Dr. Pacheco on Second-Line Therapy for ALK+ NSCLC

Jose M. Pacheco, MD, assistant professor, Medicine/Medical Oncology, Colorado University School of Medicine, discusses second-line therapy for patients with ALK-positive non—small cell lung cancer (NSCLC).

Following progression on a second-generation ALK inhibitor, Pacheco advises enrolling patients on a clinical trial with second-line brigatinib (Alunbrig). In the trial, patients will get a biopsy to determine what molecular markers they have that may help predict benefit from brigatinib following alectinib (Alecensa) or another second-generation ALK inhibitor, says Pacheco.

Physicians are gaining more insight into the mechanisms of resistance to ALK inhibitors. Physicians know that following a first-generation ALK inhibitor such as crizotinib (Xalkori), roughly 20% to 25% of patients may develop mutations in the ALK protein itself. Following a second-generation ALK inhibitor like ceritinib (Zykadia), alectinib, or brigatinib roughly 50% of patients will develop a mutation in the ALK protein that leads to resistance, says Pacheco.

Preclinically, it looks like lorlatinib may work better for a particular ALK mutation, G1202R. A patient in the phase II study of brigatinib who had a G1202R mutation responded to the tyrosine kinase inhibitor, says Pacheco. However, there have also been a lot of patients with G1202R mutations who have not responded to brigatinib. Physicians have limited data from lorlatinib in patients with that particular ALK mutation, explains Pacheco.