Abstract 3827: NCI 8628 - A randomized phase II study of Ziv-aflibercept (Z) and high dose Interleukin-2 (IL-2) or IL-2 alone for inoperable stage III or IV melanoma
Authors: Tarhini Ahmad A. , Frankel Paul H. , Ruel Christopher , Ernstoff Marc S. , Kuzel Timothy M. , Logan Theodore F. , Khushalani Nikhil I. , Tawbi Hussein A. , Margolin Kim A. , Awasthi Sanjay , McDermott David F. , Chen Alice , Lara Primo N. , Kirkwood John M. 
Published: July 2017

Abstract
Background: IL-2 plays a central role in antitumor immunity. VEGF plays a critical role in angiogenesis and host innate and adaptive immunity. High baseline serum VEGF was associated with non-response to IL-2. Z, a high-affinity soluble decoy VEGF receptor, may deplete VEGF prior to IL-2 to reverse the immunosuppressive impact of VEGF and enhance antitumor T cell response.
Methods: NCI8628 was a phase II trial of Z and IL-2 (A) versus IL-2 alone (B) randomized 2:1. Eligible patients (pts): Stage III inoperable or Stage IV melanoma. Up to two prior regimens for metastatic melanoma and stable treated brain metastases were allowed. The primary endpoint was progression-free survival (PFS).
Results: A total of 89 pts were enrolled, but 5 who never started study treatment were excluded. Six pts (4 in A and 2 in B) who were treated but withdrew early without a response assessment were considered non-responders in this analysis. Pt and disease characteristics are summarized in Table 1. Median number of IL2 cycles was 3 (A) and 2 (B) and of Z cycles in A was 3 (1 - 31). Median follow up for all alive patients was 19 months. Among 84 treated pts (55 in A and 29 in B), there was significant improvement in PFS in favor of A: median and 95% CI of 6.9 (4.2 - 8.8) months vs 2.1 (1.7 - 4.1), logrank p &lt;0.001. No significant difference in OS: median and 95% CI of 23.1 (14.4 - 35.0) months (A) vs 22.3 (12.6 - NA). Response rate (RECIST) was 22% in A (5CR, 7PR) and 17% in B (5PR). Stable disease or PR or CRwas seen in 69% in A and 48% in B. Adverse events were consistent with the AE profiles of monotherapy with IL2 and Z. Grade 4 events in A included decreased lymphocytes (41 pts) and platelets (6), renal (1), hypophosphatemia (4), hypertension (2) and thromboembolism (1).
Table 1Arm A (N=55)Arm B (N=29)Age (median and range)55 (26-73)55 (31-74)GenderFemale2211Male3318Cutaneous primary3616Mucosal54Uveal Unknown6 84 5AJCC StageIII (N3) M1a9 103 5M1b116M1c2515
Conclusions: The combination of Z and IL2 significantly improved PFS over IL2 alone, meeting the study’s primary endpoint. The regimen was relatively safe and manageable. Correlative and mechanistic studies are ongoing.
Citation Format: Ahmad A. Tarhini, Paul H. Frankel, Christopher Ruel, Marc S. Ernstoff, Timothy M. Kuzel, Theodore F. Logan, Nikhil I. Khushalani, Hussein A. Tawbi, Kim A. Margolin, Sanjay Awasthi, David F. McDermott, Alice Chen, Primo N. Lara, John M. Kirkwood. NCI 8628 - A randomized phase II study of Ziv-aflibercept (Z) and high dose Interleukin-2 (IL-2) or IL-2 alone for inoperable stage III or IV melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3827. doi:10.1158/1538-7445.AM2017-3827