This is a phase II, multi-center, single arm study of lorlarinib as a single agent in patients with ROS1-rearranged advanced NSCLC.

ROS1 rearrangement characterizes a small subset (1-2%) of non-small cell lung cancer (NSCLC) and is associated with light or never smoking patients and adenocarcinoma histology. Recently, ROS1 inhibitors such as crizotinib and ceritinib demonstrated significant efficacy in ROS1 rearranged NSCLC. Thus, identification of ROS1 rearrangement in NSCLC is mandatory to permit ROS1 targeted therapy. However, current guidelines either do not refer to ROS1 testing or mention it briefly without making any strong recommendation. The detection of ROS1rearrangement is based on in situ (immunohistochemistry [IHC], fluorescence in situ hybridization [FISH]) and extractive non-in situ assays. While FISH still represents the gold standard in clinical trials, this technique may fail to recognize rearrangements of ROS1 with some gene fusion partner. On the other hand, IHC is the most cost-effective screening technique, but it seems to be characterized by low specificity. Extractive molecular assays are expensive and laborious methods, but they specifically recognize almost all ROS1 fusions using a limited amount of mRNA even from formalin-fixed, paraffin-embedded tumor tissues. Recently, Korean Heath Insurance Review and Assessment Service (HIRA) approved next generation sequencing (NGS)-based target sequencing for NSCLC patients, which may facilitate the detection of ROS1 rearrangement in Korean patients with advanced NSCLC.

Lorlatinib is a new, potent, brain-penetrant, ATP-competitive small molecule inhibiter of ALK/ROS1. However, the objective response rate (ORR) was 17/47 (36.2%; 95% CI 22.7, 51.5) in ROS1 arm of B7461001 study, but this result may not represent the ORR of lorlatinib as a 1st line treatment since 53% had central nervous system involvement at baseline and 72% of patients had received prior crizotinib. Therefore, given the activity of lorlatinib in ROS1 rearranged lung cancer, The investigator will investigate the efficacy of lorlatinib in ROS1 inhibitor-naïve patients with ROS1- rearranged NSCLC. The investigator will also investigate the efficacy according to fusion partners and resistance mechanisms. Finally, The investigator will compare the concordance among diagnostic tests including FISH, IHC and NGS-based target sequencing and provide the clinical guidance for diagnosis of ROS1 rearrangement in NSCLC.

4.1. Inclusion criteria

1. Metastatic or recurrent NSCLC with ROS1 rearrangement identified by NGS-based target sequencing
2. Treatment naïve or one prior systemic treatment with platinum doublet chemotherapy
3. At least one measurable disease lesion according to RECIST 1.1
4. ECOG performance status 0-2
5. Age ≥ 18 years
6. Adequate hematologic, hepatic, and renal function
7. Written informed consent

4.2. Exclusion criteria

1. Life expectancy of less than 12 weeks
2. Prior treatment with a ROS1 inhibitor
3. Symptomatic uncontrolled brain metastasis
4. Other malignancy within 5 years, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
5. Uncontrolled intercurrent illness
6. Pregnancy or unwillingness to use effective birth control
7. Known hypersensitivity to lorlatinib and/or its excipients