Abstract：
OBJECTIVE: Folate receptor alpha (FRα) is overexpressed on >90% of high-grade epithelial ovarian cancers (EOC). Targeting FRα with antibody-drug conjugates has proven utility in the platinum-resistant setting. It is also a potential therapeutic target for immuno-oncologic agents, such as peptide vaccines that work primarily via adaptive and humoral immunity. We tested the hypothesis that FRα peptide immunization could improve outcomes in patients with EOC following response to platinum-based therapy.
METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS).
RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event.
CONCLUSIONS: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
METHODS: We conducted a randomized, double-blind, multicenter, phase II study to evaluate the safety and efficacy of TPIV200 (a multi-epitope FRα peptide vaccine admixed with GM-CSF) versus GM-CSF alone in 120 women who did not have disease progression after at least 4 cycles of first-line platinum-based therapy. Patients were vaccinated intradermally once every 4 weeks up to 6 times, followed by a boosting period of 6 vaccinations at 12-week intervals. Primary endpoints included safety, tolerability, and progression free survival (PFS).
RESULTS: At study termination with a median follow-up of 15.2 months (range 1.2-28.4 months), 68 of 119 intention-to-treat patients had disease progression (55% in TPIV200 + GM-CSF arm and 59% in GM-CSF alone arm). The median PFS was 11.1 months (95% CI 8.3-16.6 months) with no significant difference between the treatment groups (10.9 months with TPIV200 + GM-CSF versus 11.1 months with GM-CSF, HR, 0.85; upper 90% CI 1.17]. No patient experienced a ≥ grade 3 drug-related adverse event.
CONCLUSIONS: TPIV200 was well tolerated but was not associated with improved PFS. Additional studies are required to uncover potential synergies using multiepitope vaccines targeting FRα. Trial Registration NLM/NCBI Registry, NCT02978222, https://clinicaltrials.gov/search?term=NCT02978222.
摘要：
目的：叶酸受体α（FRα）在>90％的高级别上皮性卵巢癌（EOC）中过表达。用抗体-药物缀合物靶向FRα已被证明在铂抗性环境中具有实用性。它也是免疫肿瘤药物的潜在治疗靶点，例如主要通过适应性和体液免疫起作用的肽疫苗。我们测试了以下假设：FRα肽免疫可以改善EOC患者对基于铂的治疗产生反应后的预后。
方法：我们进行了随机，双盲,多中心，II期研究旨在评估TPIV200（一种与GM-CSF混合的多表位FRα肽疫苗）与单独GM-CSF的安全性和有效性，这些女性在至少4个周期的一线铂类治疗后没有疾病进展。患者每4周一次皮内接种疫苗，最多6次，随后是12周间隔的6次疫苗接种的加强期。主要终点包括安全性，耐受性,无进展生存期（PFS）。
结果：在研究终止时，中位随访时间为15.2个月（范围1.2-28.4个月），119例意向治疗患者中有68例出现疾病进展（TPIV200+GM-CSF组55%，单独GM-CSF组59%）。中位PFS为11.1个月（95％CI8.3-16.6个月），治疗组之间无显着差异（TPIV200GM-CSF为10.9个月，GM-CSF为11.1个月，HR,0.85；上限90%CI1.17]。无患者经历≥3级药物相关不良事件。
结论：TPIV200耐受性良好，但与PFS改善无关。需要额外的研究来揭示使用靶向FRa的多表位疫苗的潜在协同作用。试用注册NLM/NCBI注册中心，NCT02978222,https://clinicaltrials.gov/search?term=NCT02978222.
方法：我们进行了随机，双盲,多中心，II期研究旨在评估TPIV200（一种与GM-CSF混合的多表位FRα肽疫苗）与单独GM-CSF的安全性和有效性，这些女性在至少4个周期的一线铂类治疗后没有疾病进展。患者每4周一次皮内接种疫苗，最多6次，随后是12周间隔的6次疫苗接种的加强期。主要终点包括安全性，耐受性,无进展生存期（PFS）。
结果：在研究终止时，中位随访时间为15.2个月（范围1.2-28.4个月），119例意向治疗患者中有68例出现疾病进展（TPIV200+GM-CSF组55%，单独GM-CSF组59%）。中位PFS为11.1个月（95％CI8.3-16.6个月），治疗组之间无显着差异（TPIV200GM-CSF为10.9个月，GM-CSF为11.1个月，HR,0.85；上限90%CI1.17]。无患者经历≥3级药物相关不良事件。
结论：TPIV200耐受性良好，但与PFS改善无关。需要额外的研究来揭示使用靶向FRa的多表位疫苗的潜在协同作用。试用注册NLM/NCBI注册中心，NCT02978222,https://clinicaltrials.gov/search?term=NCT02978222.
