Dr Camidge on Best Practices for Biomarker Testing in NSCLC

“[ALK is] commonly part of sequencing analyses, and the only aspect to pay attention to is understanding the meaning of a negative result. [Patients might think] a negative result [means they have no] biomarkers in their cancer. [However]…if [the oncologist] just sent off a blood biopsy…and it didn’t show anything, that’s not a true negative. [In that case], you would see if there is tumor tissue you can sequence.”

D. Ross Camidge, MD, PhD, professor, medicine-medical oncology; director, Thoracic Oncology Clinical Program, Clinical Research Program, University of Colorado Cancer Center – Anschutz Medical Campus, discusses best practices for biomarker testing in non–small cell lung cancer (NSCLC) and the potential value of longitudinal biomarker testing for patients with this disease.

The discovery of ALK mutations in lung cancer fundamentally altered biomarker-driven treatment in NSCLC, Camidge begins. Although EGFR mutations had previously been identified as an actionable target, they were often viewed as an exception rather than part of a broader paradigm, he remarks. The recognition of ALK-mutated NSCLC as a second molecularly defined subtype challenged this perception and opened the door to identifying additional oncogenic drivers, establishing the foundation for precision medicine in lung cancer, he says.

ALK mutation testing is now a routine part of comprehensive genomic sequencing in patients with NSCLC, but challenges remain in interpreting negative results, Camidge continues. A negative test does not necessarily indicate the absence of actionable mutations; rather, results depend on the type of test performed, he notes. Liquid biopsies using circulating tumor DNA (ctDNA) are convenient but may yield false negative results due to limited tumor shedding, he explains. In cases where ctDNA testing is negative, tissue biopsy remains the gold standard, particularly in patients with clinical characteristics suggestive of a driver mutation, Camidge adds. Additionally, although driver mutations, such as ALK fusions, are more common in nonsmokers, they can also occur in patients with a history of smoking and even in squamous cell lung cancer, underscoring the importance of broad molecular testing for all patients with advanced disease, he reiterates.

Despite the initial efficacy of ALK inhibitors, resistance inevitably develops, Camidge states. Many treatment strategies focus on sequential ALK inhibition, transitioning patients from earlier-generation agents, such as crizotinib (Xalkori), to more potent and selective next-generation inhibitors like alectinib (Alecensa) and lorlatinib (Lorbrena), he says, adding that this approach can lead to the accumulation of compound ALK mutations that continue to drive tumor progression. In such cases, emerging fourth-generation ALK inhibitors designed to overcome resistance may be beneficial, according to Camidge. However, a substantial proportion of patients will acquire resistance mechanisms from secondary driver mutations, which involve pathways such as KRAS, EGFR, MET, and RET, rendering further ALK inhibition ineffective, Camidge notes.

The challenge in managing ALK-rearranged lung cancer lies in distinguishing patients whose disease remains dependent on ALK signaling from those whose tumors have developed alternative survival pathways, he says. The clinical response to a subsequent ALK inhibitor can provide insight into resistance mechanisms, Camidge adds. However, for patients whose tumors have shifted to alternative oncogenic pathways, combination therapy targeting multiple alterations may be necessary, he explains. Unfortunately, effective combination regimens are not always available, leaving chemotherapy, such as pemetrexed-based regimens, as the only viable option, Camidge concludes.