Outcomes of ALK positive lung cancer patients treated with crizotinib or second-generation ALK inhibitor: a monoinstitutional experience

Elisa De Carlo,Valentina Da Ros,Sandra Santarossa,Eleonora Berto,Alessandra Bearz,Lucia Fratino,Emanuela Chimienti,Maria Chiara Del Savio,Jerry Polesel

doi:10.18632/oncotarget.24573

Abstract

Rearrangement in the anaplastic lymphoma kinase (ALK) gene is one of the oncogenic drivers in non-small cell lung cancer (NSCLC) patients.Several ALK inhibitors (ALKis) have been developed and have demonstrated their efficacy, however the best treatment strategy for ALK positive NSCLC patients has yet to be determined. Our retrospective study has investigated the outcome of 40 ALK-rearranged NSCLC patients treated with two different sequential strategies in our Institute; a “classical group”, treated with crizotinib followed by second or third generation ALKis, and the “experimental group”, treated upfront with a second generation ALK inhibitor. The primary endpoints investigated were Progression-free survival (PFS) and intracranial activity. The analysis has revealed a significant improvement in PFS (p = 0.050) in the experimental group, furthermore none of these patients developed brain metastasis. There was no statistically significant difference in OS, but all patients in the experimental group were still alive after a median follow up of 15 months. Our retrospective analysis suggests that systemic and intracranial efficacy tends to be better in the experimental group; randomized prospective studies could confirm our observations.

Highlights

The echinoderm microtubule-associated proteinlike 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified for the first time in 2007 in a 62 year-old male patient with lung adenocarcinoma, ALKrearrangements serve as a key oncogenic driver that occur in 3%–7% of patients with non-small cell lung cancer (NSCLC) [1, 2]
The temporal availability of crizotinib followed by second or third generation ALK inhibitors (ALKis) led to a majority of patients treated with this sequence, which we indicate with the term “classical group”; more recently some patients started their ALK inhibition directly from a second generation ALK inhibitor, due to the opportunity of a clinical trial, leading to a different sequencing, which we call “experimental group”
We evaluated the treatment and outcomes of 40 ALK-rearranged NSCLC patients treated in 5 years in a single Italian Institution; most of the patients have been treated into clinical trials or in expanded access programs, because in Italy crizotinib has been the only ALK inhibitor available up to now

Summary

Introduction

The echinoderm microtubule-associated proteinlike 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified for the first time in 2007 in a 62 year-old male patient with lung adenocarcinoma, ALKrearrangements serve as a key oncogenic driver that occur in 3%–7% of patients with NSCLC [1, 2]. NSCLC tumors harboring the EML4-ALK fusion transcript are sensitive to ALK tyrosine kinase inhibitors (ALK-TKIs). In the PROFILE-1014 PFS was 10.9 months and RR was 74%, with crizotinib over platinumbased chemotherapy [4]. Based on these results, crizotinib received approval from Food and Drug Administration (FDA) and European Medicines Agency (EMA) for first-line treatment of ALK-positive patients. Most of the patients develop resistence to crizotinib and a disease progression within one year of the onset of the therapy [4]

Methods

Results

Conclusion