Research Papers:

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

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Oncotarget. 2017; 8:69651-69662. https://doi.org/10.18632/oncotarget.18753

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Natasha B. Leighl1,2,3, Ming-Sound Tsao1,2,3, Geoffrey Liu1,2,3, Dongsheng Tu1, Cheryl Ho1,4, Frances A. Shepherd1,2,3, Nevin Murray1,4, John R. Goffin1,5, Garth Nicholas1,6, Shingo Sakashita3, Zhuo Chen3, Lucia Kim3, Jean Powers1, Lesley Seymour1, Glenwood Goss1,6 and Penelope A. Bradbury1,2

1Canadian Cancer Trials Group (Formerly NCIC Clinical Trials Group), Kingston ON, Canada

2Princess Margaret Cancer Centre/University Health Network, Toronto ON, Canada

3Ontario Cancer Institute, Toronto ON, Canada

4British Columbia Cancer Agency, Vancouver BC, Canada

5Juravinski Cancer Centre, Hamilton ON, Canada

6Ottawa Hospital Cancer Centre, Ottawa ON, Canada

Correspondence to:

Natasha B. Leighl, email: [email protected]

Keywords: foretinib, erlotinib, MET, AXL, non-small cell

Received: April 19, 2017     Accepted: May 22, 2017     Published: June 28, 2017


Purpose: MET 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 Design: The 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.

Results: Of 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.

Conclusion: Combining foretinib and erlotinib demonstrated response in unselected advanced NSCLC but also incremental toxicity. Future development will require molecular patient selection.

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