How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease

Abstract

ROS proto-oncogene 1 (ROS1) rearrangements defines a distinct group of non-small cell lung cancer (NSCLC), mainly represented by younger subjects, never smokers and with adenocarcinoma histology. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Identification of patients harboring ROS1 rearrangements is a critical issue and current guidelines recommend screening of all advanced non-squamous NSCLC and certain squamous lung cancer patients. A number of trials have supported crizotinib as the best option for NSCLC patients with ROS1 translocations, irrespective of line of therapy. Unfortunately, the majority of patients become insensitive to crizotinib, due to the occurrence of secondary ROS1 mutations or failure within the central nervous system (CNS). Several highly potent and CNS penetrant ROS1 inhibitors have been developed and recent data highlight their potential role in the front-line treatment of this disease. Among them entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against the neurotrophin receptors TRKA, TRKB, TRKC ALK, and ROS1 with the ability to cross the blood-brain barrier. In the next few years, results of ongoing trials with novel ROS1 inhibitors and dedicated translational research studies might help to define the optimal sequence of treatment for ROS1-positive NSCLC patients.

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

“…ROS1 rearrangements are detectable in 1% to 2% of NS-NSCLC patients according to the studies and the populations [83]. These genomic alterations are sensitive to some targeted therapies, mainly involving crizotinib, but some resistant mechanisms can be present during the tumor progression, leading to the possibility of other targeted therapies at baseline, such as those involving entrectinib [84], being effective. ROS1 fusion can be assessed in tissue biopsy using ROS1 IHC, but positive results have to be confirmed by ROS1 FISH or by NGS [75,78,83,85].…”

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

“…ROS1 rearrangements (genomic architecture of major fusion variants is depicted in Figure 1, lower panel), are detectable in 1%–2% of NS‐NSCLC 39–41 . Crizotinib and entrectinib are currently approved for first‐line therapy of ROS1 ‐positive NSCLC, with the latter generally preferred in case of brain involvement at initial diagnosis 39,42–44 . ROS1 fusions can be assessed on a tissue biopsy and cytological samples using ROS1 IHC, but similar to the ALK IHC, ROS1 IHC can have false positives and therefore needs confirmation by ROS1 FISH, NGS, or with a multiplex RT‐PCR panel 22,45–48 .…”

“…[39][40][41] Crizotinib and entrectinib are currently approved for first-line therapy of ROS1-positive NSCLC, with the latter generally preferred in case of brain involvement at initial diagnosis. 39,[42][43][44] ROS1 fusions can be assessed on a tissue biopsy and cytological samples using ROS1 IHC, but similar to the ALK IHC, ROS1 IHC can have false positives and therefore needs confirmation by ROS1 FISH, NGS, or with a multiplex RT-PCR panel. 22,[45][46][47][48] ROS1 rearrangement can be assessed using plasma samples and some multiplex RT-PCR method or NGS.…”

Unique SLC12A2-ROS1 fusion is associated with marked response to crizotinib in lung adenocarcinoma

“… 1 Along with never/light smoking history, higher risk of thromboembolic events and brain metastases are also associated with ROS1 rearrangement. 2 , 3 CD74 gene is the fusion partner in approximately 40%–50% of the cases, followed by SLC34A2, EZR, SDC4, LIMA1, MSN , and TPM3 ; 4 , 5 however, there are insufficient data to support differences in their prognostic or predictive roles for the available therapeutic arsenal. 5 …”

“…Although ROS1 on tyrosine kinase inhibitors (TKIs) have demonstrated high response rates in prospective studies (~70%), uncertainties regarding their performance against rare and undescribed fusions persist, highlighting how reports in the literature may be of clinical use. 3 , 5 – 8 Moreover, it is noteworthy that an existent knowledge gap related to a comprehensive genomic characterization of tumors arising in patients of African descent have long posed additional challenges to a more informed clinical decision regarding the optimal management of these patients. 4 , 9 , 10 …”