Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.
BACKGROUND
Antiangiogenic therapies have shown potential in the treatment of advanced thyroid cancer, but it is uncertain which patients are most likely to benefit from therapy.


OBJECTIVE
This prespecified exploratory analysis investigated whether baseline levels and/or changes in circulating biomarkers could predict tumor response and/or progression-free survival (PFS) among patients enrolled in a phase 2 study of motesanib in advanced thyroid cancer.


METHODS
Patients with progressive locally advanced or metastatic medullary or differentiated thyroid cancer received motesanib 125 mg once daily for up to 48 wk in a phase 2 interventional study. Samples for assessment of circulating biomarkers of angiogenesis or apoptosis were collected at study wk 1 (baseline), 2, 4, 8, 16, 24, 32, 40, 48, and 4 wk after cessation of motesanib treatment. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors by independent review.


RESULTS
Change from baseline in serum placental growth factor (PlGF) after 1 wk of treatment correlated with best tumor response (Kendall rank correlation, 0.28; P < 0.0001). Using a Fisher exact test, the most significant separation between patients who had an objective response and those who did not was at a 4.7-fold increase in PlGF. The response rate among patients with a greater than 4.7-fold increase in PlGF was 30% compared with 3% below this threshold. There was also a significant separation between responders and nonresponders at a 1.6-fold decrease in soluble vascular endothelial growth factor (VEGF) receptor 2 after 3 wk of treatment. Patients with baseline serum VEGF less than 671 pg/ml had significantly longer PFS times than the remainder of patients.


CONCLUSIONS
Changes in PlGF and soluble VEGF receptor 2 levels after initiation of therapy predicted response to motesanib in patients with advanced differentiated thyroid cancer or metastatic medullary thyroid cancer. Lower baseline VEGF levels were associated with longer PFS.
Bass
Michael B
MB
Department of Computational Biology, Amgen Inc., Thousand Oaks, California 91320-1799, USA. mbass@amgen.com
Sherman
Steven I
SI
Schlumberger
Martin J
MJ
Schlumberger
Martn J
MJ
Davis
Michael T
MT
Kivman
Lisa
L
Khoo
Huan-Mei
HM
Notari
Kimberly H
KH
Peach
Matthew
M
Hei
Yong-Jiang
YJ
Patterson
Scott D
SD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D018276:Carcinoma, Medullary / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009841:Oligonucleotides; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D013964:Thyroid Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
D000970:Antineoplastic Agents; D015415:Biomarkers; D007211:Indoles; D009841:Oligonucleotides; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D009536:Niacinamide; D040301:Vascular Endothelial Growth Factor Receptor-2; C519562:imetelstat