ALK Testing Strategies and Navigating First-Line Treatment Options in Advanced NSCLC

This segment dives into two of the most practically important questions facing clinicians who manage ALK-positive NSCLC: how to optimally test for ALK rearrangements, and how to select among the growing number of first-line treatment options available today.

On the topic of testing, Dr. Shaw walks through the full landscape of ALK detection modalities, addressing whether clinicians should rely on tissue, liquid biopsy, or both — and within tissue testing, how to choose between immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS), including the important distinction between DNA- and RNA-based NGS approaches. She notes that while liquid biopsies using circulating tumor DNA have become increasingly common given their speed and ease of access, they carry meaningful sensitivity limitations — a negative liquid biopsy does not rule out an ALK rearrangement, making tumor tissue testing an essential follow-up step. Among tissue-based methods, NGS — and RNA-based sequencing in particular — is highlighted as especially well-suited for detecting ALK fusions, though IHC remains a faster and widely available alternative.

Dr. Lovly reinforces that no single test is 100% accurate, and that multidisciplinary collaboration with molecular pathologists is key to navigating these nuances in real-world practice.

The segment then transitions to the first-line treatment landscape for patients with advanced or metastatic ALK-positive NSCLC, where the number of available options has expanded considerably over the past decade. Dr. Shaw outlines the current NCCN-preferred agents — including second-generation inhibitors such as alectinib, brigatinib, and ensartinib, as well as the third-generation inhibitor lorlatinib — and begins to frame how clinicians can differentiate between them based on emerging clinical evidence, setting the stage for the deeper data discussion that follows.