2019AACR￨人乳頭瘤病毒相關癌症治療新希望:雙功能融合蛋白M7...

2019AACR￨人乳頭瘤病毒相關癌症治療新希望：雙功能融合蛋白M7824用於這類腫瘤患者初顯效

2019-04-10 來源：醫脈通

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2019年美國癌症研究協會(AACR)年會於2019年3月29日—4月3日在美國亞特蘭大舉行。AACR年會是世界上規模最大的癌症研究會議之一，今年AACR大會主題為「綜合性癌症科學•全球影響•個性化患者護理」。 靶向治療的發展日新月異，若靶向治療針對TGF-β信號通路可能會增強其對PD-1或PD-L1抗體的臨床應答。今年AACR年會上公布了靶向TGF-β和PD-L1的雙功能融合蛋白M7824用於人乳頭瘤病毒（HPV）相關惡性腫瘤患者的I期臨床研究，詳情如下。

研究背景：

TGF-β信號通路失調可能在HPV相關癌症的發生發展和免疫逃避中起關鍵作用，其相關癌症包括肛門癌、宮頸癌和p16陽性頭頸部鱗狀細胞癌（SCCHN）。如果靶向治療針對該信號通路可以增強其對PD-1或PD-L1抗體的臨床應答。 M7824是一種新型、存在兩個細胞外結構域的雙功能融合蛋白。在正在進行的I期M7824 臨床研究（NCT02517398）的劑量擴增隊列中，HPV特異性免疫應答的HPV相關癌症患者對M7824治療的臨床應答得到改善。本次AACR大會匯報了來自HPV相關癌症擴增隊列的HPV陽性惡性腫瘤患者的療效和安全性數據。

研究方法：

患者在劑量遞增階段接受M7824 Q2W治療或在擴增隊列階段接受推薦II期試驗劑量1200mg。一直接受治療直至疾病進展（PD），或產生不可接受的毒性或試驗終止，如果臨床上合理，允許進展後接受其他治療。 主要研究終點是劑量遞增和劑量擴增階段的安全性和總緩解率。

研究結果：

截至2018年8月24日，36例經治的HPV陽性HPV相關癌症患者（4例肛門癌，18例宮頸癌，14例頭頸部鱗狀細胞癌）接受M7824治療，中位持續時間為19.0周。10例患者產生緩解，其中2例完全緩解（CR），8例部分緩解（PR），ORR為 27.8％，另有1例患者在數據截止後產生PR，另有3例患者在最初產生疾病進展後又出現緩解（緩解率為38.9％）。CR患者和5例PR患者均有持續緩解反應，中位緩解持續時間未達到。

9例（25％）患者產生3級治療相關不良事件（TRAE），包括貧血、膀胱炎、糖尿病酮症酸中毒、γ-穀氨醯轉移酶增加、胃輕癱、角化過度、低鉀血症、角化棘皮瘤、黃斑疹、胸腔積液、肺炎。胃輕癱患者還有無症狀3~4級低鉀血症（1例4級TRAE，2.7％）。無治療相關死亡事件發生。6例患者（16.7％）由於治療相關不良事件（胃輕癱、輸液相關反應、膀胱炎、肺炎、痤瘡和牛皮癬）永久停用M7824。

結論：

M7824具有可控的安全性，並且在HPV陽性HPV相關癌症患者中顯示出較好的臨床療效。M7824是這類患者人群中有潛力和希望的治療方案，且正在進行Ib期和II期臨床試驗以進一步評估療效。

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.

參考文獻：

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

點擊直達》2019 AACR會議專題

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