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June 12, 2024
The results of the 5-year follow-up to the CROWN study have shown the promise of using the third-generation tyronise kinase inhibitor (TKI) lorlantinib (Lorbrena) for patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Study authors say it provided the longest progression-free survival (PFS) that has ever been reported in advanced lung cancer.
The research was presented at this year’s American Society of Clinical Oncology (ASCO) conference and simultaneously published in the Journal of Clinical Oncology. In this trial, patients with newly diagnosed advanced ALK-positive NSCLC were randomized to receive either lorlatinib (Lorbrena) or crizotinib (Xalkori).
Lorlatinib is a third-generation brain-penetrant tyrosine kinase inhibitor (TKI) which was initially approved by the FDA in November 2018 in second- and third-line setting — the CROWN study evaluates its efficacy in the frontline setting.
Previous reports of the CROWN study had also been quite promising. In the most recent previous publication of the results, lorlatinib continued to show superiority over crizotinib regardless of the presence of brain metastases at diagnosis. With 36.7 months of follow-up, progression-free survival was not reached (NR) for lorlatinib, and time to intracranial progression was also longer. Lorlatinib thus received FDA-approval as a frontline treatment in March 2021.
“It is encouraging that the upfront benefits of lorlatinib over crizotinib continue for several years in more than half the patients. It also is encouraging that patients receiving lorlatinib had much fewer incidences of brain metastasis, which can be devastating,” Dr. Leslie Busby, a medical oncologist at Rocky Mountain Cancer Centers, told SurvivorNet.
The Data
In the trial patients were randomized 1:1 to receive lorlatinib 100 mg once daily (n=149) or crizotinib (n=147) 250 mg twice daily in 28-day cycles as the first treatment after diagnosis with advanced ALK+ NSCLC. The primary endpoint was PFS and the key secondary endpoint was overall survival (OS), which will be analyzed in the future at the protocol-specified second interim analysis (after at least 139 deaths have occurred). The present study was a post hoc analysis and it is important to note that efficacy was by investigator assessment only rather than by blind independent central review, as this only occurred through the first three years per the protocol.
The median follow-up was 60.2 months in the lorlatinib group and 55.1 months in the crizotinib group. The PFS hazard ratio (HR) for lorlatinib vs. crizotinib was 0.19 (95% confidence interval [CI] 0.13, 0.27). Median PFS was NR for lorlatinib and 9.1 months (95% CI 7.4, 10.9) with crizotinib. Five-year PFS was 60% (95% CI 51, 68) among patients who received lorlatinib as compared to only 8% (95% CI 3, 14) among patients who received crizotinib.
The study authors commented that this was the longest PFS to ever been reported in advanced NSCLC.
The PFS benefit seen in the lorlatinib group extended both to patients with and without brain metastases. Among 73 patients with brain metastases at baseline, the PFS HR was 0.08 (95% CI 0.04, 0.19). The PFS HR was 0.24 (95% CI 0.16, 0.36) among patients without baseline brain metastases.
Similarly, the time to intracranial progression was also substantially longer in patients that received lorlatinib with a HR of 0.06 (95% CI 0.03, 0.12). The median time to intracranial progression was NR for lorlatinib (95% CI NI, NI) vs. 16.4 months (95% CI 12.7, 21.9) with crizotinib.
Among the 114 patients assigned to lorlatinib who did not have brain metastases at time of diagnosis, only 4 (3.5%) patients went on to develop brain metastases during the five years of available follow-up time.
Lorlatinib’s Safety Profile
The overall safety profile of lorlatinib was consistent with previous analyses of the drug, and no new concerning safety signals were detected.
The rate of adverse events during the study period was higher in patients who received lorlatinib as compared to those who received crizotinib (77% vs. 57%, respectively, for grade 3/4 adverse events). More patients in the lorlatinib group developed hypertriglyceridemia (25% vs. 0%), hypercholesterolemia (21% vs. 0%), weight gain (23% vs. 2%) and hypertension (12% vs. 1%), but the rate of cardiovascular adverse events was similar in both groups at 28%.
For patients receiving lorlatinib vs. crizotinib, all cause adverse events lead to dose reduction in 23% vs. 15%, respectively, temporary treatment discontinuation in 62% vs. 48%, and permanent discontinuation in 11% vs. 11%. The authors carried out a post hoc analysis examining patients receiving lorlatinib who had a dose reduction in the first 16 weeks of treatment with those who did not. There did not appear to be any determinantal effect on PFS or time to intracranial progression.
Dr. Busby explained that the new data on lorlatinib means doctors treating patients with this specific type of NSCLC have an exciting new treatment in their tool kit.
“There are now three ALK inhibitors that have shown benefit over crizotinib in first line ALK positive NSCLC: lorlatinib, alectinib, and brigatinib,” Dr. Busby explained. “Most physicians were moving away from using crizotinib first line prior to this abstract. However, those decision were made before long term data was widely available and this helps support that decision.”
“One issue that is a challenge to determine is with three highly effective drugs, which one is the best both in terms of efficacy AND toxicity,” he added.
There are no direct comparisons of the complication profiles of the three drugs, and cross-trial comparisons are known to be problematic, Dr. Busby said.
He explained that it’s important to await additional data on patients’ overall survival (OS) to assess the true benefit of using lorlatinib over other available TKIs.
“Due to problems around using PFS as the primary outcome, I am interested to see if this benefit ends up improving overall survival,” he said, adding that if a smaller-than-anticipated difference in overall survival is seen in the future, it could be because some patients in the crizotinib arm may have received lorlatinib after crizotinib was stopped, a clinical trial phenomenon known as crossover.
Finally, Dr. Busby noted that these data raise numerous interesting questions that will hopefully be explored in future studies.
“With many patients doing so well for so long, future questions to look at include whether there are patients with such a good response that they can safely stop the drug. Another question is whether adding these drugs to another active therapy such as immunotherapy will deepen the response and allow coming off therapy. Essentially, are there patients we are able to cure?”