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Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression

Rui-Lian Chen¹, Jun Zhao², Xu-Chao Zhang¹

¹Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080, China.

|November 28, 2018

Abstract

Objective:

Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression.

Methods:

Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression.

Results:

Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2.

Conclusions:

C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.

Insights

Crizotinib shows promising efficacy in advanced non-small-cell lung cancer (NSCLC) patients with both anaplastic lymphoma kinase (ALK) rearrangement and c-Met overexpression. This targeted therapy may offer improved outcomes for this specific NSCLC patient subgroup.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) effective against anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) pathways.
ALK rearrangements are known drivers in a subset of non-small-cell lung cancer (NSCLC).
The role of concurrent c-Met overexpression in ALK-rearranged NSCLC treated with crizotinib requires further investigation.

Purpose of the Study:

To evaluate the efficacy of crizotinib in advanced NSCLC patients presenting with both ALK rearrangement and c-Met overexpression.
To compare treatment outcomes between ALK-rearranged NSCLC patients with and without c-Met overexpression.

Main Methods:

Screening of 4622 advanced NSCLC patients for ALK rearrangement using IHC, RACE-coupled PCR, or FISH.
Assessment of c-Met expression via IHC in ALK-rearranged patients, defining overexpression as >50% cells with high staining.
Analysis of crizotinib efficacy, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in ALK-rearranged patients with or without c-Met overexpression.

Main Results:

C-Met overexpression was identified in 10.0% (16/160) of ALK-rearranged NSCLC patients.
The ORR for crizotinib was significantly higher in patients with c-Met overexpression (86.7%) compared to those without (59.4%; P=0.041).
Median PFS showed a trend towards superiority in the c-Met overexpression group (15.2 vs. 11.0 months), and median OS was significantly longer (33.5 months) in this group.

Conclusions:

C-Met overexpression co-occurs with ALK rearrangement in a small subset of advanced NSCLC.
Crizotinib demonstrates a trend towards favorable efficacy in advanced NSCLC patients with concomitant ALK rearrangement and c-Met overexpression.
These findings suggest potential benefit of targeting both ALK and MET pathways in specific NSCLC populations.

Read full analysis

Keywords:

Anaplastic lymphoma kinase C-Met, overexpression Mesenchymal epithelial transition Non-small-cell lung cancer Rearrangement

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