A phase I study of foretinib plus erlotinib in patients with previously treated advanced non-small cell lung cancer: Canadian cancer trials group IND.196.

Natasha B Leighl,Frances A Shepherd,Ming-Sound Tsao,Shingo Sakashita,Cheryl Ho,Garth Nicholas,John R Goffin,Lucia Kim,Dongsheng Tu,Jean Powers,Nevin Murray,Glenwood Goss,Zhuo Chen,Penelope A Bradbury,Geoffrey Liu,Lesley Seymour

doi:10.18632/oncotarget.18753

Natasha B Leighl, Frances A Shepherd + Show 14 more

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https://doi.org/10.18632/oncotarget.18753

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PurposeMET and AXL mediate resistance to EGFR TKI in NSCLC. Foretinib, a MET/RON/AXL/TIE-2/VEGFR kinase inhibitor may overcome EGFR kinase resistance. This dose escalation study combined foretinib and erlotinib in advanced pretreated NSCLC patients.Experimental DesignThe primary endpoint was to define the RP2D of foretinib plus erlotinib as continuous oral daily dosing. Secondary objectives included safety, pharmacokinetics, response and potential biomarkers of response including EGFR, KRAS genotype, MET, AXL expression, and circulating HGF levels. Erlotinib (E100-150 mg) was commenced on day 1 cycle 1; if well tolerated, foretinib (F30-45 mg) was added on day 15 cycle 1, using standard 3+3 dose escalation.ResultsOf 31 patients enrolled in 3 dose levels, 6 were inevaluable for DLT and replaced. DLT occurred in 3/15 patients at DL2 (E150 mg, F30 mg): Gr3 pain, mucositis, fatigue and rash. Cycle 1 DLT was not seen at DL3 (E150 mg, F45 mg) but 27% experienced dose reduction/interruption. Adverse events in ≥20% included diarrhea, fatigue, anorexia, dry skin, rash and hypertension. No PK interaction was seen with the combination. RP2D was defined as erlotinib 150 mg daily x 14 days with foretinib 30 mg added on day 15 (continuous dosing in 28-day cycles). Responses were seen in 17.8% of response evaluable patients (5/28). In 18 samples, baseline MET expression uncontrolled for EGFR genotype appeared associated with response. AXL expression was associated with neither EGFR mutation nor response.ConclusionCombining foretinib and erlotinib demonstrated response in unselected advanced NSCLC but also incremental toxicity. Future development will require molecular patient selection.

Highlights

Foretinib is a multitargeted kinase inhibitor, targeting MET, RON, AXL, TIE-2, VEGF receptors and ROS-1, with documented activity in papillary renal carcinoma and hepatocellular carcinoma [1,2,3]
RP2D was defined as erlotinib 150 mg daily x 14 days with foretinib 30 mg added on day 15
Semaphorin or juxtamembrane mutations may not lead to MET activation, while splice site mutations seen in 4% of lung adenocarcinomas and 2% of squamous cases may lead to MET activation via exon 14 skipping in MET mRNA with response to MET inhibitors [10]

Summary

Introduction

Foretinib is a multitargeted kinase inhibitor, targeting MET, RON, AXL, TIE-2, VEGF receptors and ROS-1, with documented activity in papillary renal carcinoma and hepatocellular carcinoma [1,2,3]. High MET copy number has been detected in 5% of EGFR mutant cases in the setting of acquired EGFR kinase resistance, and even primary resistance to EGFR kinase inhibitors may be mediated via upregulation of hepatocyte growth factor (HGF)-MET signaling [11,12,13]. Foretinib significantly increases sensitivity in EGFR mutant lung cancer cells with upregulated HGF and increased MET copy number when added to erlotinib [14]. Activation of AXL kinase has been associated with acquired resistance to EGFR kinase inhibitors in EGFR mutant lung cancer, with evidence for epithelial-tomesenchymal transition in preclinical models and restored EGFR kinase inhibitor sensitivity upon AXL inhibition [15, 16]

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