MEDI0457 联合度伐利尤单抗治疗人乳头瘤病毒相关复发性/转移性头颈部鳞状细胞癌患者的安全性和疗效。
Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.
机构信息
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Winship Cancer Institute, Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
出版信息
Clin Cancer Res. 2023 Feb 1;29(3):560-570. doi: 10.1158/1078-0432.CCR-22-1987.
PURPOSE
Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC.
PATIENTS AND METHODS
In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS).
RESULTS
Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells.
CONCLUSIONS
MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
目的
肿瘤程序性细胞死亡配体 1（PD-L1）在人乳头瘤病毒（HPV）相关头颈部鳞状细胞癌（HNSCC）中较为常见。我们评估了 HPV-16/18 E6/E7 靶向 DNA 疫苗与 IL12 佐剂（MEDI0457）联合 PD-L1 抑制剂 durvalumab 是否可以增强 HPV 特异性 T 细胞反应，并改善复发性/转移性 HPV-16/18 相关 HNSCC 的预后。
患者和方法
在这项 Ib/IIa 期研究中，接受过≥1 种含铂方案（新辅助/辅助治疗或复发性/转移性疾病）的免疫治疗初治患者接受 MEDI0457 7mg 肌内注射，联合电穿孔，在第 1、3、7 和 12 周，然后每 8 周一次，联合 durvalumab 1500mg 静脉输注，在第 4、8 和 12 周，然后每 4 周一次，直至确认疾病进展和/或不可接受的毒性。主要研究目的是安全性和客观缓解率（ORR；H0：ORR≤15%）；次要研究目的包括 16 周疾病控制率（DCR-16）、总生存期（OS）和无进展生存期（PFS）。
结果
在 35 例接受治疗的患者中，有 29 例（确认 HPV 相关疾病；接受两种药物治疗）可评估反应。ORR 为 27.6%（95%CI，12.7-47.2；4 例完全缓解，4 例部分缓解）；反应与 PD-L1 肿瘤细胞表达无关（≥25%与<25%）。DCR-16 为 44.8%（95%CI，26.5-64.3）。中位 PFS 为 3.5 个月（95%CI，1.9-9.0）；中位 OS 为 29.2 个月（15.2-未计算）。28 例（80.0%）患者发生治疗相关不良事件（3 级：5 例[14.3%]；无 4/5 级），2 例（5.7%）患者因不良事件停药。治疗期间 HPV-16/18 特异性 T 细胞增加；8 例可评估患者中有 4 例肿瘤浸润 CD8+T 细胞增加了>2 倍。
结论
MEDI0457 联合 durvalumab 耐受性良好。虽然主要疗效终点未达到，但临床获益令人鼓舞。
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