Lorlatinib ‘highly effective’ as first-line therapy for ALK-positive NSCLC
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Lorlatinib appeared superior to crizotinib as first-line treatment for advanced ALK-positive non-small cell lung cancer, according to an interim analysis of the randomized phase 3 CROWN study presented at ESMO Virtual Congress 2020.
Patients assigned lorlatinib (Lorbrena, Pfizer) achieved longer PFS and were more likely to achieve objective or cranial response. Lorlatinib also was associated with improvements in patient-reported quality of life, results showed.
“ALK rearrangements are found in about 3% to 5% of NSCLCs and result in sensitivity to ALK tyrosine kinase inhibitors. However, acquired resistance to treatment and disease progression, particularly in the brain, remain problematic,” Benjamin Solomon, MBBS, PhD, FRACP, consultant medical oncologist at Peter MacCallum Cancer Center in Australia, said during his presentation.
Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK inhibitor approved for patients previously treated with ALK TKIs.
The open-label, multicenter CROWN study compared lorlatinib with the ALK inhibitor crizotinib (Xalkori; Pfizer, EMD Serono) as first-line treatment for advanced ALK-positive NSCLC. All 296 patients had stage IIIB to stage IV disease and ECOG performance status of 0 to 2.
Solomon and colleagues randomly assigned patients to 100 mg lorlatinib once daily (n = 149) or 250 mg crizotinib twice daily (n = 147). Investigators stratified patients based upon presence of central nervous system metastases and ethnicity.
PFS as measured by blinded independent central review per RECIST v1.1 served as the primary endpoint. Secondary endpoints included PFS by investigator review, objective response rate by investigator and blinded independent central review, intracranial response rate, OS, safety and quality of life as assessed by the EORTC quality-of-life questionnaire.
Five patients in the crizotinib group did not receive treatment but were included in the intention-to-treat-population.
At data cutoff, researchers observed 133 PFS events.
Median duration of follow-up for PFS was 18.3 months with lorlatinib and 14.8 months with crizotinib.
Results showed lorlatinib significantly improved PFS compared with crizotinib by blinded independent central review (median, not estimable vs. 9.3 months; HR = 0.28; 95% CI, 0.19-0.41), with 1-year PFS rates of 78% (95% CI, 70-84) vs. 39% (95% CI, 30-48).
Investigator-assessed PFS also showed benefit with lorlatinib (median, not estimable vs. 9.1 months; HR = 0.21; 95% CI, 0.14-0.31). One-year PFS rates were 80% (95% CI, 73-86) vs. 35% (95% CI, 27-43).
“The benefit of lorlatinib over crizotinib was consistently observed across all prespecified subgroups. The HR for PFS was 0.2 among patients with brain metastases vs. 0.32 among those without brain metastases,” Solomon said.
Moreover, ORR by blinded independent central review was significantly higher with lorlatinib (76% vs. 58%). Median duration of response was not reached with lorlatinib vs. 11 months (95% CI, 9-12.9) with crizotinib.
Confirmed intracranial ORR by blinded independent central review of MRI scans was significantly higher with lorlatinib among patients with measurable and immeasurable brain metastases at baseline (66% vs. 20%; OR = 8.41; 95% CI, 2.59-27.23), as well as among those with measurable brain metastases (82% vs. 23%; OR = 16.83; 95% CI, 1.95-163.23).
“The intracranial complete response rate to lorlatinib in patients with measurable brain metastases was a remarkable 71%, and the time to progression was improved with a remarkable HR of 0.07 that was highly statistically significant,” Solomon said. “These data indicate the ability of lorlatinib not only to delay progression of existing brain metastases, but also to prevent the development of new brain metastases in patients with ALK-positive NSCLC.”
Although OS data were immature at the time of data cutoff for the interim analysis, the HR for OS was 0.72 (95% CI, 0.41-1.25) in favor of lorlatinib.
A higher percentage of lorlatinib-treated patients experienced grade 3 to grade 4 adverse events that required treatment discontinuation (73% vs. 56%). The most common grade 3 to grade 4 adverse events among lorlatinib-treated patients included asymptomatic elevations of cholesterol and triglycerides, Solomon said.
Patient-reported outcomes showed significantly greater improvement in baseline global quality of life among patients treated with lorlatinib.
“Compared with crizotinib, lorlatinib significantly improved PFS, resulted in higher overall intracranial response rates and improved global quality of life in first-line, treatment-naive, ALK-positive NSCLC,” Solomon said. “Notably, lorlatinib showed substantial intracranial activity, including high responses rates and longer time to intracranial progression. These results of the CROWN study support the use of lorlatinib as a highly effective first-line therapy for [this population of patients].”
Perspective
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Christine M. Lovly, MD, PhD
The results of the CROWN study by Solomon and colleagues are wonderful news and I look forward to seeing even more data from this trial in the future.
The care of patients with lung cancer in 2020 involves a complex array of biomarker assessments that help us inform care, and ALK is one of those biomarkers. ALK rearrangements are found in approximately 5% of all NSCLC cancers, typically but not always in never-smokers and adenocarcinoma. Importantly, research has now shown that patients who have ALK rearrangements within their tumors derive significant benefit from ALK TKI therapy. Lorlatinib was strategically designed to have high potency and selectivity against ALK, to be efficacious against ALK kinase mutations and to be highly CNS-penetrant.
As we treat patients for longer durations with these agents, it is important that we consider the toxicity profile. In this study, multiple patients experienced asymptomatic elevations of cholesterol and triglycerides, but these lipid effects are quite common and exclusive with lorlatinib. Neurocognitive effects also can occur with administration of lorlatinib, although they are less common than the cholesterol issues.
Among the questions we need to address to continue to push the efficacy of ALK TKI therapy and to best help our patients is whether we can crown a victor across all ALK TKIs. We have multiple options for first-line ALK TKI therapy, but how do we continue to move the needle? I would strongly argue that we need to make sure all patients are molecularly tested for ALK mutations and for all actionable biomarkers in lung cancer. We also need to increase representation in clinical trials for ALK mutations and beyond in lung cancer.
Further, we need to think about survivorship care issues so that we are not only treating the cancer but also ensuring that quality of life remains high.
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Solomon B, et al. Abstract LBA2. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
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