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      Lorlatinib in ALK- or ROS1-rearranged non-small cell lung cancer: an international, multicenter, open-label phase 1 trial

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          Most patients with ALK- or ROS1-rearranged non-small cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the central nervous system (CNS). This study aimed to determine the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK/ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK- or ROS1-positive NSCLC.


          In this ongoing, multicenter phase 1 study, eligible patients had advanced ALK- or ROS1-positive NSCLC. Lorlatinib was orally administered at doses ranging from 10–200 mg once daily or 35–100 mg twice daily. For some patients, tumor biopsy was performed before lorlatinib treatment to identify ALK resistance mutations. Safety was evaluated in patients who received ≥1 treatment; efficacy was evaluated in the intention-to-treat population (patients who received ≥1 dose of study treatment and were positive for either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities (DLTs) during cycle 1; secondary endpoints included safety, pharmacokinetics, and overall response rate (ORR). This study is registered with ClinicalTrials.gov, NCT01970865.


          Fifty-four patients were treated, including 41 with ALK-positive and 12 with ROS1-positive NSCLC. Twenty-eight patients had received ≥2 TKIs, and 39 patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolemia (39 [72%] of 54 patients), hypertriglyceridemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral edema (21 [39%] of 54 patients). One DLT occurred at 200 mg (failure to deliver at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, in this case grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected to be 100 mg daily. Among ALK-positive patients, the ORR was 19 (46%) of 41 patients (95% CI, 31–63%); among those who had received ≥2 TKIs, the ORR was 11 (42%) of 26 patients (95% CI, 23–63%). Among ROS1-positive patients, including seven crizotinib-pretreated patients, ORR was 6 (50%) of 12 patients (95% CI, 21–79%). Responses were observed in the CNS and in patients with tumors harboring resistance mutations such as ALK G1202R.


          In this phase 1, dose-escalation study, lorlatinib demonstrated both systemic and intracranial activity in patients with advanced ALK- or ROS1-positive NSCLC, most of whom had CNS metastases and had failed ≥2 TKIs. Therefore, lorlatinib may represent an effective therapeutic strategy for patients who have become resistant to currently available TKIs, including second-generation ALK TKIs in ALK-positive NSCLC.



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          Most cited references 20

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          Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

          Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
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            ROS1 rearrangements define a unique molecular class of lung cancers.

            Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase gene have recently been described in a subset of non-small-cell lung cancers (NSCLCs). Because little is known about these tumors, we examined the clinical characteristics and treatment outcomes of patients with NSCLC with ROS1 rearrangement. Using a ROS1 fluorescent in situ hybridization (FISH) assay, we screened 1,073 patients with NSCLC and correlated ROS1 rearrangement status with clinical characteristics, overall survival, and when available, ALK rearrangement status. In vitro studies assessed the responsiveness of cells with ROS1 rearrangement to the tyrosine kinase inhibitor crizotinib. The clinical response of one patient with ROS1-rearranged NSCLC to crizotinib was investigated as part of an expanded phase I cohort. Of 1,073 tumors screened, 18 (1.7%) were ROS1 rearranged by FISH, and 31 (2.9%) were ALK rearranged. Compared with the ROS1-negative group, patients with ROS1 rearrangements were significantly younger and more likely to be never-smokers (each P < .001). All of the ROS1-positive tumors were adenocarcinomas, with a tendency toward higher grade. ROS1-positive and -negative groups showed no difference in overall survival. The HCC78 ROS1-rearranged NSCLC cell line and 293 cells transfected with CD74-ROS1 showed evidence of sensitivity to crizotinib. The patient treated with crizotinib showed tumor shrinkage, with a near complete response. ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLC. Crizotinib shows in vitro activity and early evidence of clinical activity in ROS1-rearranged NSCLC.
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              First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study


                Author and article information

                Lancet Oncol
                Lancet Oncol.
                The Lancet. Oncology
                21 December 2017
                23 October 2017
                December 2017
                01 December 2018
                : 18
                : 12
                : 1590-1599
                [1 ]Massachusetts General Hospital, Boston, MA, USA
                [2 ]Vall d’Hebron Institute of Oncology, Barcelona, Spain
                [3 ]Sarah Cannon Cancer Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA
                [4 ]Gustave Roussy Cancer Campus, Villejuif, France and Paris-Sud University, Orsay, France
                [5 ]Pfizer Oncology, New York, NY, USA
                [6 ]Inventiv Clinical, Princeton, NJ, USA
                [7 ]Pfizer Oncology, La Jolla, CA, USA
                [8 ]Pfizer Oncology, Milan, Italy
                [9 ]Peter MacCallum Cancer Centre, Melbourne, Australia
                Author notes
                [* ]Correspondence to: Alice T. Shaw, Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit Street, Boston, MA 02114, USA, Phone: 617-724-4000, ashaw1@ 123456mgh.harvard.edu

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.


                Oncology & Radiotherapy


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