Computational Systems Biology Methods and Protocols.7z

two phase III trials showed that crizotinib was superior to first- and

second-line cytotoxic chemotherapy in advanced ALK-rearranged

NSCLC [72, 73]. The promising result was that the objective

response rate (ORR) in ALK-positive NSCLC patients ranged from

60 to 74%, with median progression-free survival (PFS) of 8–-

11 months across all crizotinib trials. In addition, two second-

generation ALK inhibitors, ceritinib and alectinib, thereafter,

received accelerated approval for patients with ALK-positive

NSCLC previously treated with crizotinib. In the phase I

ASCEND-1 trial, ceritinib demonstrated an ORR of 56% and

median PFS of 6.9 months in crizotinib-pretreated patients with

ALK-rearranged NSCLC [68, 71]. In two phase II studies, alectinib

induced objective responses in50% of crizotinib-resistant NSCLCs

with ALK rearrangement, in which median PFS in both studies was

8–9 months [69, 70]. Brigatinib, another second-generation inhibi-

tor, has been associated with confirmed ORR of 62% and median

Table 2
First-, second-, and third-generation ALK TKIs

Drug Indications Targets Approval

First

generation

ALK-TKI

Crizotinib XALKORI Metastatic NSCLC whose

tumors are ALK-positive as

detected by an FDA-

approved tests. Metastatic

NSCLC whose tumors are

ROS1-positive.

MET

amplification,

14 exon

skipping ROS 1

fusion and ALK

fusion

2011

Second

generation

ALK-TKI

Ceritinib ZYKADIA ALK-positive metastatic

NSCLC who have

progressed on or are

intolerant to crizotinib.

ALK fusion 2014

Alectinib ALECENSA ALK-positive, metastatic

NSCLC who have

progressed on or are

intolerant or crizotinib.

ALK fusion 2015

Brigatinib ALUNBRIG ALK-positive metastatic

NSCLC who have

progressed on or are

intolerant to crizonitib.

ALK fusion 2017

Third

generation

ALK-TKI

Lorlatinib FDA grants Lorlatinib

breakthrough therapy

designation for the

treatment of patients with

ALK-positive metastatic

NSCLC who were

previously treated with one

or more ALK inhibitors.

ALK fusion 2017

The Introduction and Clinical Application of Cell-Free Tumor DNA 59