SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
The discovery of chromosomal rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, and their sensitivity to ALK inhibitors, paved the way to the development of small-molecule ALK Tyrosine Kinase Inhibitors. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET, NTRK and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.
ALK inhibitors include first-generation XALKORI® (Crizotinib) and second-generation ALK inhibitors such as ZYKADIA® (Ceritinib), ALECENSA® (Alectinib) and ALUNBRIG® (Brigatinib). Despite the improved efficacy of second-generation ALK inhibitors, recurrent disease due to drug resistance including CNS disease progression can still develop.
Lorlatinib (LORBRENA®) is a novel third-generation ALK inhibitor that is more potent than second-generation inhibitors, and has the broadest coverage of ALK resistance mutations that have been identified. Lorlatinib crosses the blood-brain barrier and has marked intracranial activity in previously treated patients with baseline CNS disease, including leptomeningeal disease.
The CROWN study is an ongoing, multicenter, global, open-label, randomized Phase III trial, conducted to compare the efficacy and safety of Lorlatinib versus Crizotinib in treatment-naive patients with advanced Stage IIIB/IV or recurrent ALK-positive NSCLC. In this study, 296 eligible patients were randomly assigned 1:1 to receive Lorlatinib 100 mg orally once daily (N=149) versus Crizotinib 250 mg orally twice daily (N=147) in cycles of 28 days. Treatment was continued until disease progression or unacceptable toxicities. Eligible patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay. Patients with asymptomatic treated or untreated CNS metastases were eligible and had to have at least one extracranial measurable target lesion that had not been previously irradiated. Patients were stratified according to the presence of brain metastases and ethnic group (Asian or non-Asian) and crossover between the treatment groups was not permitted. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included independently assessed Overall Survival (OS), Objective Response Rate (ORR) and intracranial objective response, time to intracranial progression, Duration of Response, and duration of intracranial response. At a planned interim analysis, treatment with Lorlatinib resulted in statistically significant and clinically meaningful improvement in PFS as assessed by BICR, with a Hazard Ratio of 0.28 (P<0.001), corresponding to a 72% reduction in the risk of disease progression or death. The median PFS was Not Reached in the Lorlatinib arm and was 9.3 months for those treated with Crizotinib. Based on these results, the FDA in 2021, the FDA granted regular approval to Lorlatinib for patients with previously untreated, advanced metastatic NSCLC, whose tumors are ALK-positive.
Given that the median PFS was Not Reached (NR) after 3 years of follow-up, the researchers conducted this post hoc analysis of the Phase III CROWN study, to evaluate the long-term outcomes of Lorlatinib versus Crizotinib at the clinically meaningful landmark follow-up of 5 years, and updated investigator-assessed efficacy outcomes, safety, and biomarker analyses.
With a median follow-up for PFS of 60.2 months for Lorlatinib and 55.1 months for Crizotinib, the median PFS was Not Reached (NR) with Lorlatinib after 5 years and was 9.1 months with Crizotinib (HR=0.19; 95% CI 0.13 to 0.27), The 5-year PFS was 60% and 8% respectively. This represents the longest reported PFS with any molecular targeted therapy in advanced NSCLC and across metastatic solid tumors. The median time to intracranial progression was NR with Lorlatinib and 16.4 months with Crizotinib (HR=0.06; 95% CI, 0.03 to 0.12). New ALK resistance mutations were not detected in circulating tumor DNA collected at the end of Lorlatinib treatment.
The confirmed ORR by investigator assessment was 81% with Lorlatinib and 63% with Crizotinib and the median Duration of Response was NR and 9.2 months respectively. In patients with measurable and/or nonmeasurable baseline brain metastases, intracranial objective response was also greater with Lorlatinib than with Crizotinib (60% versus 11%, respectively) and intracranial complete response was reported in 49% and 5% of patients, respectively. The median duration of intracranial response was NR with Lorlatinib and 12.8 months with Crizotinib.
Treatment related Grade 3-4 adverse events were noted in 66% of patients in the Lorlatinib group and 39% of patients in the Crizotinib group leading to dose reduction in 21% and 13% respectively. However, dose reduction did not impact median PFS or time to intracranial progression in these patients.
In summary, the CROWN study represents a pivotal trial that establishes Lorlatinib as a milestone in ALK-targeted therapy, providing unprecedented Progression Free Survival and intracranial efficacy in treatment-naive patients with advanced ALK-positive NSCLC, setting a new standard in the treatment landscape of this disease. Overall Survival data were not mature at the time of this analysis and continued research into optimal sequencing of ALK inhibitors and exploration of biomarkers are essential to predict treatment response and resistance.
Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. Solomon BJ, Liu G, Felip E, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA8503). DOI:10.1200/JCO.2024.42.17_suppl.LBA8503
