Lorlatinib was strategically designed to have activity against ALK and to be highly CNS-penetrant,” said formal discussant Christine M. Lovly, MD, PhD, of Vanderbilt Ingram Cancer Center, Nashville. “We look forward to seeing more data from this trial. Alectinib had a progression-free survival of about 3 years, which was remarkable. We await the data on lorlatinib,” she added.

Christine M. Lovly, MD, PhD

“As we treat longer with these drugs, toxicity is important. In CROWN, hypercholesterolemia and triglyceridemia are exclusive to lorlatinib, and neurocognitive effects were seen with lorlatinib, although less commonly. It appears that any tyrosine kinase inhibitor will achieve high response rates and long progression-free survival, but that is not a cure,” continued. Dr. Lovly.

“Toxicity profiles will be important as well as mechanisms of resistance to lorlatinib, as we figure out the optimal way to sequence the available ALK tyrosine kinase inhibitors. We need more data and we need data on combinations,” Dr. Lovly said.

Clinical Implications and Remaining Questions

“We have multiple first-line options for ALK-positive NSCLC. We have to continue to move the needle and learn how best to deploy these drugs. We need to make sure all patients are tested for ALK and other biomarkers. If we don’t do the testing, we can’t deploy the drugs. We need to increase representation in clinical trials for ALK-positive and other subtypes of NSCLC and also need to explore combinations as front-line and second-line treatments,” commented Dr. Lovly.

“Furthermore, we need to implement dynamic monitoring of response to ALK tyrosine kinase inhibitor therapy using circulating tumor DNA. We also need to consider co-mutations, such as TP53,” she added.

Moving forward, Dr. Lovly noted that studies of ALK tyrosine kinase inhibitors are necessary in the adjuvant setting in ALK-positive NSCLC. “Since we will be using these drugs for years, we need to think about survivorship issues and quality of life,” she stated. “We also should consider how these findings can be translated to other tumor types that harbor ALK mutations. This will require more rigorous studies on toxicity and sequencing.” 

DISCLOSURE: Dr. Lovly has served as a consultant to Pfizer, Novartis, AstraZeneca, Genoptix, Sequenom, Ariad, Takeda, Blueprints Medicine, Cepheid, Foundation Medicine, Eli Lilly/Loxo, Genentech, and Amgen and has received research grants from AstraZeneca, Novartis, and Xcovery.