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

Abstract

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.

Modeling NSCLC Progression: Recent Advances and Opportunities Available

“…Their objective was to simulate the overall survival (OS) for NSCLC patients receiving C/P plus motesanib or bevacizumab and C/P alone. The simulated results were compared with the results of an actual phase III trial (MONET1) comparing the use of motesanib or placebo in addition to C/P (73). The hazard ratios were comparable yet the model underestimated the OS.…”

Platelet-derived growth factor receptor inhibitors for non-small cell lung cancer: is the odyssey over?

“…[6,7] Similarly, cediranib and motesanib failed to show a survival benefit when added to carboplatin and paclitaxel as first-line therapy. [8,9] Recently, a further failure of motesanib was beforehand announced by its pharmaceutical company since that the phase III MONET-A study, including Asian patients with advanced non-squamous NSCLC randomized to motesanib in combination with carboplatin and paclitaxel or chemotherapy alone, did not meet the primary end point of improving PFS. The MONET-A trial started among Asian patients, following the completion of a previous phase III trial (MONET1) which compared motesanib in combination with carboplatin and paclitaxel versus placebo in patients with non-squamous NSCLC.…”

“…Although the MONET1 trial failed to demonstrate a statistically significant improvement in OS, a subgroup preplanned analysis revealed a significant benefit in term of response rate, PFS, and OS in the Asian population, providing the rationale for further investigation in the MONET-A trial. [9] In the context of pretreated patients with NSCLC, sorafenib and sunitinib employing as single agent did not improve OS compared with placebo or erlotinib, respectively. [10,11] Moreover, the employment of anti-PDGFR agents has been also adopted in the context of the switch maintenance strategy.…”

Novel anti-angiogenic therapeutic strategies in colorectal cancer

“…In advanced NSCLC patients, motesanib combined with carboplatin/paclitaxel resulted in modest clinical benefit in terms of PFR and ORR, and in increased toxicity leading to study discontinuation in patients with squamous histology [56].…”

“…Patients treated with motesanib experienced more frequently gallbladder related disorders, such as cholecystitis, cholelithiasis and gallbladder enlargement. Finally, thyroid disorders were reported (elevated serum thyroid stimulating hormone) [56,57].…”