Zandberg Dan P, Allred Jacob B, Rosenberg Ari J, Kaczmar John M, Swiecicki Paul, Julian Ricklie A, Poklepovic Andrew S, Bauman Jessica R, Phan Minh D, Saba Nabil F, Rivera Edgardo, Rowland Kendrith, Davar Diwakar, Cordes Julia, Ho Alan L, Zhang Miao, Berg Stephanie A, Munster Pamela N, Schwartz Gary K
UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.
Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN.
J Clin Oncol. 2025 Jul 20;43(21):2398-2408. doi: 10.1200/JCO-25-00759. Epub 2025 May 31.
Continued improvement in outcomes is needed for advanced cutaneous squamous cell carcinoma (cSCC).
Alliance A091802 is a randomized phase II trial of avelumab (800 mg IV once every 2 weeks) plus cetuximab (500 mg/m IV once every 2 weeks) versus avelumab alone once every 2 weeks for up to 2 years. Cetuximab was given for 1 year in the avelumab + cetuximab arm. Crossover at progression to avelumab + cetuximab was allowed. Randomization was 1:1, stratified by PD-L1 and HIV status. Patients had distant metastatic or unresectable locally advanced cSCC, were anti-PD-1/PD-L1 monoclonal antibody-naive, had no previous cetuximab in the advanced setting, had an Eastern Cooperative Oncology Group performance status of 0-2, and could be HIV+ (CD4 >200, viral load <200). Patients with chronic lymphocytic leukemia, immunosuppression, or active autoimmune diseases were excluded. The primary end point was progression-free survival (PFS; null hypothesis: median = 12 months alternative hypothesis: 21 months or a 75% improvement, power of 80% with one-sided alpha .2, n = 57, 37 PFS events required). Secondary end points were overall survival, objective response rates (ORRs), clinical benefit rate, and toxicity.
Sixty patients were enrolled; 57 patients were evaluable. The median age was 72 years, all were HIV-; 75.4% was PD-L1+, 84.2% had head/neck origin, 47.4% had distant metastasis, and there were no differences in baseline characteristics by arm. Avelumab + cetuximab significantly improved PFS versus avelumab (median, 11.1 [7.6-not reached (NR)] 3.0 months [2.7-13.6] hazard ratio, 0.48 [95% CI, 0.23 to 0.97], = .018). Avelumab patients who crossed over (n = 9) to combination had a median PFS after crossover of 11.3 months (5.8-NR). The confirmed ORR was 27.6% with avelumab + cetuximab and 21.4% with avelumab. Grade 3 treatment-related adverse events occurred in 48.3% and 21.5% of patients with avelumab + cetuximab (most common: rash [20.7%], infusion reaction [20.7%]) and avelumab, respectively.
Avelumab + cetuximab significantly improved PFS versus avelumab alone in patients with advanced cSCC. Alliance A091802 supports a larger confirmatory study with the combination of cetuximab and PD-1:PD-(L)1 blockade.
晚期皮肤鳞状细胞癌（cSCC）的治疗效果仍需持续改善。
联盟A091802是一项随机II期试验，比较阿维鲁单抗（800mg静脉注射，每2周一次）联合西妥昔单抗（500mg/m²静脉注射，每2周一次）与单独使用阿维鲁单抗（每2周一次），持续2年。在阿维鲁单抗联合西妥昔单抗组中，西妥昔单抗使用1年。疾病进展时允许交叉使用阿维鲁单抗联合西妥昔单抗。随机分组比例为1:1，按PD-L1和HIV状态分层。患者患有远处转移性或不可切除的局部晚期cSCC，未接受过抗PD-1/PD-L1单克隆抗体治疗，在晚期阶段未使用过西妥昔单抗，东部肿瘤协作组体能状态为0-2，且HIV检测可为阳性（CD4>200，病毒载量<200）。排除患有慢性淋巴细胞白血病、免疫抑制或活动性自身免疫性疾病的患者。主要终点为无进展生存期（PFS；原假设：中位数=12个月；备择假设：21个月或改善75%，单侧α=0.2时检验效能为80%，n=57，需要37个PFS事件）。次要终点为总生存期、客观缓解率（ORR）、临床获益率和毒性。
共入组60例患者；57例患者可评估。中位年龄为72岁，均为HIV阴性；75.4%为PD-L1阳性，84.2%起源于头颈部，47.4%有远处转移，两组基线特征无差异。与阿维鲁单抗相比，阿维鲁单抗联合西妥昔单抗显著改善了PFS（中位数，11.1[7.6-未达到（NR）]对3.0个月[2.7-13.6]；风险比，0.48[95%CI，0.23至0.97]，P=.018）。交叉使用联合治疗的阿维鲁单抗患者（n=9）交叉后的中位PFS为11.3个月（5.8-NR）。阿维鲁单抗联合西妥昔单抗的确认ORR为27.6%，阿维鲁单抗为21.4%。阿维鲁单抗联合西妥昔单抗组和阿维鲁单抗组3级治疗相关不良事件分别发生在48.3%和21.5%的患者中（最常见的是：皮疹[20.7%]，输液反应[20.7%]）。
在晚期cSCC患者中，与单独使用阿维鲁单抗相比，阿维鲁单抗联合西妥昔单抗显著改善了PFS。联盟A091802支持开展一项更大规模的西妥昔单抗与PD-1:PD-(L)1阻断联合治疗的验证性研究。
