人类乳突病毒治疗(人类乳突病毒症状)

2019年美国癌症研究协会(AACR)年会于2019年3月29日—4月3日在美国亚特兰大举行。AACR年会是世界上规模最大的癌症研究会议之一，今年AACR大会主题为“综合性癌症科学•全球影响•个性化患者护理”。 靶向治疗的发展日新月异，若靶向治疗针对TGF-β信号通路可能会增强其对PD-1或PD-L1抗体的临床应答。今年AACR年会上公布了靶向TGF-β和PD-L1的双功能融合蛋白M7824用于人乳头瘤病毒（HPV）相关恶性肿瘤患者的I期临床研究，以下简要介绍这项研究。

研究背景：

TGF-β信号通路失调可能在HPV相关癌症的发生发展和免疫逃避中起关键作用，其相关癌症包括肛门癌、宫颈癌和p16阳性头颈部鳞状细胞癌（SCCHN）。如果靶向治疗针对该信号通路可以增强其对PD-1或PD-L1抗体的临床应答。 M7824是一种新型、存在两个细胞外结构域的双功能融合蛋白。在正在进行的I期M7824 临床研究（NCT02517398）的剂量扩增队列中，HPV特异性免疫应答的HPV相关癌症患者对M7824治疗的临床应答得到改善。本次AACR大会汇报了来自HPV相关癌症扩增队列的HPV阳性恶性肿瘤患者的疗效和安全性数据。

研究方法：

患者在剂量递增阶段接受M7824 Q2W治疗或在扩增队列阶段接受推荐II期试验剂量1200mg。一直接受治疗直至疾病进展（PD），或产生不可接受的毒性或试验终止，如果临床上合理，允许进展后接受其他治疗。 主要研究终点是剂量递增和剂量扩增阶段的安全性和总缓解率。

研究结果：

截至2018年8月24日，36例经治的HPV阳性HPV相关癌症患者（4例肛门癌，18例宫颈癌，14例头颈部鳞状细胞癌）接受M7824治疗，中位持续时间为19.0周。10例患者产生缓解，其中2例完全缓解（CR），8例部分缓解（PR），ORR为 27.8％，另有1例患者在数据截止后产生PR，另有3例患者在最初产生疾病进展后又出现缓解（缓解率为38.9％）。CR患者和5例PR患者均有持续缓解反应，中位缓解持续时间未达到。

9例（25％）患者产生3级治疗相关不良事件（TRAE），包括贫血、膀胱炎、糖尿病酮症酸中毒、γ-谷氨酰转移酶增加、胃轻瘫、角化过度、低钾血症、角化棘皮瘤、黄斑疹、胸腔积液、肺炎。胃轻瘫患者还有无症状3~4级低钾血症（1例4级TRAE，2.7％）。无治疗相关死亡事件发生。6例患者（16.7％）由于治疗相关不良事件（胃轻瘫、输液相关反应、膀胱炎、肺炎、痤疮和牛皮癣）永久停用M7824。

结论：

M7824具有可控的安全性，并且在HPV阳性HPV相关癌症患者中显示出较好的临床疗效。M7824是这类患者人群中有潜力和希望的治疗方案，且正在进行Ib期和II期临床试验以进一步评估疗效。

英文摘要

Background:

TGF-β pathway dysregulation may play a critical role in carcinogenesis and immune evasion in HPV-associated cancers (HACs), including anal, cervical, and p16+ squamous cell carcinoma of the head and neck (SCCHN). Targeting this pathway may also enhance clinical response to PD-(L)1 antibodies. M7824 is an innovative first-in-class bifunctional fusion protein composed of two extracellular domains of TGF-βRII (a TGF-β “trap”) fused with a human IgG1 monoclonal antibody against PD-L1. In the dose-escalation cohort of the ongoing Phase I trial of M7824 (NCT02517398), patients with HACs who developed an HPV-specific immune response on M7824 had improved clinical responses. Here we report efficacy and safety data from patients with HPV-positive malignancies from the dose-escalation cohort pooled with data from HAC expansion cohorts for patients with HPV-positive disease.

Methods:

Patients received M7824 Q2W at 1-30 mg/kg in the dose-escalation phase or at the recommended phase 2 dose of 1200 mg in the expansion cohorts. Treatment continued until progressive disease (PD), unacceptable toxicity, or trial withdrawal; treatment past PD was allowed if clinically justified. Safety and best overall response by RECIST v1.1 were the primary endpoints of the dose-escalation and expansion phases, respectively.

Results:

As of August 24, 2018, 36 patients with pretreated HPV-positive HACs (4 anal; 18 cervical; 14 SCCHN) had received M7824 for a median duration of 19.0 weeks (range, 2.0-96.0). 10 patients had a response per investigator (2 complete response [CR]; 8 partial response [PR]; ORR 27.8%). 1 additional patient developed a PR after data cutoff; 3 additional patients had a delayed PR after initial PD (total clinical response rate 38.9%). Both patients with CR and 5 patients with PR have an ongoing response. The median duration of response was not reached (range, 4-22+ months). 9 patients (25%) had grade 3 treatment-related adverse events (TRAE): anemia, cystitis, diabetic ketoacidosis, increased γ-glutamyltransferase, gastroparesis, hyperkeratosis, hypokalemia, keratoacanthoma, macular rash, pleural effusion, pneumonitis, and skin SCC. The patient with gastroparesis had asymptomatic grade 3→4 hypokalemia (1 grade 4 TRAE, 2.7%). No treatment-related deaths occurred. 6 patients (16.7%) permanently discontinued M7824 due to TRAEs (gastroparesis, infusion-related reaction, cystitis, pneumonitis, and acneiform and psoriasiform dermatitis).

Conclusions:

M7824 has a manageable safety profile and shows encouraging clinical efficacy in patients with HPV-positive HACs (total clinical response rate 38.9%). M7824 is a promising therapeutic agent for these patients and is under further evaluation in phase 1b and 2 trials. Updated survival results will be reported.

参考文献：

Phase I evaluation of M7824, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus (HPV)-associated malignancies. abstract CT075

2019 AACR 专题

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