E4206: AMG 706 and Octreotide in Patients with Low-Grade Neuroendocrine Tumors
Sam Lubner, Yang Feng, Mary Mulcahy, Peter O'Dwyer, Guang-Yu Giang, J Louis Hinshaw, Dustin Deming, Leonard Klein, Ursina Teitelbaum, Jennifer Payne, Paul Engstrom, Philip Stella, Neal Meropol, Al Benson, Sam Lubner, Yang Feng, Mary Mulcahy, Peter O'Dwyer, Guang-Yu Giang, J Louis Hinshaw, Dustin Deming, Leonard Klein, Ursina Teitelbaum, Jennifer Payne, Paul Engstrom, Philip Stella, Neal Meropol, Al Benson
Abstract
Lessons learned: Rate of progression-free survival at a particular point in time, i.e., a landmark analysis, is a difficult endpoint for a heterogenous malignancy such as neuroendocrine cancer.Landmark analyses can also be complicated by evolution in the standard of care during the conduct of a clinical trial.Improvements in biomarker development would be useful in developing future clinical trials in NET to better tailor individualized therapies and assess for possible efficacy endpoints.
Background: Neuroendocrine tumors (NETs) are rare malignancies of the gastrointestinal (GI) tract that are highly vascularized and overexpress vascular-endothelial growth factor (VEGF). Sunitinib has demonstrated efficacy in the pancreatic subset of NET. This study explored the activity of another oral VEGF inhibitor, AMG 706 or motesanib, a multikinase inhibitor that targets receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, KIT, RET, and PDGFR (IC50s = 2, 3, 6, 8, 59, and 84 nM, respectively).
Methods: This was a single-arm, first-line, phase II study run through the Eastern Cooperative Oncology Group. Patients with low-grade NET (as defined by central confirmation of Ki-67 of 0%-2%) were administered a flat dose of 125 mg per day orally combined with octreotide long acting-repeatable (LAR) for patients who had been on a stable dose. The primary objective was to determine the 4-month progression-free survival (PFS).
Results: Forty-four patients were evaluated per protocol. The 4-month PFS was 78.5%. The partial response rate was 13.6% (6/44), stable disease was 54.5% (24/44), 9.1% (4/44) had progressive disease, and 10/44 were not evaluable for response. Common toxicities included fatigue, hypertension, nausea, and headache, and most were grade 1-2. Median PFS was 8.7 months, and overall survival was 27.5 months.
Conclusion: Motesanib (AMG 706) demonstrated a 4-month PFS that met the per-protocol definition of efficacy. Fatigue and hypertension were the most common toxicities, and few grade 3-4 toxicities were encountered. The progression-free survival of 8.7 months in all NETs merits further study.
Trial registration: ClinicalTrials.gov NCT00427349.
© AlphaMed Press; the data published online to support this summary are the property of the authors.
References
- Zhang J, Jia Z, Li Q et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression‐free survival among patients with low‐grade neuroendocrine tumors. Cancer 2007;109:1478–1486.
- Yao JC, Phan A, Hoff PM et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: A random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha‐2b. J Clin Oncol 2008;26:1316–1323.
- Yao JC, Guthrie K, Moran C et al. SWOG S0518: Phase III prospective randomized comparison of depot octreotide plus interferon alpha‐2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients (NCT00569127). J Clin Oncol 2015;33(suppl 15):4004A.
- Rinke A, Müller HH, Schade‐Brittinger C et al. Placebo‐controlled, double‐blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: A report from the PROMID Study Group. J Clin Oncol 2009;27:4656–4663.
- Kulke MH, Lenz HJ, Meropol NJ et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403–3410.
- Raymond E, Dahan L, Raoul JL et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501–513.
- Yao JC, Shah MH, Ito T et al.; Third Trial (RADIANT‐3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514–523.
- Pavel ME, Hainsworth JD, Baudin E et al. Everolimus plus octreotide long‐acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT‐2): A randomised, placebo‐controlled, phase 3 study. Lancet 2011;378:2005–2012.
- Yao JC, Fazio N, Singh S et al. Everolimus for the treatment of advanced, non‐functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT‐4): A randomised, placebo‐controlled, phase 3 study. Lancet 2016;387:968–977.
Source: PubMed