Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations.
First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes.



We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival.



After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results.



Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer.
Cancer Clinical Research Unit, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Natasha B
NB
Leighl
Department of Hematology and Oncology, Columbia University Medical Center, New York, NY.
Naiyer A
NA
Rizvi
Oncoclinicas Group, Hcor Onco, Sao Paulo, SP, Brazil; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD.
Lopes Gilberto
LG
de Lima
National Cancer Research, Bangkok, Thailand.
Wichit
W
Arpornwirat
Memorial Sloan Kettering Cancer Center, New York, NY.
Charles M
CM
Rudin
Moffitt Cancer Center, Tampa, FL.
Alberto A
AA
Chiappori
Department of Hematology and Oncology, Sungkyunkwan University, Seoul, South Korea.
Myung-Ju
MJ
Ahn
University of Washington, Seattle, WA.
Laura Q M
LQ
Chow
Department of Clinical Oncology, School of Medicine, UC San Diego Moores Cancer Center, San Diego, CA.
Lyudmila
L
Bazhenova
Departments of Pathology, Hematology, and Surgery, Prince of Songkla University, Songkhla, Thailand.
Arunee
A
Dechaphunkul
Department of Internal Medicine, Prince of Songkla University, Songkhla, Thailand.
Patrapim
P
Sunpaweravong
Prince of Songkla University, Songkhla, Thailand; Medical Oncology at University of Washington School of Medicine, Seattle Cancer Care Alliance, Seattle, WA.
Keith
K
Eaton
Astellas, Northbrook, IL.
Jihong
J
Chen
Astellas, Northbrook, IL.
Sonja
S
Medley
Astellas, Northbrook, IL.
Srinivasu
S
Poondru
Astellas, Northbrook, IL.
Margaret
M
Singh
Astellas, Northbrook, IL.
Joyce
J
Steinberg
Juravinski Cancer Centre, Department of Oncology, McMaster University, Hamilton, ON, Canada. Electronic address: juergensr@hhsc.ca.
Rosalyn A
RA
Juergens
Karmanos Cancer Institute, Wayne State University, Detroit, MI; Hematology-Oncology, Wayne State University, Detroit, MI.
Shirish M
SM
Gadgeel
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D011719:Pyrazines / Q000008:administration & dosage; D015996:Survival Rate
C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D014408:Biomarkers, Tumor; D007093:Imidazoles; D011719:Pyrazines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
Combination; Epidermal growth factor receptor inhibitor; First-line therapy; Insulin-like growth factor-1 inhibitor; Tyrosine kinase inhibitor
Eur J Cancer. 2009 Jan;45(2):228-47
19097774
Lancet Oncol. 2015 Apr;16(4):426-35
25795408
Ann Oncol. 2015 Mar;26(3):497-504
25395283
Clin Cancer Res. 2007 May 1;13(9):2795-803
17473213
Clin Cancer Res. 2011 Mar 1;17(5):1169-80
21248300
Future Med Chem. 2009 Sep;1(6):1153-71
21425998
N Engl J Med. 2009 Sep 3;361(10):958-67
19692684
J Clin Oncol. 2001 Jul 1;19(13):3267-79
11432895
Clin Pharmacol Ther. 2006 Aug;80(2):136-45
16890575
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8686-98
16361555
PLoS Genet. 2012;8(3):e1002609
22479204
Science. 2007 May 18;316(5827):1039-43
17463250
Cancer Res. 2006 Oct 15;66(20):10100-11
17047074
N Engl J Med. 2009 Sep 3;361(10):947-57
19692680
J Thorac Oncol. 2012 Feb;7(2):419-26
22237261
Clin Cancer Res. 2015 Oct 15;21(20):4686-97
26124204
Clin Cancer Res. 2011 Sep 1;17(17):5530-7
21775534
Mol Cancer Ther. 2013 Jun;12(6):1131-9
23515613
Lung Cancer. 2017 Nov;113:37-44
29110846
Endocr Rev. 2009 Oct;30(6):586-623
19752219
Cancer Res. 2008 Oct 15;68(20):8322-32
18922904
Oncogene. 2007 Mar 22;26(13):1932-40
17001314
Clin Lung Cancer. 2014 May;15(3):213-21
24485233
Proc Natl Acad Sci U S A. 2010 Jun 15;107(24):10791-8
20457905
J Clin Oncol. 2013 Sep 20;31(27):3327-34
23816960
J Clin Oncol. 2009 May 20;27(15):2516-22
19380445
Transl Lung Cancer Res. 2015 Feb;4(1):67-81
25806347
Clin Cancer Res. 2015 Feb 15;21(4):693-700
25208878
Nat Rev Cancer. 2012 Feb 16;12(3):159-69
22337149
Endocr Relat Cancer. 2004 Dec;11(4):793-814
15613453
Transl Lung Cancer Res. 2013 Feb;2(1):14-22
25806201
Clin Cancer Res. 2016 Jun 15;22(12):2897-907
26831715
Mol Cancer Ther. 2007 Aug;6(8):2158-67
17671083
Ther Adv Med Oncol. 2012 Mar;4(2):51-60
22423264
Nat Genet. 2012 Jul 01;44(8):852-60
22751098
Clin Cancer Res. 2011 May 15;17(10):3332-40
21257723
Clin Cancer Res. 2015 Feb 15;21(4):701-11
25212606
Anticancer Res. 2012 Feb;32(2):537-52
22287743
Cancer Res. 2012 Jan 1;72(1):3-12
22215692
Clin Cancer Res. 2013 Jan 1;19(1):279-90
23091115
Sci Transl Med. 2011 Mar 23;3(75):75ra26
21430269
Mol Cancer Ther. 2010 Oct;9(10):2652-64
20924128
J Clin Oncol. 2011 Dec 1;29(34):4574-80
22025157
Lancet Oncol. 2012 Mar;13(3):239-46
22285168