Lorlatinib significantly improved progression-free survival compared with crizotinib in the first-line treatment of patients with advanced ALK-positive non–small cell lung cancer (NSCLC), according to a planned interim analysis of the phase III CROWN trial presented at the European Society for Medical Oncology (ESMO) Virtual Meeting 2020.1
Ben Solomon, MD
“Lorlatinib resulted in a significantly longer progression-free survival, significantly higher overall and intracranial response rates, and improved global quality of life compared with crizotinib as first-line treatment for ALK-positive NSCLC. Safety was similar to that reported in previous studies. These results support the use of lorlatinib as an effective first-line therapy for patients with advanced ALK-positive NSCLC,” said lead study author Ben Solomon, MD, of Peter MacCallum Cancer Centre, Melbourne.
“These data sets are amazing with absolutely astonishing results,” said ESMO President Solange Peters, MD, PhD, who moderated the session where Dr. Solomon presented the CROWN trial results. Dr. Peters is a medical oncologist at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
ALK rearrangements occur in an estimated 3% to 7% of NSCLCs, and tumors with these alterations are sensitive to small-molecule ALK tyrosine kinase inhibitors. Crizotinib was the first ALK inhibitor to be approved for the treatment of ALK-positive NSCLC and set the standard. Lorlatinib is a third-generation ALK tyrosine kinase inhibitor with overall and intracranial activity in ALK-positive NSCLC.
Study Details
The CROWN study included patients with stage IIIB/IV ALK-positive NSCLC who have had no prior treatment of metastatic disease. Asymptomatic treated or untreated central nervous system (CNS) metastases were allowed. A total of 296 patients from 104 study sites in 23 countries were randomly assigned 1:1 to treatment with lorlatinib at 100 mg/d (n = 149) or crizotinib at 250 mg twice daily (n = 147). All patients underwent restaging CT scans and brain imaging every 8 weeks.
Solange Peters, MD, PhD
As of data cutoff for the interim analysis, 103 patients treated with lorlatinib and 31 patients with crizotinib remained on study treatment. The median follow-up for the primary endpoint of progression-free survival was 18.3 months for lorlatinib and 14.8 months for crizotinib.
For the primary endpoint of progression-free survival by blinded independent central review, median progression-free survival was not reached with lorlatinib vs 9.3 months with crizotinib (P < .001). The 12-month progression-free survival was 78% with lorlatinib vs 39% with crizotinib.
The objective response rate by blinded independent central review was 76% vs 58%, respectively. The median duration of response was not evaluable in the lorlatinib group vs 11 months in the crizotinib group. The median time to response was 1.8 months in both groups.
Intracranial Response Rates
“Lorlatinib has the ability to delay progression of existing brain metastases and also to prevent the development of new brain metastasis in patients with ALK-positive NSCLC,” Dr. Solomon stated.
The intracranial objective response by blinded independent central review was 66% with lorlatinib and 20% with crizotinib among those with nonmeasurable brain metastasis; among those with measurable brain metastasis, the intracranial objective response by blinded independent central review was 82% and 23%, respectively. The median time to CNS progression by blinded independent central review was not evaluable in the lorlatinib group vs 16.6 months in the crizotinib group (P < .001).
Overall survival was not evaluable in either group. Even though the survival data are immature, there was an observed trend for a 28% improvement in survival, Dr. Solomon noted.
Safety and Tolerability
Safety and tolerability were comparable in both groups. Almost all patients in both groups had an adverse event of any grade. Grades 3 and 4 adverse events were reported in 72% and 56%, respectively. Serious adverse events occurred in 34% and 27%, respectively. Fatal adverse events occurred in seven patients in each treatment arm. Adverse events leading to treatment discontinuation occurred in 7% and 9%, respectively. Temporary dose interruptions were required in 49% and 47%, respectively.
“Although grade 3 and 4 adverse events were more frequent with lorlatinib, the majority were laboratory abnormalities that were asymptomatic and readily managed,” Dr. Solomon stated.
KEY POINTS
- Interim analysis of the phase III CROWN study showed superior progression-free survival with lorlatinib over crizotinib in ALK-positive advanced NSCLC.
- Lorlatinib appeared to have the advantage over crizotinib in terms of superior intracranial responses, but it has a unique side-effect profile among ALK inhibitors.
- Further study is needed to determine best use of available ALK inhibitors in ALK-positive NSCLC.
Hypercholesterolemia, elevated triglyceride levels, edema, weight gain, peripheral neuropathy, and cognitive effects were more common with lorlatinib, whereas diarrhea, fatigue, vision disorder, increased liver enzyme levels, and nausea/vomiting were more common with crizotinib.
According to global quality-of-life scores on the European Organisation for the Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, patients taking lorlatinib maintained their quality of life throughout treatment, whereas for those taking crizotinib, quality of life deteriorated over the course of the study.
DISCLOSURE: Dr. Solomon has received honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche/Genentech; has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Loxo, Merck Sharp & Dohme, and Roche/Genentech; has served as an institutional consultant or advisor to Pfizer; has received institutional research funding from Pfizer; and has received royalties from UpToDate and Veristrat. Dr. Peters has received institutional honoraria from AstraZeneca, Bristol Myers Squibb, Illumina, MSD, Novartis, Pfizer, Roche, and Takeda; has served as a consultant or advisor to AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo, Debiopharm, Illumina, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Pfizer, Pharma Mar, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, and Vaccibody; has received institutional research funding from Amgen, AstraZeneca, Biodesix, Bristol Myers Squibb, Boehringer Ingelheim, Illumina, Iovance, Lilly, Merck Serono, MSD, Novartis, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb, Incyte, MSD, Roche, and Sanofi.
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