Q&A With Dr Shaw: ALK/ROS1 Inhibition in Patients With Non-small Cell Lung Cancer

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Alice T. Shaw, MD, PhD
Alice T. Shaw, MD, PhD

A decade ago, patients with non–small cell lung cancer (NSCLC) were found to have oncogenic ALK and ROS1 fusion kinases, opening the door to treatment with ALK and ROS1-targeted agents.

Despite ALK and ROS1 sharing a high degree of homology, only crizotinib is approved for ROS1-positive NSCLC, as Alice T. Shaw, MD, PhD, associate professor of medicine at Harvard Medical School and director of the thoracic cancer program at Massachusetts General Hospital in Boston, pointed out in an editorial in the Journal of Clinical Oncology.1

Cancer Therapy Advisor asked Dr Shaw to discuss ALK- and ROS1-positive NSCLC, including currently available agents and ongoing research to develop additional targeted therapies.

Cancer Therapy Advisor (CTA): What percentage of patients with NSCLC have ALK/ROS1 rearrangements?

Dr Shaw: Approximately 5% of patients have ALK rearrangements, and approximately 1% of patients have ROS1 rearrangements.

Unlike EGFR mutations, which are enriched in the Asian population of patients with lung cancer, the incidence of ALK and ROS1 rearrangements is similar across ethnicities.

The majority of ALK/ROS1 patients are younger never or light-smokers, though ALK and ROS1 rearrangements can be found even in patients who are current or former smokers.

CTA: What agents target ALK? ROS1?

Dr Shaw: Many (but not all) ALK inhibitors also target ROS1.

Currently, the standard therapy for ROS1-positive NSCLC is crizotinib, which is an ALK/ROS1/MET inhibitor. Another ALK/ROS1 inhibitor, ceritinib, has also shown activity in tyrosine kinase inhibitor (TKI)-naive, ROS1-positive NSCLC.2

Notably, the ALK inhibitor, alectinib, does not inhibit ROS1 at all, so should never be used in ROS1-positive NSCLC. The third generation ALK/ROS1 inhibitor lorlatinib is being studied for both ALK and ROS1 among patients previously treated with TKIs like crizotinib.

CTA: The editorial notes: “For now, on the basis of the available data, crizotinib remains the standard therapy for advanced ROS1-positive NSCLC.” In addition to approved agents, what others are being studied for first-line use? Second-line use?

Dr Shaw: For ROS1-positive NSCLC, ceritinib has also been studied in TKI-naive patients. It appears as active as crizotinib in ROS1-positive NSCLC, but does have significantly more side effects.

Of note, ceritinib does not appear to have activity in crizotinib-resistant ROS1-positive patients. Other agents being studied for ROS1-positive NSCLC include lorlatinib, DS-6051b, cabozantinib, and TPX-0005. These are primarily being studied in the post-crizotinib setting.

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