A Study of LDK378 in Patients With Non-small Cell Lung Cancer Harboring ROS1 Rearrangement
Status:
Unknown status
Trial end date:
2020-10-01
Target enrollment:
Participant gender:
Summary
Lung cancer is the most leading cause of cancer-related mortality worldwide. Most of the
patients with lung cancer are advanced stage at the time of diagnosis.
The two oncogenes that are important in lung cancer are epidermal growth factor receptor
(EGFR) and K-ras, mutated in 10% and 15% of non-small cell lung cancer (NSCLC) patients.
Large-scale DNA sequencing efforts have identified mutations in BRAF, PI3KCA and ERBB2 that
together represent another 5% of NSCLC patients. The success of EGFR tyrosine kinase
inhibitors (TKIs), such as gefitinib or erlotinib, and more recently ALK/MET TKI, crizotinib,
highlights the need to develop more genetically matched therapies. Therefore, genetic
classification of lung cancer has become increasingly important along with the advances with
targeted therapies.
ROS1 is a receptor tyrosine kinase with constitutive kinase activity. ROS1 was previously
discovered in cell lines where ROS1 fused with other proteins to act as a driver oncogene. In
2007, Rikova et al reported ROS1 fusion as driver mutations in NSCLC cell line (HCC78;
SLC34A2-ROS1) and NSCLC patient (CD74-ROS1). Li et al also found about 1% of samples
harboring CD74-ROS1 fusion in 202 resected lung adenocarcinomas from never smokers. The
incidence was as high as 10% in East Asian population. Currently there are now at least 13
ROS1 fusion variants involving 8 fusion partners (CD74-, SLC34A2-, FIG-, TPM3-, SDC4-,
LRIG3-, ERZ-, KDERL2-) identified in ROS1 positive NSCLC.
Interestingly, preclinical and clinical data have shown ROS1-positive tumors are sensitive to
crizotinib, because of potentially high common amino acid residues in the kinase domain
between ALK and ROS1, which explain why crizotinib can inhibit both ROS1 and ALK to similar
extent. Preliminary report from a phase I clinical trial of crizotinib in the ROS1-positive
NSCLC expansion cohort showed an overall response rate (ORR) of 57%. Given that crizotinib
has made remarkable clinical outcomes in phase I trial of ALK-positive NSCLC patients,
clinical development of ROS1 inhibitors, including crizotinib, should be accelerated to
provide targeted therapies to ROS1-positive NSCLC patients.