Placental growth factor as a marker of therapeutic response to treatment with motesanib in patients with progressive advanced thyroid cancer, advanced nonsquamous non-small cell lung cancer, and locally recurrent or advanced metastatic breast cancer.

Bass, Michael; Davis, Melissa; Kivman, Lisa; Khoo, Huan Mei; Notari, Kimberly H.; Blumenschein, G. R.; Mackey, John R.; Sherman, Steven I.; Hei, Yong Jiang; Patterson, Scott D.

doi:10.1200/jco.2010.28.15_suppl.3037

Cited by 6 publications

(9 citation statements)

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“…MONET1 confirmed the pharmacodynamic increase in PLGF in response to motesanib treatment that was reported previously 9,12,16,17 (data not shown). However, among patients in the motesanib arm who had evaluable PLGF samples at baseline (n ϭ 356, 33%), there was no association between the log-transformed fold-change in PLGF from baseline to week 4 (continuous variable) and OS (unadjusted Cox model, HR, 0.98; 95% CI, 0.79 to 1.22; P ϭ .868).…”

Section: Assessment Of Plgf As a Biomarkersupporting

confidence: 73%

“…Data from the preceding phase II study of carboplatin/paclitaxel plus motesanib or bevacizumab suggested that increased PLGF might be a marker of therapeutic response to motesanib treatment. 12 This hypothesis was supported by similar findings of associations between fold-change in PLGF and outcomes in patients with advanced thyroid cancer 17 and human epidermal growth factor receptor 2-negative metastatic breast cancer 12 receiving motesanib. However, the data could not be confirmed in MONET1; there was no association between changes in PLGF and OS in the motesanib arm.…”

Section: ‫ء‬supporting

confidence: 72%

“…12 PLGF is a VEGF homolog that can promote angiogenesis by activating VEGFR-1. 13 The primary objective of the MONET1 (Motesanib NSCLC Efficacy and Tolerability) study was to determine whether motesanib combined with carboplatin/paclitaxel improved OS, compared with placebo plus carboplatin/paclitaxel, in patients with advanced nonsquamous NSCLC and in the subset of patients with adenocarcinoma histology.…”

Section: Journal Of Clinical Oncologymentioning

confidence: 99%

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International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1

Scagliotti

Vynnychenko²,

Park³

et al. 2012

JCO

162

110

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Purpose We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non–small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma. Patients and Methods Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m2) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS. Results A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio [HR], 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment. Conclusion Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.

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Section: Assessment Of Plgf As a Biomarkersupporting

confidence: 73%

Section: ‫ء‬supporting

confidence: 72%

Section: Journal Of Clinical Oncologymentioning

confidence: 99%

See 1 more Smart Citation

International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1

Scagliotti

Vynnychenko²,

Park³

et al. 2012

JCO

162

110

View full text Add to dashboard Cite

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“…In an analysis of biomarkers, a greater than 5.3-fold increase in concentration of placental growth factor after 3 weeks of therapy was predictive of an increased likelihood of objective response across the two cohorts. 38 Overall, the drug was well tolerated, with similar side effects as reported in the phase I trial. An unanticipated side effect of motesanib therapy was a 30% increase in the mean dosages of levothyroxine required to maintain TSH suppression or euthyroidism, respectively, in DTC and MTC cohorts, and 60-70% of patients experienced peak TSH concentrations out of the therapeutic ranges.…”

Section: Motesanibsupporting

confidence: 55%

Targeted therapies for thyroid tumors

Sherman

2011

Modern Pathology

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Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more commonly observed. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. At least one randomized, placebo-controlled phase III trial has been successfully completed, showing improved progression-free survival in patients with advanced or metastatic medullary thyroid carcinoma treated with vandetanib. Randomized trials for other agents are currently underway. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

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“…The increase in PLGF following motesanib treatment possibly represents a compensatory upregulation in response to VEGF pathway blockade. Subsequent phase 2 studies with motesanib showed a consistent association between increased levels from baseline in PLGF and outcomes across different tumor types, including thyroid cancer, breast cancer, and non–small-cell lung cancer (NSCLC) [8] , [18] – [20] . Furthermore, other inhibitors of the VEGF pathway have been known to induce pharmacodynamic changes in PLGF [21] – [26] , which, in some cases, have been associated with outcomes including objective response and OS.…”

Section: Introductionmentioning

confidence: 97%

Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience

et al. 2014

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PurposeWe sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer.Experimental DesignPlacental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models.ResultsIn the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12–0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79–1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67–1.15, P = 0.340).ConclusionsOur results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.Trial RegistrationClinicalTrials.gov NCT00460317, NCT00369070

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Placental growth factor as a marker of therapeutic response to treatment with motesanib in patients with progressive advanced thyroid cancer, advanced nonsquamous non-small cell lung cancer, and locally recurrent or advanced metastatic breast cancer.

Cited by 6 publications

References 0 publications

International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1

International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1

Targeted therapies for thyroid tumors

Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience

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