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Published on: August 11, 2017
Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors
Valentine M Macaulay1, Mark R Middleton2, S Gail Eckhardt3
1University Department of Oncology, Oxford Cancer and Haematology Centre, Headington, Oxford, United Kingdom. valentine.macaulay@oncology.ox.ac.uk.
Purpose:
Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib.
Experimental Design:
This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort.
Results:
Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks.
Conclusions:
The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. ©2016 AACR.
Insights
This study found the combination of linsitinib and erlotinib to be tolerable, showing preliminary antitumor activity and durable responses in patients with cancers resistant to single-agent therapy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cross-talk between insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) signaling pathways contributes to therapeutic resistance.
- Targeting these receptor tyrosine kinases individually can be overcome by compensatory signaling, necessitating combination strategies.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, an IGF1R/INSR inhibitor, in combination with erlotinib, an EGFR inhibitor.
- To explore different dosing schedules of linsitinib combined with erlotinib.
Main Methods:
- An open-label, dose-escalation study enrolled 95 patients across three linsitinib schedules (intermittent daily, continuous daily, continuous twice-daily) combined with erlotinib (100-150 mg daily).
- A non-small cell lung cancer (NSCLC) expansion cohort was included.
- Safety, pharmacokinetics, pharmacodynamics (including IGF-1 levels and receptor phosphorylation), and antitumor responses were assessed.
Main Results:
- The MTDs for linsitinib/erlotinib were established as 450/150 mg (Schedule 1) and 400/100 mg (Schedule 2).
- Common adverse events included drug eruption, diarrhea, fatigue, and nausea. Dose-limiting toxicities involved QTc prolongation and liver function abnormalities.
- Preliminary antitumor activity was observed, with 7% of evaluable patients achieving partial responses (including spinal chordoma, rectal cancer, and NSCLC) and 51% achieving disease control. Durable responses were noted in patients unlikely to respond to erlotinib monotherapy.
- Pharmacodynamic analyses indicated pathway inhibition, with elevated IGF-1 and reduced IGF1R/INSR phosphorylation.
Conclusions:
- The combination of linsitinib and erlotinib demonstrated tolerability and preliminary antitumor activity.
- Durable responses were observed in specific cancer types, suggesting potential efficacy in treatment-resistant settings.
- The combination warrants further investigation in phase II trials.
