Two trials (E4599 and AVAiL) have suggested a benefit to adding the anti–vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin) to chemotherapy in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). Bevacizumab acts by binding directly to circulating VEGF and preventing interaction of VEGF with its receptors. It has been believed that small-molecule tyrosine kinase inhibitors that target multiple angiogenesis pathways would offer advantages over single-target agents.
Motesanib inhibits multiple angiogenic pathways by inhibiting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit tyrosine kinases. The agent was shown to have antitumor activity alone and in combination regimens in early-phase trials. However, the multinational randomized, double-blind, placebo-controlled MONET1 trial, recently reported by Giorgio V. Scagliotti, MD, University of Turin, Torino, Italy, and colleagues in the Journal of Clinical Oncology, showed that adding motesanib to carboplatin/paclitaxel resulted in no improvement in overall survival and an excess of serious toxicities.1
Enrollment of Squamous Histology Stopped
MONET1 initially enrolled patients with advanced squamous or nonsquamous NSCLC. However, a planned independent data monitoring committee review after enrollment of 600 patients, including 223 with squamous histology, showed higher early mortality and a higher incidence of gross hemoptysis among motesanib recipients with squamous histology. Thereafter, only patients with nonsquamous histology were enrolled.
In total, 1,090 patients with stage IIIB/IV or recurrent nonsquamous NSCLC received carboplatin (area under the curve 6 mg/mL × min) and paclitaxel (200 mg/m2) for up to six 3-week cycles plus daily placebo (n = 549) or motesanib 125 mg (n = 541). Patients had no prior therapy for advanced disease.
Median age was 60 years in both groups, and similar proportions of motesanib patients vs control group patients were former smokers (72%), male (62% vs 61%), and white (67% vs 64%) and had ECOG performance status ≥ 1 (65% vs 62%), histology of adenocarcinoma (83% vs 81%), stage IV/recurrent disease (87% vs 86%), and measureable disease (97% vs 96%). Two percent of patients in both groups had received prior adjuvant chemotherapy.
No Overall Survival Improvement
Patients in both groups were treated for a median of 4.1 months. There was no difference in median overall survival between the motesanib group and the control group (13.0 vs 11.0 months, hazard ratio [HR] = 0.90, 95% confidence interval [CI] = 0.78–1.04, P = .14). There was also no difference between groups when only patients with adenocarcinoma were considered (n = 448 vs 442, 13.5 vs 11.0 months, HR = 0.88, 95% CI = 0.75–1.03, P = .11).
Prespecified subgroup analyses suggested prolonged survival with motesanib in nonwhite patients (n = 375, HR = 0.76, 95% CI = 0.59–0.97) and patients enrolled outside the United States/Canada/Australia/European Union (n = 414, HR = 0.77, 95% CI = 0.61–0.98); most of these patients were Asian. Median progression-free survival was significantly but modestly prolonged in the motesanib group (5.6 vs 5.4 months, HR = 0.79, 95% CI = 0.68–0.90, P < .001), with a similar outcome in patients with adenocarcinoma.
Objective response rate was significantly higher with motesanib (40% vs 26%, P < .001), with a similar outcome in patients with adenocarcinoma. Earlier motesanib studies suggested a relationship between increased levels of placental growth factor and efficacy outcomes in motesanib treatment, but no association between placental growth factor and response rate or survival was observed in the current study.
Increased Toxicity
Discontinuation of study treatment occurred in 31% of motesanib recipients vs 15% of the control group. Numerous adverse events occurred with at least 5% greater frequency in motesanib patients, including diarrhea, nausea, vomiting, abdominal pain, hypertension, pneumonia, and gallbladder-related disorders (eg, cholecystitis, cholelithiasis, gallbladder enlargement).
Motesanib patients had higher rates of serious adverse events (49% vs 34%), grade 4 adverse events (21% vs 14%), and serious grade 3 or higher adverse events, including neutropenia (5% vs 2%), diarrhea (5% vs <1%), pneumonia (4% vs 1%), and dehydration (4% vs < 1%). Among adverse events typically associated with VEGF inhibition, frequencies were higher in the motesanib group for hypertension (any grade 26% vs 6%) and grade 3 or higher arterial thromboembolic (2% vs < 1%) and hemorrhagic (3% vs 1%) events. Hemorrhagic events consisted of gastrointestinal hemorrhage (1 vs 0), pulmonary hemorrhage (2 vs 1), and hemoptysis (3 vs 1).
Death due to adverse events within 30 days of completing treatment occurred more frequently in motesanib patients (14% vs 9%). Adverse events leading to death that occurred in at least four patients in either treatment group were pneumonia (7 vs 0), general physical health deterioration (6 vs 1), respiratory failure (5 vs 2), pulmonary embolism (3 vs 6), and cardiorespiratory arrest (1 vs 4).
Lack of Validated Predictive Markers
As stated in an accompanying editorial by Daniel Morgensztern, MD, and Roy S. Herbst, MD, PhD, of Yale Comprehensive Cancer Center, New Haven, Connecticut, the MONET1 trial adds to a growing list of trials that have shown no benefit of adding multitargeted tyrosine kinase inhibitors to chemotherapy in advanced NSCLC, including phase III trials of sorafenib (Nexavar) in first-line treatment and vandetanib (Caprelsa) in second-line treatment.2 This phenomenon has also been observed with the addition of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (eg, gefitinib [Iressa, discontinued in the U.S.] and erlotinib [Tarceva]) to chemotherapy, whereas results have been mixed with the addition of the anti-EGFR monoclonal antibody cetuximab (Erbitux) to chemotherapy.
The reasons that tyrosine kinase inhibitors have failed to improve survival when added to chemotherapy are unclear. However, a potential mechanism for the lack of synergy between these agents and chemotherapy may be G1 phase cell-cycle arrest caused by tyrosine kinase inhibitors, which may interfere with the cycle-dependent cytotoxicity of chemotherapy.
Drs. Morgensztern and Herbst observed that in addition to not improving survival in NSCLC, multitargeted antiangiogenic tyrosine kinase inhibitors have been associated with significant additional toxicity; meta-analyses have shown that the VEGF receptor tyrosine kinase inhibitors sorafenib and sunitinib (Sutent) are associated with two- to threefold increased risks for bleeding, arterial thrombotic events, and treatment-related mortality. The commentators noted, “It seems likely that, similarly to EGFR [tyrosine kinase inhibitors], combination with chemotherapy might not be the best setting for the use of multitargeted angiogenesis inhibitors.”
As concluded by Drs. Morgensztern and Herbst, “One of the primary problems with antiangiogenic therapy is the lack of validated predictive markers. Because there are no trials that show a benefit from the addition of antiangiogenic [tyrosine kinase inhibitors] to chemotherapy, additional studies using this unselected approach are not recommended. Therefore, there is a definite need for an improved understanding of the complex mechanisms that are involved in the angiogenesis pathways, and for the development of molecular markers to allow a better treatment decision on the basis of the probability of response. This would also help avoid the unnecessary use of potentially toxic drugs in patients with known resistance and would facilitate the discovery of new targets and drugs on the basis of the resistance mechanisms.” ■
Disclosure: Dr. Scagliotti has served in a consulting or advisory role for Eli Lilly, Keunchil Park, and Amgen, and has received honoraria from AstraZeneca, Eli Lilly, Pfizer, and Roche. Dr. Morgensztern has served in a consulting or advisory role for Genentech. Dr. Herbst has served as consultant or advisor for Amgen.
References
1. Scagliotti GV, Vynnychenko I, Park K, et al: 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. J Clin Oncol. July 2, 2012 (early release online).
2. Morgensztern D, Herbst RS: Multitargeted tyrosine kinase inhibitors in unselected patients with advanced non-small-cell lung cancer (NSCLC): Impressions from MONET (the Motesanib NSCLC Efficacy and Tolerability study). J Clin Oncol. July 2, 2012 (early release online).
