伊马替尼对照干扰素辅助治疗c-Kit突变的黑色素瘤患者的Ⅱ期临床研究
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摘要
目的伊马替尼已经改变了c-Kit的晚期黑色素瘤的治疗模式,但在辅助治疗中尚无尝试。我们开展这项临床研究(NCT01782508),旨在比较伊马替尼和大剂量干扰素(HDI)在c-Kit突变的术后高危患者中的疗效及安全性。方法 48例存在c-Kit 9、11或13号外显子突变的高危黑色素瘤患者被纳入此项研究,并随机(1∶2)分入伊马替尼组(400 mg/d)或HDI组(15×106 U/m2 d1~d5/周×4周,之后9×106 U,每周3次×48周)。主要终点指标为无复发生存期(RFS),次要终点指标为无远处转移生存时间(DMFS)、总生存时间(OS)及耐受性。结果最常见的c-Kit突变为c-KitL576P(13/48)。截至2015年10月,HDI组中的中位RFS为29.8个月(95%CI 23.3~36.3个月),明显优于伊马替尼组(10.0个月;95%CI 0~20.0个月)(P=0.029)。在c-KitL576P突变的患者中观察到类似的趋势(P=0.005)(伊马替尼组仅4.8个月,而HDI组达34.2个月)。两组患者的预计OS相似(P=0.43)。在HDI组中记录到更多的3~4度不良反应。结论在此项研究中,伊马替尼与HDI相比并未延长c-Kit突变高危黑色素瘤患者的RFS。伊马替尼可能不适合被推荐单独用于c-Kit突变高危黑色素瘤患者的辅助治疗。
Objective Imatinib has changed the treatment paradigm for metastatic melanoma with c-Kit aberrations. However, it has not been trailed whether imatinib could be used as adjuvant therapy for melanomas. We conducted a randomized phase Ⅱ clinical trial(NCT01782508) in high-risk melanoma patients bearing c-Kit mutations to compare the efficacy and safety of imatinib with high-dose IFN-α2b(HDI). Methods Forty-eight high-risk melanoma patients(stage Ⅱb-Ⅲc) with c-Kit mutations in exons 9, 11 or 13 after surgery without prior systemic therapy were randomized(ratio of 1∶2) to imatinib(400 mg daily) or HDI(15×106 Unit/m2 d1-5/week×4 weeks plus 9×106 Unit, 3 times a week×48 weeks) arm. The primary endpoint was recurrence-free survival(RFS), and the secondary endpoints were distant metastasis-free survival(DMFS), overall survival(OS) and tolerability. Results The most common c-Kit mutation in patients was c-KitL576P(13/48). By October 2015, the median RFS of patients in HDI arm was 29.8 months(95% CI: 23.3-36.3 months), which was significantly(P=0.029) superior to that in imatinib arm(10.0 months; 95% CI: 0-20.0 months). Similar trend of RFS(P=0.005) was observed in patients harboring c-KitL576 P mutation(4.8 months in imatinib arm versus 34.2 months in HDI arm). The estimated median OS was similar in both arms(P=0.43). More Grade 3/4 toxicities were recorded in the HDI arm. Conclusions Imatinib could not prolong RFS when compared with HDI as adjuvant therapy for high-risk melanoma patients with c-Kit mutations. Imatinib alone is not suitable for recommendation as adjuvant therapy for the high-risk melanoma patients with c-Kit mutations.
Objective Imatinib has changed the treatment paradigm for metastatic melanoma with c-Kit aberrations. However, it has not been trailed whether imatinib could be used as adjuvant therapy for melanomas. We conducted a randomized phase Ⅱ clinical trial(NCT01782508) in high-risk melanoma patients bearing c-Kit mutations to compare the efficacy and safety of imatinib with high-dose IFN-α2b(HDI). Methods Forty-eight high-risk melanoma patients(stage Ⅱb-Ⅲc) with c-Kit mutations in exons 9, 11 or 13 after surgery without prior systemic therapy were randomized(ratio of 1∶2) to imatinib(400 mg daily) or HDI(15×106 Unit/m2 d1-5/week×4 weeks plus 9×106 Unit, 3 times a week×48 weeks) arm. The primary endpoint was recurrence-free survival(RFS), and the secondary endpoints were distant metastasis-free survival(DMFS), overall survival(OS) and tolerability. Results The most common c-Kit mutation in patients was c-KitL576P(13/48). By October 2015, the median RFS of patients in HDI arm was 29.8 months(95% CI: 23.3-36.3 months), which was significantly(P=0.029) superior to that in imatinib arm(10.0 months; 95% CI: 0-20.0 months). Similar trend of RFS(P=0.005) was observed in patients harboring c-KitL576 P mutation(4.8 months in imatinib arm versus 34.2 months in HDI arm). The estimated median OS was similar in both arms(P=0.43). More Grade 3/4 toxicities were recorded in the HDI arm. Conclusions Imatinib could not prolong RFS when compared with HDI as adjuvant therapy for high-risk melanoma patients with c-Kit mutations. Imatinib alone is not suitable for recommendation as adjuvant therapy for the high-risk melanoma patients with c-Kit mutations.
引文
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[12]Alberts SR,Sargent DJ,Nair S,et al.Effect of oxaliplatin,fluorouracil,and leucovorin with or without cetuximab on survival among patients with resected stageⅢcolon cancer:a randomized trial[J].JAMA,2012,307(13):1383-1393.
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[14]Allegra CJ,Yothers G,O'Connell MJ,et al.Bevacizumab in stageⅡ-Ⅲcolon cancer:5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial[J].J Clin Oncol,2013,31(3):359-364.
[15]Haas NB,Manola J,Ky B,et al.Effects of Adjuvant Sorafenib and Sunitinib on Cardiac Function in Renal Cell Carcinoma Patients without Overt Metastases:Results from ASSURE,ECOG 2805[J].Clin Cancer Res,2015,21(18):4048-4054.
[16]Norton L.Conceptual and practical implications of breast tissue geometry:toward a more effective,less toxic therapy[J].Oncologist,2005,10(6):370-381.
[17]Davies H,Bignell GR,Cox C,et al.Mutations of the BRAF gene in human cancer[J].Nature,2002,417(6892):949-954.
[18]Kong Y,Si L,Zhu Y,et al.Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma[J].Clin Cancer Res,2011,17(7):1684-1691.
[19]Kirkwood JM,Strawderman MH,Ernstoff MS,et al.Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma:the Eastern Cooperative Oncology Group Trial EST 1684[J].J Clin Oncol,1996,14(1):7-17.
[20]Heinzelmann-Schwarz VA,Nixdorf S,Valadan M,et al.A clinicopathological review of 33 patients with vulvar melanoma identifies c-Kit as a prognostic marker[J].Int J Mol Med,2014,33(4):784-794.
[21]Todd JR,Scurr LL,Becker TM,et al.The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma[J].Oncogene,2014,33(2):236-245.
[22]Eggermont AM,Chiarion-Sileni V,Grob JJ,et al.Adjuvant ipilimumab versus placebo after complete resection of high-risk stageⅢmelanoma(EORTC 18071):a randomised,double-blind,phase 3trial[J].Lancet Oncol,2015,16(5):522-530.
[23]Ascierto PA,Kirkwood JM.Adjuvant therapy of melanoma with interferon:lessons of the past decade[J].J Transl Med,2008,6:62.
[24]Rafique I,Kirkwood JM,Tarhini AA.Immune checkpoint blockade and interferon-αin melanoma[J].Semin Oncol,2015,42(3):436-447.
[2]Mocellin S,Pasquali S,Rossi CR,et al.Interferon alpha adjuvant therapy in patients with high-risk melanoma:a systematic review and meta-analysis[J].J Natl Cancer Inst,2010,102(7):493-501.
[3]Young K,Minchom A,Larkin J.BRIM-1,-2 and-3 trials:improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E)mutation[J].Future Oncol,2012,8(5):499-507.
[4]Guo J,Si L,Kong Y,et al.Phase II,open-label,single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification[J].J Clin Oncol,2011,29(21):2904-2909.
[5]Carvajal RD,Antonescu CR,Wolchok JD,et al.KIT as a therapeutic target in metastatic melanoma[J].JAMA,2011,305(22):2327-2334.
[6]Hodi FS,Corless CL,Giobbie-Hurder A,et al.Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal,acral,and chronically sun-damaged skin[J].J Clin Oncol,2013,31(26):3182-3190.
[7]Lian B,Si L,Cui C,et al.Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma[J].Clin Cancer Res,2013,19(16):4488-4498.
[8]Mao L,Si L,Chi Z,et al.A randomised phase II trial of 1 month versus 1 year of adjuvant high-dose interferonα-2b in high-risk acral melanoma patients[J].Eur J Cancer,2011,47(10):1498-1503.
[9]Heinrich MC,Corless CL,Blanke CD,et al.Molecular correlates of imatinib resistance in gastrointestinal stromal tumors[J].J Clin Oncol,2006,24(29):4764-4774.
[10]Chen LL,Trent JC,Wu EF,et al.A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors[J].Cancer Res,2004,64(17):5913-5919.
[11]Chen H,Isozaki K,Kinoshita K,et al.Imatinib inhibits various types of activating mutant kit found in gastrointestinal stromal tumors[J].Int J Cancer,2003,105(1):130-135.
[12]Alberts SR,Sargent DJ,Nair S,et al.Effect of oxaliplatin,fluorouracil,and leucovorin with or without cetuximab on survival among patients with resected stageⅢcolon cancer:a randomized trial[J].JAMA,2012,307(13):1383-1393.
[13]de Gramont A,Van Cutsem E,Schmoll HJ,et al.Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer(AVANT):a phase 3 randomised controlled trial[J].Lancet Oncol,2012,13(12):1225-1233.
[14]Allegra CJ,Yothers G,O'Connell MJ,et al.Bevacizumab in stageⅡ-Ⅲcolon cancer:5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial[J].J Clin Oncol,2013,31(3):359-364.
[15]Haas NB,Manola J,Ky B,et al.Effects of Adjuvant Sorafenib and Sunitinib on Cardiac Function in Renal Cell Carcinoma Patients without Overt Metastases:Results from ASSURE,ECOG 2805[J].Clin Cancer Res,2015,21(18):4048-4054.
[16]Norton L.Conceptual and practical implications of breast tissue geometry:toward a more effective,less toxic therapy[J].Oncologist,2005,10(6):370-381.
[17]Davies H,Bignell GR,Cox C,et al.Mutations of the BRAF gene in human cancer[J].Nature,2002,417(6892):949-954.
[18]Kong Y,Si L,Zhu Y,et al.Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma[J].Clin Cancer Res,2011,17(7):1684-1691.
[19]Kirkwood JM,Strawderman MH,Ernstoff MS,et al.Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma:the Eastern Cooperative Oncology Group Trial EST 1684[J].J Clin Oncol,1996,14(1):7-17.
[20]Heinzelmann-Schwarz VA,Nixdorf S,Valadan M,et al.A clinicopathological review of 33 patients with vulvar melanoma identifies c-Kit as a prognostic marker[J].Int J Mol Med,2014,33(4):784-794.
[21]Todd JR,Scurr LL,Becker TM,et al.The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma[J].Oncogene,2014,33(2):236-245.
[22]Eggermont AM,Chiarion-Sileni V,Grob JJ,et al.Adjuvant ipilimumab versus placebo after complete resection of high-risk stageⅢmelanoma(EORTC 18071):a randomised,double-blind,phase 3trial[J].Lancet Oncol,2015,16(5):522-530.
[23]Ascierto PA,Kirkwood JM.Adjuvant therapy of melanoma with interferon:lessons of the past decade[J].J Transl Med,2008,6:62.
[24]Rafique I,Kirkwood JM,Tarhini AA.Immune checkpoint blockade and interferon-αin melanoma[J].Semin Oncol,2015,42(3):436-447.