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12月3日，第58届美国血液学年会（ASH，12月3日~6日）于美国圣地亚哥召开。其间，在“
背景
皮肤T细胞淋巴瘤（CTCL）是一种严重影响生活质量的慢性疾病，晚期发病，预后差。目前的系统性疗法很难产生可靠持久的响应，并且也没有一种系统性药物表现出来的预后能够优于标准方案如
方法
该研究纳入了曾接受过至少1种方案治疗的CD表达蕈样肉芽肿（MF）患者以及曾接受过至少1种方案治疗或放疗的原发性皮肤间变性大细胞淋巴瘤（pcALCL）患者，按照1：1将其随机分配至BV组（1.8 mg/kg IV， 每3周1次）或PC组（MTX 5–50 mg PO， 每周1次，或Bex 300 mg/m² （靶剂量） PO，每日1次），持续16个疗程（3周为1疗程），直至疾病进展或产生不可耐受的毒性。主要终点是持续4个月以上的ORR率，次要终点是CR率、PFS和症状负担。
结果
该研究最终纳入128名为意向治疗人群（97 MF， 31 pcALCL），并将其分配至BV 组（n=64）或PC组（n=64）。除BV 组有更多的患者存在髓外病变以外，两组的其它基线特征均被平衡（表）。BV组和PC组患者的中位年龄分别为62 （22–83）岁 vs 58 （22–83）岁，ECOG体能状态评分0~1的比例分别为95% vs 97%，先前接受的系统治疗中位数均为2。
中位随访17.5个月，BV组和PC组的ORR4和中位PFS分别为56% vs 13%和6.7 vs 3.5个月，差异显著（图1、2），ORR分别为67% （n=43） vs 20% （n=13），CR率分别为16% vs 2%。Skindex-29表明，BV组的症状减少比PC组更显著。
患者接受的治疗疗程中位数分别为：BV 12 （1–16），Bex5.5 （1–16）和MTX3 （1–16）。BV组和PC组的3~4级所有原因/药物相关不良反应发生率分别为41% / 29% 和47% / 29%，严重不良反应发生率均为29%，任意级别的外周神经病变率分别为67%和6%。最后一次随访时，BV组36/44 （82%）名患者外周神经病变明显改善或恢复。两组的不良反应所致的治疗中断率分别为24% （BV） vs 8% （PC）。BV组中有4名患者在最后一次剂量后的30天内死亡。其他不良反应与曾报道的药物不良反应相一致。
结论
该3期研究表明，对于治疗CTCL而言，BV所产生的临床预后明显优于标准治疗方案，ORR4和中位PFS改善相当显著，分别为44%和13.2个月，ORR和CR率也明显更高，症状负担明显减小。BV的安全性与已知的耐受性一致。这些数据强有力地支持了BV治疗CD30表达的CTCL的有效性和安全性优于医生选择（Bex或MTX）。
摘要详情
182 Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice （Methotrexate or Bexarotene）： The Phase 3 Alcanza Study
Background
Cutaneous T cell lymphoma （CTCL） is a chronic disease that negatively impacts quality of life （QoL） and， in advanced stages， has poor prognosis. Current systemic therapies rarely provide reliable and durable responses， and to date， no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate （MTX） or bexarotene （Bex）. CD30-directed antibody-drug conjugate brentuximab vedotin （BV） has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates （ORR） of about 70%. These results led to ALCANZA， a randomized， open-label， multicenter phase 3 trial of the efficacy and safety of BV vs physician's choice （PC） of MTX or Bex， in previously treated patients with CD30-expressing CTCL （NCT01578499）. This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL.
Methods
Adults with CD30-expressing （≥10% of infiltrate by central review） mycosis fungoides （MF） who received ≥1 prior systemic therapy or primary cutaneous anaplastic large cell lymphoma （pcALCL） who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1：1 to receive BV 1.8 mg/kg IV， once every 3 weeks， or PC of either MTX 5–50 mg PO， once weekly， or Bex 300 mg/m² （target dose） PO， once daily， for up to 16 three-week cycles， until disease progression or unacceptable toxicity.
Primary endpoint was ORR4， defined as ORR lasting ≥4 months， an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation （modified severity weighted assessment tool）， radiographic assessment， and Sézary cell enumeration. Key secondary endpoints were CR rate， PFS， and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events （AEs） were evaluated according to NCI CTCAE v4.03.
Results
131 patients were randomized with 128 patients in the intent-to-treat population （97 MF， 31 pcALCL； 3 excluded for insufficient CD30 expression） and assigned to BV （n=64） or PC （n=64）. Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm （Table）. In BV vs PC arms， respectively， median age was 62 （22–83） vs 58 （22–83） years； ECOG performance status 0–1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies.
At a median follow-up of 17.5 months， ORR4 （primary endpoint） and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% （p<0.0001） and median PFS of 16.7 vs 3.5 months （HR 0.270； 95% CI， 0.169–0.430； p<0.0001）， respectively （Fig 1， 2）. ORR was 67% （n=43） with CR 16% for BV， compared with ORR of 20% （n=13） with CR 2% for PC （ORR， p<0.0001； CR， p=0.0046）. Skindex-29 showed significantly greater symptom reduction for BV compared with PC （-27.96 vs -8.62； p<0.0001）.
Patients received a median of 12 （1–16） cycles of BV vs 5.5 （1–16） Bex and 3 （1–16） cycles of MTX. Grade 3–4 AEs， all cause / drug-related， were seen in 41% / 29% with BV vs 47% / 29% with PC. Serious AEs were seen in 29% of patients in each arm. Peripheral neuropathy （PN）， any grade， was seen in 67% in the BV arm （32% grade 2， 9% grade 3） and 6% in the PC arm. At last follow-up， 36/44 （82%） patients in the BV arm had improvement or resolution of PN. Discontinuation due to AEs occurred in 24% （BV） vs 8% （PC）. Four deaths in the BV arm （3 unrelated to study drug） occurred within 30 days of the last dose. Other AEs were consistent with reported safety profiles for the individual agents.
Conclusions
In this first report of a randomized phase 3 trial evaluating a new agent vs standard-of-care options in CTCL， the clinical outcome of BV was far superior to PC （MTX or Bex）. Highly statistically significant improvements in ORR4 （44%） and median PFS （13.2 months） were observed with BV. Greater ORR with higher CR rate and reduction in symptoms per Skindex-29 symptom domain were also observed in the BV arm. Safety data for BV were consistent with the established tolerability profile. The data from this randomized trial provide compelling evidence favoring BV over PC of Bex or MTX in CD30-expressing CTCL.
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