Targetable Gene Rearrangements in Advanced Lung Cancer: Optimized Testing and Management - Episode 5

ROS1 Alterations in Advanced NSCLC

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Ben Levy, Mark Socinski, and Stephen Liu explain the role of a ROS1 alteration in NSCLC and its value as a targetable biomarker.

Mark A. Socinski, MD: ROS1 is interesting in that it shares significant homology with ALK. They're close to 70 to 80% homologous proteins, if you will. ROS1 was discovered in the mid-1980s. And to my knowledge, I don't know that we understand the normal functioning of ROS1, nor do we understand what the ligands for this receptor may be. Again, about 10 years ago, it was discovered in non-small cell lung cancer, [NSCLC] that about 1% of patients had a ROS fusion. Remarkably similar impact like we've talked about with ALK in that this with the fusion becomes an oncogenic driver. It's ligand-independent, even though we don't know what the ligands are. It seems to be independent of a ligand and turns on the growth pathway and survival pathways, giving the cancer cell an advantage over the normal cells. Of course, this also has been a target for the development of drugs, and we have a couple of drugs approved in this setting for specific use in ROS1-positive patients. And again, should be part of your comprehensive genomic testing platform in advanced non-small cell lung cancer.

Stephen Liu, MD: ROS1 fusions are present in about 1-2% of non-small cell lung cancer. These are gene fusions or chromosomal rearrangements, most common partners CD74. That accounts for about 40% of them. There are a lot of others that occur a little less frequently, ECR, SLC-34A1, STC4, there are at least 10 others. The significance of the fusion partner clinically isn't known. It'll take a little while to uncover those differences given the rarity of these specific fusions. As of today, it does not influence our treatment decisions.

Benjamin Levy, MD: Every patient that walks in my door should – in my clinic is tested for ROS1 rearrangements. There are challenges to this. We know that ROS1-rearranged lung cancer is roughly 1 to 2% of all lung adenocarcinoma. That said, when we identify these rearrangements, we can wed them to targeted therapies. There are 2 now that are approved, and potentially a 3rd coming down the pike. The best way to interrogate for ROS1 rearrangements is probably through a RNA-based next-generation sequencing platform. We order tissue analysis for both DNA and RNA, specifically RNA to identify these fusions. We also order a liquid biopsy. Again, liquid biopsies are probably not the optimal way as a stand-alone test to detect fusions. But supplement to tissue may be helpful. There are gaps in testing for sure. We know that based on ASCO [American Society of Clinical Oncology meeting] data in 2021 that we are not doing the best job of next-generation sequencing for our patients with non-small cell lung cancer. And we need to understand what the best platforms are to interrogate fusions. And in that regard, both DNA and RNA, specifically RNA-based sequencing platforms are important. And importantly doing both tissue and plasma on our patients. A liquid biopsy and the tissue biopsy, both can enhance the capture of alterations that are potentially targetable. We need to address these gaps. We need to do better. But I’m confident that over the next 3 to 5 years – there’s just too many good therapies now – that all of us will be doing a good job of interrogating lung cancer tumors to identify all actionable mutations including ROS1 rearrangements.

Transcript edited for clarity.