Hillemanns Peter, Zikan Michal, Forget Frédéric, Denys Hannelore G, Baurain Jean-Francois, Rob Lukas, Woelber Linn, Blecharz Pawel, Bidzinski Mariusz, Chovanec Josef, Marmé Frederik, Link Theresa, Dannecker Christian, Rosholm Anders, Berg Kaja C G, Oliveri Roberto S, Lindemann Kristina
Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany.
Department of Obstetrics and Gynecology, Bulovka University Hospital Na Bulovce Budinova 67/2, Prague, Czech Republic.
J Immunother Cancer. 2025 Jan 7;13(1):e010827. doi: 10.1136/jitc-2024-010827.
Second-line treatment options for persistent, recurrent or metastatic (r/m) cervical cancer are limited. We investigated the safety, efficacy, and immunogenicity of the therapeutic DNA-based vaccine VB10.16 combined with the immune checkpoint inhibitor atezolizumab in patients with human papillomavirus (HPV)16-positive r/m cervical cancer.
This multicenter, single-arm, phase 2a study (NCT04405349, registered 26 May 2020) enrolled adult patients with persistent, r/m HPV16-positive cervical cancer. Patients received 3 mg VB10.16 (every 3 weeks (Q3W) for 12 weeks, hereafter every 6 weeks) combined with 1,200 mg atezolizumab (Q3W) for 48 weeks in total with a 12-month follow-up. The primary endpoints were incidence and severity of adverse events (AEs) and objective response rate (ORR; Response Evaluation Criteria in Solid Tumor V.1.1). ORR was assessed in the efficacy population, being all response-evaluable patients who received any administration of VB10.16 and atezolizumab and had at least one post-baseline imaging assessment.
Between June 16, 2020, and January 25, 2022, 52 patients received at least one administration of study treatment. Of these, 47 patients had a minimum of one post-baseline tumor assessment. The median follow-up time for survival was 11.7 months. AEs related to VB10.16 were non-serious and mainly mild injection site reactions (9 of 52 patients). There were no signs of new toxicities other than what was already described with atezolizumab. ORR was 19.1% (95% CI 9.1% to 33.3%). Median duration of response was not reached (n.r.) (95% CI 2.2 to n.r.), median progression-free survival was 4.1 months (95% CI 2.1 to 6.2), and median overall survival was 21.3 months (95% CI 8.5 to n.r.). In programmed death-ligand 1 (PD-L1)-positive patients (n=24), ORR was 29.2% (95% CI 12.6 to 51.1). HPV16-specific T-cell responses were analyzed in 36 of 47 patients with an increase observed in 22/36 (61%).
The therapeutic DNA-based vaccine VB10.16 combined with atezolizumab was safe and well tolerated showing a promising clinically meaningful efficacy with durable responses in patients with persistent, r/m HPV16-positive cervical cancer, especially if PD-L1-positive.
持续性、复发性或转移性（r/m）宫颈癌的二线治疗选择有限。我们研究了基于治疗性DNA的疫苗VB10.16联合免疫检查点抑制剂阿替利珠单抗在人乳头瘤病毒（HPV）16阳性r/m宫颈癌患者中的安全性、疗效和免疫原性。
这项多中心、单臂2a期研究（NCT04405349，于2020年5月26日注册）纳入了患有持续性、r/m HPV16阳性宫颈癌的成年患者。患者接受3mg VB10.16（每3周一次（Q3W），共12周，此后每6周一次）联合1200mg阿替利珠单抗（Q3W），总共治疗48周，并进行12个月的随访。主要终点是不良事件（AE）的发生率和严重程度以及客观缓解率（ORR；实体瘤疗效评价标准第1.1版）。在疗效人群中评估ORR，疗效人群为所有接受过任何剂量VB10.16和阿替利珠单抗治疗且至少有一次基线后影像学评估的可评估缓解情况的患者。
在2020年6月16日至2022年1月25日期间，52例患者接受了至少一次研究治疗。其中，47例患者至少有一次基线后肿瘤评估。生存的中位随访时间为11.7个月。与VB10.16相关的AE不严重，主要为轻度注射部位反应（52例患者中有9例）。除了阿替利珠单抗已描述的毒性外，没有新的毒性迹象。ORR为19.1%（95%CI 9.1%至33.3%）。中位缓解持续时间未达到（n.r.）（95%CI 2.2至n.r.），中位无进展生存期为4.1个月（95%CI 2.1至6.2），中位总生存期为21.3个月（95%CI 8.5至n.r.）。在程序性死亡配体1（PD-L1）阳性患者（n = 24）中，ORR为29.2%（95%CI 12.6%至51.1%）。在接受分析的47例患者中的36例中分析了HPV16特异性T细胞反应，其中22/36（61%）观察到反应增加。
基于治疗性DNA的疫苗VB10.16联合阿替利珠单抗是安全的，耐受性良好，在持续性、r/m HPV16阳性宫颈癌患者中显示出有前景的具有临床意义的疗效和持久反应，尤其是PD-L1阳性患者。
