Overview of Actionable Mutations and Molecular Profiling in NSCLC


Expert perspective on the current landscape of actionable mutations and molecular profiling in non–small cell lung cancer management.


Meghan J. Mooradian, MD: Hello, and welcome to this OncLive®program, The Evolving Landscape of Molecular Alterations and Non-Small Cell Lung Cancer; optimizing testing and treatment to improve outcomes. I’m Meghan Mooradian, assistant professor at Harvard Medical School and clinical oncologist at the Massachusetts General Hospital. Today, I’m going to discuss several updates in the testing and treatment of molecular alterations in advanced non–small cell lung cancer. We’ll discuss the data in the context of the landscape and the impact on clinical practice. Let’s get started on our first topic.

In advanced non–small cell lung cancer, we’ve really seen a transformation in the clinical care of patients. Now clinicians can identify an increasing number of actual genomic alterations with FDA [Food and Drug Administration]-approved therapies. In addition to therapies targeting some of our well-known alterations, alterations that have been around for several decades such as EGFR and ALK, now we’re armed with medications and approvals in several different oncogenes, including RET-rearranged non–small cell lung cancer, MET-mutated lung cancer, and KRAS G12C just to name a few. What we’ve learned is that these targeted agents are often more effective than standard chemotherapy. In many of these oncotypes, or oncogene addicted lung cancers, targeted therapies are also outperforming immunotherapy. Identifying the target and providing our patients with the specific targeted therapy really can optimize their overall response rate, progression-free survival, and overall survival. That’s why it’s critically important to obtain next-generation sequencing at the time of diagnosis to inform these very important decisions.

There have been several actual mutations that have been identified in non–small cell lung cancer, specifically adenocarcinoma. Currently, expert guidelines around molecular testing are really asking clinicians to have routine testing in non–small cell adenocarcinoma for EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK fusions, and HER2. In addition, I think that broad-based next-generation sequencing is also very important in identifying other mutations including co-occurring mutations. In addition to this important molecular testing, expert guidelines also recommend that all of these tumor types have reflex PD-L1 [programmed death-ligand 1] IHC [immunohistochemistry] performed.

When we’re first meeting a patient in the clinic, there are several testing methods that we should be thinking of to identify some of these key molecular alterations. I think if [we] rewind 10-20 years when we were really only identifying and looking for EGFR and ALK, some of the more specific PCR [polymerase chain reaction]-based testing was commonly employed but now that we’re in a time and era where the landscape has remarkably changed and we are looking for near a dozen molecular alterations, a broad-based panel next-generation sequencing approach is the recommended molecular testing of choice. This type of panel minimizes tumor use and potential wastage. When we’re thinking about how best to perform it, it’s often best performed on tumor tissue. Ideally, we can work hand in hand with our surgical colleagues and our interventional pulmonologists to obtain adequate tumor tissue at the time of diagnosis. Ideally, this would be with core biopsy, and potentially surgical excision to ensure that we have sufficient tumor tissue to perform this testing.

Transcript edited for clarity.

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