Abstract
Purpose: Our study aimed to provide data on effectiveness, safety of crizotinib treatment, brain metastases, progression patterns, and sequential therapy beyond crizotinib treatment in patients with advanced ALK-positive NSCLC in China.Methods: We reviewed the medical records of crizotinib-treated NSCLC patients with ALK-rearrangement between May 2014 and May 2018 at Fudan University Shanghai Cancer Center. All patients received crizotinib with 250 mg twice daily. Main outcome measures were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), the second PFS (PFS2), overall survival (OS), and adverse events.Results: One hundred and four patients with ALK-positive NSCLC were included in this retrospective study. ORR and DCR were 82.7 and 98.1%, respectively. The estimated PFS and OS were 13.0 months (95% CI 9.0–17.0 months) and 36.0 months (95% CI 31.0–41.0 months), respectively. Multivariable analysis showed that young age, presence of baseline adrenal gland metastases and non-adenocarcinoma were independent predictive factors for poorer PFS. Presence of baseline adrenal gland metastases, non-adenocarcinoma, intrathoracic progression and shorter crizotinib treatment time were associated with worse OS. Patients without baseline brain metastases (BBM) who were administered with crizotinib as first-line therapy can achieve a significantly longer PFS than those who received crizotinib as second or later line therapy (p = 0.006). For patients with BBM receiving sequential therapy beyond the first disease progression after crizotinib treatment (1st PD), crizotinib beyond progressive disease (CBPD) plus local therapy can lead to a significantly longer PFS2 (67.0 vs. 21.0 weeks; p = 0.046). Additionally, the OS was significantly longer in patients achieving 1st PD who received CBPD plus local therapy than those who did not receive CBPD or local therapy (35.0 vs. 24.0 months, p = 0.041). Presence of brain metastases at any time was in association with worse PFS. No unexpected adverse effects were reported.Conclusions: Crizotinib was effective and well tolerated in Chinese patients with ALK-positive, advanced NSCLC in real-world clinical practice. For patients without BBM, crizotinib as first-line therapy can lead to a longer PFS than second-or later line therapy. CBPD plus local therapy after 1st PD beyond crizotinib is feasible and effective in clinical routine practice.
Highlights
Non-small-cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer [1]
Twenty-one patients who did not receive crizotinib, 4 patients who were treated with crizotinib combined with chemotherapy, 11 who were lost to follow-up and 8 who did not take crizotinib for at least 1 month, nor complete the tumor response assessment were excluded from the study
A total of 104 patients were eligible for our study, among whom 40 (38.5%) patients presented with baseline brain metastasis (BBM) at the initiation of crizotinib treatment and 64 (61.5%) patients did not have baseline brain metastasis (Non-BBM)
Summary
Non-small-cell lung cancer (NSCLC) accounts for 80-85% of all lung cancer [1]. Approximately 3–5% of NSCLC patients harbor a rearrangement of the ALK gene, resulting in ∼40,000 new cases worldwide per year [2]. In 2007, Soda et al firstly discovered the ALK gene rearrangement with ELM leading to an in-frame fusion protein with oncogenic activity in vitro in NSCLC [3]. Crizotinib, the multitargeted mesenchymal-epithelial transition/hepatocyte growth factor receptor (MET)/ALK/c-ros oncogene 1 (ROS1) inhibitor, was approved initially by the US Food and Drug Administration (FDA) in 2011 for the treatment of advanced ALK-positive NSCLC based on phase I (profile 1001) and phase II (profile 1005) clinical trials that demonstrated significant ORRs of ∼60% and improved PFS of 8 months in pretreated ALK-positive patients [7, 8]. Two randomized phase III trials (PROFILE 1014 and 1007) compared crizotinib with standard chemotherapy, leading to full approval for crizotinib as the standard first-line therapy for advanced ALK-positive NSCLC in 2015 [9, 10]. Crizotinib was approved by China food and drug administration (CFDA) for ALK-positive patients in January 2013
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