在刚刚落幕的2024年ESMO年会上，法国里昂大学医院Benoit You在优选口头报告（Proffered paper session）专场发布了I/II期TROPHAMET试验结果（摘要号711O），并接受《肿瘤瞭望》专访。

 

 

妊娠滋养细胞肿瘤(GTT)是年轻女性在怀孕期间患上的罕见肿瘤。在FIGO评分≤6的低风险GTT中，标准方案是8天甲氨蝶呤(MTX)，已知可诱导约70%患者的人绒毛膜促性腺激素（hCG）正常化。免疫检查点抑制剂Avelumab在化疗耐药患者中有效(You，JCO 2020)。TROPHAMET试验的目的是观察联合Avelumab与8天MTX治疗是否可以提高疗效并助力根除低风险GTT。

 

研究方案

 

2024 ESMO研究结果显示，在26名可评估疗效的患者（I/II/III期分别占：42%/4%/54%；FIGO评分1-2：31%；FIGO评分3-4：31%；FIGO 5-6：38%）中，该方案的总体耐受性良好。24名患者（89%）出现1-3级治疗相关不良事件(TRAE)，其中5名患者（19%）为3级；3级TRAE包括口腔炎(n=2)、ALT/AST升高(n=2)和导管感染(n=1)；未报告4-5级TRAE。96.2%的患者（95%CI[85.8-97.3]；n=25/26）在中位治疗期3.32个月（IQR 2.51-4.02）后成功恢复hCG正常化。中位随访期24.8个月后，治疗停止后未观察到复发，意味着疾病可能治愈。

 

TROPHAMET研究表明，Avelumab与MTX方案的联合使用是可行的，并且显著提高了疗效，可以治愈＞95%的低风险GTT患者。

 

试验结果

Dr.You：滋养细胞肿瘤是一种源于胎盘滋养细胞的肿瘤，通常发生在女性妊娠后。GTT的标准一线治疗依赖于甲氨蝶呤，已知甲氨蝶呤可诱导约70%的GTT发生hCG正常化。文献中有大量证据表明免疫疗法治疗GTT肿瘤有效，因此我们决定进行一项试验，以证明PD-L1单克隆抗体Avelumab与甲氨蝶呤联合可以将hCG正常化率提高到>90%。

 

为了实现这一目标，我们设计了一项法国多中心试验，并招募了26名患者。在26名可评估疗效的患者中，25名患者发生了hCG正常化。经过两年多的随访，没有一名患者复发，这意味着这些患者很可能被治愈。换句话说，GTT治愈率约为96%，远高于我们的预期。

 

Dr.You:Gestational trophoblastic tumors(GTT)are rare tumors developed from the placenta in the context of pregnancy.Standard first-line treatment relies on methotrexate which is known to be associated with hCG normalization at the rate of about 70%.In the literature，there is plenty of evidence suggesting that immunotherapy is active in these cases，so we decided to conduct a trial to show that the combination of the PD-L1 monoclonal antibody，avelumab，combined with methotrexate could increase the hCG normalization rate to>90%.To achieve that aim，we designed a French multicenter trial and enrolled 26 patients.Out of 26 assessable patients，25 patient experienced hCG normalization.With more than two years follow-up，none of the patients have relapsed，meaning that these patients are likely to be cured.In other words，the GTT cure rate is close to 96%，which is far above our expectations.

 

Dr.You：甲氨蝶呤+Avelumab的耐受性非常好。大多数副作用都是1级或2级。没有观察到4级或5级治疗相关不良事件。少数患者出现3级治疗相关不良事件，包括两名患者出现口腔炎（甲氨蝶呤的常见症状），两名患者出现免疫相关肝炎，一名患者出现导管感染。当然，也有患者发生免疫治疗相关不良事件，但除一名患者的甲状腺功能障碍外，所有不良事件均已解决。

 

Dr.You:The tolerability of methotrexate plus avelumab was excellent.Most side effects were grade 1 or grade 2.No grade 4 or 5 were observed.A few patients had grade 3 adverse events including two patients with stomatitis(well known with methotrexate)，two patients had immune-related hepatitis，and one patient had a catheter infection.There were，of course，immune-related adverse events，but all of them resolved，except for one patient who had dysthyroidism.

 

Dr.You：抗PD-(L)1单克隆抗体免疫疗法对高风险和低风险妊娠滋养细胞肿瘤均有效。根据TROPHAMET试验结果和之前发表的TROPHIMMUN试验，我们知道Avelumab对低风险患者有效。

 

对于高风险患者，有几份病例报告显示了帕博利珠单抗（pembrolizumab）有一定疗效。此外，还有一项中国II期试验采用PD-1抑制剂卡瑞利珠单抗联合阿帕替尼的方案，在高危化疗难治性或复发性妊娠滋养细胞肿瘤患者（n=20）中显示完全缓解率（CR）为50%。

 

Dr.You:Immunotherapy with anti-PD-1/anti-PD-L1 monoclonal antibodies has activity in both high-risk and low-risk disease.Based on the result of the TROPHAMET trial and the previously published TROPHIMMUN trial，we know that avelumab is active in patients with low-risk gestational trophoblastic tumors.Regarding high-risk disease，there are several case reports showing the efficacy of pembrolizumab.Moreover，there is a Chinese phase II trial with camrelizumab plus apatinib showing a complete response rate of 50%in patients with chemotherapy resistant disease.

 

Dr.You：我对KEYNOTE-A18的结果印象深刻（摘要号709O），该研究评估了帕博利珠单抗联合放化疗（CRT）对复发风险高的局部或局部晚期宫颈癌患者的疗效。这类患者的标准治疗依赖于放化疗，在KEYNOTE-A18试验中，研究人员比较了放化疗联合或不联合帕博利珠单抗，随后再使用帕博利珠单抗或安慰剂两年（15个周期）。我们已经从第一次中期分析中知道，在放化疗中加入帕博利珠单抗可以提高疾病控制率，两年内无进展生存（PFS）率可提升10%~11%（67.8%vs.57.3%），2024 ESMO发布了总生存（OS）的结果，3年OS率提高了约8%（82.6%vs.74.8%）。这是一个很大的进步，因为我们可以为提高宫颈癌的治愈率做出贡献。

 

Dr.You:I was very impressed with the outcome of KEYNOTE-A18 that assessed the efficacy of pembrolizumab combined with chemoradiation in patients with localized or locally advanced cervical cancer at high risk of recurrence.Standard treatment relies on chemoradiation，and in the trial，the investigators compared chemoradiation with or without pembrolizumab，followed by pembrolizumab for two years.We already knew the addition of pembrolizumab to chemoradiation would increase disease control by increasing progression-free survival by 10-11%at two years，but we now have the results for overall survival，and we could see that there was an improvement in overall survival by about 8%at three years.This is a great improvement，because we can contribute to increasing the rate of cure of cervical cancer.

 

参考文献：

1.You B，et al.Avelumab+methotrexate to eradicate low-risk gestational trophoblastic tumors in first-line setting:TROPHAMET phase I/II trial.ESMO Congress 2024，Abstract 711O.