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

Ahmad A. Tarhini, Paul Frankel, Christopher Ruel, Marc S. Ernstoff, Timothy M. Kuzel, Theodore F. Logan, Nikhil I. Khushalani, Hussein A. Tawbi, Kim A. Margolin, Sanjay Awasthi, Lisa H. Butterfield, David McDermott, Alice Chen, Primo N Lara, John M. Kirkwood

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
JournalCancer
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Interleukin-2
Melanoma
Vascular Endothelial Growth Factor A
Confidence Intervals
Disease-Free Survival
aflibercept
Vascular Endothelial Growth Factor Receptor-2
Natural Killer T-Cells
Adaptive Immunity
Innate Immunity
Intercellular Signaling Peptides and Proteins
Cytokines
T-Lymphocytes
Survival
Serum

Keywords

  • angiogenesis
  • immunotherapy
  • interleukin 2
  • melanoma
  • vascular endothelial growth factor
  • ziv-aflibercept

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Tarhini, Ahmad A.; Frankel, Paul; Ruel, Christopher; Ernstoff, Marc S.; Kuzel, Timothy M.; Logan, Theodore F.; Khushalani, Nikhil I.; Tawbi, Hussein A.; Margolin, Kim A.; Awasthi, Sanjay; Butterfield, Lisa H.; McDermott, David; Chen, Alice; Lara, Primo N; Kirkwood, John M.

In: Cancer, 01.01.2018.

Research output: Contribution to journalArticle

Tarhini, AA, Frankel, P, Ruel, C, Ernstoff, MS, Kuzel, TM, Logan, TF, Khushalani, NI, Tawbi, HA, Margolin, KA, Awasthi, S, Butterfield, LH, McDermott, D, Chen, A, Lara, PN & Kirkwood, JM 2018, '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', Cancer. https://doi.org/10.1002/cncr.31734
Tarhini, Ahmad A. ; Frankel, Paul ; Ruel, Christopher ; Ernstoff, Marc S. ; Kuzel, Timothy M. ; Logan, Theodore F. ; Khushalani, Nikhil I. ; Tawbi, Hussein A. ; Margolin, Kim A. ; Awasthi, Sanjay ; Butterfield, Lisa H. ; McDermott, David ; Chen, Alice ; Lara, Primo N ; Kirkwood, John M. / 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. In: Cancer. 2018.
@article{8be3626b0df6443c998381bb1bd0a25d,
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.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/cncr.31734",
language = "English (US)",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - NCI 8628

T2 - 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

AU - Tarhini, Ahmad A.

AU - Frankel, Paul

AU - Ruel, Christopher

AU - Ernstoff, Marc S.

AU - Kuzel, Timothy M.

AU - Logan, Theodore F.

AU - Khushalani, Nikhil I.

AU - Tawbi, Hussein A.

AU - Margolin, Kim A.

AU - Awasthi, Sanjay

AU - Butterfield, Lisa H.

AU - McDermott, David

AU - Chen, Alice

AU - Lara, Primo N

AU - Kirkwood, John M.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - angiogenesis

KW - immunotherapy

KW - interleukin 2

KW - melanoma

KW - vascular endothelial growth factor

KW - ziv-aflibercept

UR - http://www.scopus.com/inward/record.url?scp=85054687792&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054687792&partnerID=8YFLogxK

U2 - 10.1002/cncr.31734

DO - 10.1002/cncr.31734

M3 - Article

C2 - 30303516

AN - SCOPUS:85054687792

JO - Cancer

JF - Cancer

SN - 0008-543X

ER -