Finding Balance Between Intracranial Efficacy and Adverse Effects of ALK Kinase Inhibition
More than 7 years – that is the current median survival of patients with non-small cell lung cancer (NSCLC) with a mutation in the anaplastic lymphoma kinase (ALK) gene who are receiving targeted therapy. Therefore, the quality of life of patients on treatment and the search for a balance between its antitumor efficacy and adverse effects (AEs) is becoming the focus of clinical research. Recently, lorlatinib has been discussed in this context.
Longer Progression-Free Survival in the CNS
Lorlatinib is among the most effective inhibitors of ALK. It acts despite the most common mutations that cause resistance to other ALK inhibitors and is capable of crossing the blood-brain barrier. Its efficacy was first confirmed in clinical trials with pretreated patients and later in the 1st line of treatment for NSCLC.
We reported on the design and results of the CROWN study, in which lorlatinib was administered to patients not previously treated with ALK inhibitors, in one of our previous articles. Recently, a post hoc analysis of data from this study focusing specifically on the intracranial efficacy and safety of lorlatinib was published.
This analysis confirmed that lorlatinib suppresses the formation and development of metastases in the central nervous system (CNS). The cumulative incidence of CNS progression at 12 months was 1% in patients without brain metastases (BM) at the start of the study treated with lorlatinib, compared to 18% in those treated with crizotinib (hazard ratio [HR] 0.05; 95% confidence interval [CI] 0.01–0.42). Among patients with pre-existing BM, the incidence was 7% with lorlatinib and 72% with crizotinib (HR 0.07; 95% CI 0.02–0.24).
Adverse Effects of Treatment
Both lorlatinib and other ALK inhibitors that cross the blood-brain barrier can cause neuropsychiatric adverse effects in patients. Studies have described impacts on cognitive functions (memory, attention, orientation impairment), mood (anxiety, depression, mood swings, irritability), speech (articulation disorders, slowed speech), and the development of psychosis. The mechanism by which these AEs occur is not yet clear.
In the CROWN clinical trial, 35% of participants experienced neuropsychiatric adverse events. The incidence was slightly higher among patients with BM at the start of the study. The post hoc analysis indicated that affective disorders and psychotic symptoms appeared first (approximately 5-6 weeks into treatment), while cognitive problems and speech disorders emerged later (about 3 months). Most events were of mild intensity (grade 1; 62%) or moderate (grade 2; 29%). There were 6 more severe events (grade 3): confusion (in 2 individuals), cognitive disorder, irritability, bipolar disorder, and speech disorder.
Managing AEs
More than half (62%) of CNS adverse events did not require any medical intervention, and 53% of these events resolved spontaneously. Treatment was discontinued in 2 patients due to confusion. Dose adjustments (treatment interruption, dose reduction, or a combination of both) were made in 23% of cases. This approach has not yet affected the efficacy of treatment, but data are only available from short-term monitoring of patients with dose reduction (16 weeks), so they cannot be fully relied upon. However, it is possible that this result will be confirmed in the future, as phase I/II studies have shown that the objective response rate to treatment, including intracranial response, is not dependent on plasma concentrations of lorlatinib.
45% of neuropsychiatric adverse events that did not require treatment did not resolve. These events need to be addressed, and recommendations for their management need to be developed, even though the majority were of mild intensity. Their persistence adversely affects the daily life of the patient and their close ones. Although the post hoc analysis of the CROWN study found that the occurrence of neuropsychiatric symptoms did not negatively impact patients' quality of life, other research indicates that these AEs are not adequately monitored and reported in oncology by either patients or physicians.
Conclusion
Lorlatinib administered in the 1st line of treatment for ALK+ NSCLC provides a significant benefit in terms of high efficacy in both the CNS and outside it. It is suitable for patients with brain metastases at the start of treatment as well as those without them. The life extension that lorlatinib can provide must not come at the expense of its quality, and so it is essential to also address the issues of neuropsychiatric adverse effects of treatment. Studies so far indicate that about half of these adverse reactions resolve on their own without intervention, and the remaining part is well manageable with dose adjustments.
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Sources:
1. Solomon B. J., Bauer T. M., Ou S. H. I. et al. Post hoc analysis of lorlatinib intracranial efficacy and safety in patients with ALK-positive advanced non–small-cell lung cancer from the phase III CROWN study. J Clin Oncol 2022; 40 (31): 3593–3602, doi: 10.1200/JCO.21.02278.
2. Pérol M., Swalduz A. Lorlatinib in frontline therapy for ALK+ advanced non–small-cell lung cancer: still a matter of debate? J Clin Oncol 2022; 40 (31): 3564–3568, doi: 10.1200/JCO.22.00859.
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