inhibitors, Thromboprophylactic Treatments and Thromboembolic Events? Mechanisms and Impact in Non-Small Cell Lung Cancer Patients

“…Similarly, in order to demonstrate a direct correlation between ICIs and TE events, a control arm of patients with similar characteristics not receiving immunotherapy would have been optimal. However, this comparison is hard to perform, since NSCLC patients treated with chemotherapy are at even higher risk of TE events, as are patients with driver mutations receiving targeted therapies [54][55][56]. Moreover, if tested, lower rates of PD-L1 positivity would be found in these populations, as this might represent the reason to omit ICIs.…”

Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion

“…200 Ng and colleagues also reported a higher incidence of thromboembolic disease in patients with ROS1 (34.7%) than patients with ALK (22.3%), EGFR (13.7%) or K-RAS (18.4%) mutations. 201 Overall, patients with ROS1 may have a better outcome with mOS of 3 years in those who had received only standard chemotherapy and over 5 years in those with both chemotherapy and crizotinib ( Table 3). 202 Crizotinib is the first TKI reported to have significant activity in ROS1 fusion mNSCLC.…”