Guo J, Carvajal R D, Dummer R, Hauschild A, Daud A, Bastian B C, Markovic S N, Queirolo P, Arance A, Berking C, Camargo V, Herchenhorn D, Petrella T M, Schadendorf D, Sharfman W, Testori A, Novick S, Hertle S, Nourry C, Chen Q, Hodi F S
Department of Renal Cancer & Melanona, Peking University Cancer Hospital & Institute, Beijing, China.
Division of Hematology/Oncology, Columbia University Medical Center, New York, USA.
Ann Oncol. 2017 Jun 1;28(6):1380-1387. doi: 10.1093/annonc/mdx079.
The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.
Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.
ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.
Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.
ClinicalTrials.gov, NCT01028222.
单臂II期替西罗莫司在晚期黑色素瘤中的疗效（TEAM）试验评估了KIT选择性酪氨酸激酶抑制剂尼洛替尼在未经KIT抑制剂治疗的KIT突变晚期黑色素瘤患者中的疗效。
42例KIT突变晚期黑色素瘤患者入组，接受尼洛替尼400mg每日两次治疗。TEAM试验最初纳入了接受达卡巴嗪（DTIC）治疗的患者作为对照臂；由于观察到KIT突变黑色素瘤患者数量较少，试验设计修改为单臂试验。在方案修订删除该研究臂之前，13例患者被随机分配至DTIC组。主要终点为客观缓解率（ORR），根据实体瘤疗效评价标准确定。
ORR为26.2%（n = 11/42；95%CI，13.9%-42.0%），足以拒绝原假设（ORR≤10%）。所有观察到的缓解均为部分缓解（PRs；中位缓解持续时间，7.1个月）。20例患者（47.6%）疾病稳定，10例（23.8%）疾病进展；1例（2.4%）患者的缓解情况未知。11例缓解患者中有10例存在外显子11突变，4例为L576P突变。中位无进展生存期和总生存期分别为4.2个月和18.0个月。13例接受DTIC治疗的患者中有3例达到PR，另1例患者在换用尼洛替尼后达到PR。
尼洛替尼在晚期KIT突变黑色素瘤患者中的活性与伊马替尼治疗患者的历史数据相似。DTIC治疗显示出潜在活性，尽管患者数量较少限制了结果解读。与先前伊马替尼报道的结果相似，尼洛替尼在包括L576P在内的外显子11突变患者中显示出更大活性，提示尼洛替尼可能是特定KIT突变患者的有效治疗选择。
ClinicalTrials.gov，NCT01028222。
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