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.
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.
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NCI 8628：单独使用ZIV-Aflibercept和高剂量白细胞介素2或高剂量白细胞介素2的随机2研究，用于无法手术III期或IV期黑色素瘤。
DOI：
10.1002/cncr.31734
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发表时间：
2018-11-15
期刊：
影响因子：
6.2
通讯作者：
Kirkwood JM
中科院分区：
文献类型：
--
作者：
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
白介素2(IL2)是T和NK细胞的生长因子，促进促炎细胞因子，并可导致黑色素瘤的持久反应。血管内皮生长因子促进血管生成，调节宿主的先天免疫和获得性免疫。高水平的血管内皮细胞生长因子水平与IL2无反应有关。ZIV-AFLibercept可耗尽血管内皮生长因子，从而增强抗肿瘤T细胞反应，支持与IL2联合免疫治疗策略。NCI 8628是Ziv-afLibercept和IL2(A组)与IL2单独组(B组)的II期随机试验，分别为2：1。符合条件的患者患有无法手术的III或IV期黑色素瘤。主要终点是无进展生存期(PFS)。入选患者84例。中位随访时间为41.4个月。在接受治疗的患者(A组55例，B组29例)中，PFS显著改善为A：中位数(95%CI)为6.9月(4.18.7月)比2.3月(1.63.5月)，p<；0.001。OS无显著差异：中位数(95%CI)为26.9(14.4-63.6)个月(A)和24.2(11.3-36.4)个月(B)。A组(4CR，8PR)有效率为22%，B组(1CR，4PR)为17%。A组有65%的患者病情稳定或PR或CR，B组有48%的患者病情稳定。在血清VEGF和VEGFR2水平高低的患者中，联合治疗优于单一治疗。不良事件与IL2和Ziv-afLibercept单一治疗的预期情况一致。与单独使用IL2相比，ZIV-afLibercept和IL2显著改善了PFS，达到了研究的主要终点。我们的发现支持进一步研究涉及血管内皮生长因子抑制剂的免疫治疗组合策略。由于高水平的血管内皮细胞生长因子水平与对IL2的无反应有关，Ziv-afLibercept联合IL2可能通过捕获游离的血管内皮生长因子而具有免疫增强和抗血管生成作用。这项II期研究表明，在不能手术的III或IV期黑色素瘤患者中，联合使用IL2显著改善了PFS，达到了研究的主要终点。
Interleukin-2 (IL2) is a growth factor for T and NK cells, promotes pro-inflammatory cytokines and can lead to durable responses in melanoma. VEGF promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were associated with nonresponse to IL2. Ziv- aflibercept may deplete VEGF and thereby enhance antitumor T cell responses, supporting a combination immunotherapeutic strategy with IL2. NCI 8628 was a phase II trial of ziv-aflibercept and IL2 (arm A) versus IL2 alone (arm B) randomized 2:1 respectively. Eligible patients had inoperable Stage III or IV melanoma. The primary endpoint was progression-free survival (PFS). 89 patients were enrolled and 84 treated. Median follow up was 41.4 months. Among treated patients (55 in A, 29 in B), PFS was significantly improved in favor of A: median (95% CI) of 6.9 (4.1–8.7) months versus 2.3 (1.6–3.5) months, p <0.001. No significant difference in OS: median (95% CI) of 26.9 (14.4–63.6) months (A) and 24.2 (11.3–36.4) months (B). Response rate (RECIST) was 22% in A (4CR, 8PR) and 17% in B (1CR, 4PR). Stable disease or PR or CR was seen in 65% in A and 48% in B. The combination was superior to monotherapy in patients with high and low levels of serum VEGF and VEGFR2. Adverse events were consistent with the expected profiles of monotherapy with IL2 and ziv- aflibercept. Ziv-aflibercept and IL2 significantly improved PFS over IL2 alone, meeting the study’s primary endpoint. Our findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors. Since high VEGF levels were associated with nonresponse to IL2, ziv-aflibercept combined with IL2 may have immune enhancing and antiangiogenic activity via capturing free VEGF. This phase II study demonstrated significantly improved PFS with the combination versus IL2 alone in patients with inoperable Stage III or IV melanoma, meeting the study’s primary endpoint.
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影响因子：
3.9
作者：
Grignol, Valerie P.;Olencki, Thomas;Carson, William E., III
通讯作者：
Carson, William E., III
DOI：
10.1056/nejmoa1709684
发表时间：
2017-10-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Wolchok JD;Chiarion-Sileni V;Gonzalez R;Rutkowski P;Grob JJ;Cowey CL;Lao CD;Wagstaff J;Schadendorf D;Ferrucci PF;Smylie M;Dummer R;Hill A;Hogg D;Haanen J;Carlino MS;Bechter O;Maio M;Marquez-Rodas I;Guidoboni M;McArthur G;Lebbé C;Ascierto PA;Long GV;Cebon J;Sosman J;Postow MA;Callahan MK;Walker D;Rollin L;Bhore R;Hodi FS;Larkin J
通讯作者：
Larkin J
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
2.2
作者：
Tas, Faruk;Duranyildiz, Derya;Topuz, Erkan
通讯作者：
Topuz, Erkan
影响因子：
10.1
作者：
Hodi FS;Lawrence D;Lezcano C;Wu X;Zhou J;Sasada T;Zeng W;Giobbie-Hurder A;Atkins MB;Ibrahim N;Friedlander P;Flaherty KT;Murphy GF;Rodig S;Velazquez EF;Mihm MC Jr;Russell S;DiPiro PJ;Yap JT;Ramaiya N;Van den Abbeele AD;Gargano M;McDermott D
通讯作者：
McDermott D