@article{4247aedb7c5a4f97953c48a918d57e19,
title = "NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma",
abstract = "Background: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. Methods: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). Results: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept. Conclusions: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.",
keywords = "angiogenesis, immunotherapy, interleukin 2, melanoma, vascular endothelial growth factor, ziv-aflibercept",
author = "Tarhini, {Ahmad A.} and Paul Frankel and Christopher Ruel and Ernstoff, {Marc S.} and Kuzel, {Timothy M.} and Logan, {Theodore F.} and Khushalani, {Nikhil I.} and Tawbi, {Hussein A.} and Margolin, {Kim A.} and Sanjay Awasthi and Butterfield, {Lisa H.} and David McDermott and Alice Chen and Lara, {Primo N.} and Kirkwood, {John M.}",
note = "Funding Information: Ahmad A. Tarhini has acted as a paid consultant for Sanofi Aventis for work not related to the current study. Timothy M. Kuzel has received speaking honoraria for a different drug from Sanofi Aventis. Theodore F. Logan has received a grant to his institution from Prometheus for work performed as part of the current study. In addition, Sanofi provided the drug used in the current study. Dr. Logan also has received grants to his institution from Abbott, Abraxis, Acceleron, Amgen, Argos, AstraZeneca, Aveo, BioVex Inc, Bristol-Myers Squibb, Eisai, Lilly, GlaxoSmithKline, Roche, Immatics, Merck, Novartis, Pfizer, Synta Pharmaceuticals Inc, Threshold, Millennium, Tracon, Cerulean, EMD Serono, Prometheus, MacroGenics, Peloton, Iovance Biotherapeutics, MedImmune, and Dynvax Technologies and has acted as a paid member of the advisory board of Prometheus for work performed outside of the current study. Nikhil I. Khushalani has received a grant to his study institution from the National Cancer Institute for work performed as part of the current study and has received clinical trial support to his institution from and acted as a member of the advisory board for Bristol-Myers Squibb, HUYA Bioscience International, and Regeneron; acted as a member of the advisory board for EMD Serono and Genentech; acted as a member of the Data Safety Monitoring Board for AstraZeneca; received clinical trial support to his institution from Merck, GlaxoSmithKline, Novartis, and Amgen; and owns common stock in Mazor Robotics and Bellicum Pharmaceuticals. Hussein A. Tawbi has received research funding to his institution from Bristol-Myers Squibb, Merck, Novartis, Celgene, and GlaxoSmithKline and has acted as a paid consultant for Bristol-Myers Squibb, Merck, and Novartis for work performed outside of the current study. Kim A. Margolin has acted a paid consultant for ImaginAb, as a member of the Data Safety Monitoring Board for Amgen and Iovance Biotherapeutics, as a member of the advisory board for Iovance Biotherapeutics, and received personal fees from Nektar for work performed outside of the current study. David McDermott has received a grant from and acted as a paid consultant for Bristol-Myers Squibb; has acted as a paid consultant for Pfizer, Merck, Novartis, Eisai, Exelixis, Array BioPharma, and Genentech BioOncology; and received a Kidney Cancer Research Support grant from Prometheus for work performed outside of the current study. John M. Kirkwood has received personal fees from Bristol-Myers Squibb; a grant and personal fees from Merck; personal fees from Novartis, Roche, Genentech, EMD Serrono, and Array Biopharma; and grants from Prometheus and Merck for work performed outside of the current study. Publisher Copyright: {\textcopyright} 2018 American Cancer Society",
year = "2018",
month = nov,
day = "15",
doi = "10.1002/cncr.31734",
language = "English (US)",
volume = "124",
pages = "4332--4341",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "22",
}