Lorlatinib Yields No Unexpected Toxicities in ALK-Positive NSCLC

Misako Nagasaka, MD, PhD, spoke with CancerNetwork® about how the safety profile of lorlatinib (Lorbrena) may differ from those of other tyrosine kinase inhibitors such as crizotinib (Xalkori), alectinib (Alecensa), and brigatinib (Alunbrig) in the treatment of those with ALK-positive non–small cell lung cancer (NSCLC). She spoke in the context of findings from the 5-year progression-free survival (PFS) analysis of the phase 3 CROWN trial (NCT03052608) assessing lorlatinib vs crizotinib for this patient population presented at the 2024 American Society of Clinical Oncology Annual Meeting.

Although there were no head-to-head comparisons of safety profiles between the aforementioned therapies, 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, noted a higher rate of grade 3 to 5 treatment-emergent adverse effects (AEs)with lorlatinib vs other agents. Additionally, the 5-year PFS analysis of the CROWN trial did not highlight any increase in the likelihood of cardiovascular events with lorlatinib.

Overall, Nagasaka concluded that the updated findings from the CROWN trial showed no unexpected toxicities.

Transcript:

There were no unexpected toxicities, and it’s a bit difficult to compare these first-line treatments because of the limitation of doing a cross-trial comparison. But the good thing is that in CROWN, lorlatinib was compared [with] crizotinib, alectinib was compared [with] crizotinib in ALEX [NCT02075840], and brigatinib, the other first-line option that’s available on NCCN [guidelines], was also compared [with] crizotinib. Because the comparator of crizotinib is the same, we have an idea of what the toxicity profile would look like. However, it’s important to note that these were not direct head-to-head comparisons.

As you know, all drugs have some sort of toxicity. The things that we see are slightly different with lorlatinib, alectinib, and brigatinib. First of all, there was a greater incidence of treatment-emergent grade 3 to 5 [AEs] with lorlatinib when we compare it with alectinib or brigatinib over the caveat of cross-trial comparisons. The majority of patients receiving lorlatinib had hyperlipidemia, with a quarter of patients experiencing a grade 3 to 4 [AE]. There was also a higher incidence of weight gain, although we also see that with alectinib. In conjunction with the issue with hyperlipidemia, this might raise the concern of long-term risk of cardiovascular disease among patients using lorlatinib for many years as a frontline therapy. However, as far as we are aware, at the 5-year follow-up [of the CROWN trial], there was no increase in cardiovascular events with lorlatinib across all patients. But I think [what is] more important would be the longer follow-up to tease that out. Again, there were no unexpected [AEs]...seen [in] the CROWN study with the use of lorlatinib up-front.

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.