Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer

Abstract

Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m IV and carboplatin area under the concentration-time curve 6 mg/mL ⋅ min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months ( P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% ( P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade ≥ 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer.

Tumor Growth Dynamic Modeling in Oncology Drug Development and Regulatory Approval: Past, Present, and Future Opportunities

“…49 Although a phase III study later conducted in Asian patients failed to demonstrate motesanib benefit in combination with carboplatin/paclitaxel with PFS as the primary end point, the model predicted an HR of 0.74, which was very close to the observed value (0.81) in the clinical trial. 50 Most reported the TGD model focused on the SLD of all target lesions, therefore, the characterization of tumor dynamic represents the average of all target lesions. However, the dynamic of single lesions could be drastically different, in which some may be more aggressive than others.…”

Cancer stem cells as therapeutic targets of pancreatic cancer

“…Dysregulation of miRNAs is associated with initiation and progression of a wide range of diseases such as diabetes, cardiovascular diseases, cancer, neurodegenerative diseases, infection diseases, and depression [91][92][93][94][95][96][97][98][99]. Hence, it seems that these molecules could be introduced as diagnostic, prognostic, and therapeutic Berberine SOX2, NANOG, NOTCH1, and POU5F1 Pancreatic cancer [113] curcumin and epigallocatechin gallate STAT3-NFkB Breast cancer [114] Telomerase inhibitors (motesanib) -Non-small-cell lung cancer [160] BMPs BMPR1B Glioblastoma [161] all-trans retinoic acid (ATRA) Histone deacetylase Glioma [162] Cancer stem cell pancreatic cancer therapy biomarkers in different diseases [100][101][102][103][104][105][106][107][108][109]. In this regard, several studies revealed that different miRNAs were related to pancreatic CSCs progression and could be employed as new targets in PC treatment [110,111].…”

Anti-angiogenic therapy in nonsquamous non-small cell lung cancer (NSCLC) with tyrosine kinase inhibition (TKI) that targets the VEGF receptor (VEGFR): perspective on phase III clinical trials

“…The addition of motesanib to chemotherapy led to no significant difference in median PFS or OS ( Table 2). Similar to previous studies that have documented increased adverse events among patients on motesanib, side effects included gastrointestinal upset, hypertension and gallbladder pathology (12). Because the hypothesized improvement in PFS was not met, and increased AE with motesanib, the study was terminated and evaluation of OS and other secondary end points were not performed.…”

“…Kubota et al conducted a phase III trial of carboplatin and paclitaxel with motesanib compared to the same chemotherapy alone randomized to East Asian patients with stage IV nonsquamous NSCLC to evaluate the efficacy of motesanib (12). Given the known differences in incidence of epidermal growth factor receptor (EGFR) mutations in Asian vs. non-Asian subjects, the study was stratified for EGFR mutational status.…”