Lorlatinib Yields Distinguishing CNS Benefit in ALK-Positive NSCLC

Lorlatinib (Lorbrena) might be considered as a frontline therapeutic option for most patients with ALK-positive non–small cell lung cancer (NSCLC), according to Misako Nagasaka, MD, PhD.

CancerNetwork® spoke with Nagasaka, an associate clinical professor of medicine in the Division of Hematology and Oncology at the University of California, Irvine (UCI) School of Medicine of UCI Health, about the “distinguishing benefit” of lorlatinib vs other tyrosine kinase inhibitors (TKIs) for this NSCLC population. She spoke in the context of findings from the phase 3 CROWN trial (NCT03052608) presented at the 2024 American Society of Clinical Oncology Annual Meeting.

Across different trials assessing various TKIs for ALK-positive NSCLC, Nagasaka noted similar intracranial responses with lorlatinib compared with agents such as alectinib (Alecensa) and brigatinib (Alunbrig). However, she described that lorlatinib had an “unprecedented” benefit of decreasing the risk of central nervous system (CNS) progression.

Based on these findings and characteristics, Nagasaka stated that she considers using lorlatinib for most of her patients, even as a method for protecting against the development of brain metastases.

Transcript:

We know from earlier studies and from preclinical studies that lorlatinib penetrates the brain very well. We also know from the frontline studies of CROWN, ALEX [NCT02075840], and ALTA-1L [NCT02737501] trials [that] the intracranial objective response rates and intracranial complete response rates were similar between the 3 ALK-TKIs. But there is this key distinguishing benefit of lorlatinib that was reported from the CROWN update: its unprecedented decrease in the risk of CNS progression compared with what was previously reported with alectinib and brigatinib. To give numbers, at the 5-year [update of CROWN], 83% of patients with baseline brain metastasis and 96% of patients without baseline brain metastasis were free of CNS disease.

I consider using lorlatinib even in patients who don’t have a baseline brain metastasis just because of the protective effect lorlatinib might have against the development of brain metastasis, and that’s something you want to avoid as an oncologist. In conclusion, I consider lorlatinib for most of my patients as a frontline therapy, with careful counseling of the patient and family members and candid discussion on [its] risks and benefits.

Reference

Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: five-year progression-free survival and safety from the CROWN study. J Clin Oncol. 2024;42(suppl 17):LBA8503.