ESMO摘要速递 | 子宫内膜癌
115P
PD-L1 expression landscape and microsatellite instability status in Chinese endometrial and cervical cancer patients
J. Yang , J. Yang , H. Zhang , D. Huang , X. Shen , X. She
Background
The malignant tumors of female genital system account for most morbidity and mortality among women worldwide. With the increasing knowledge about BRCA mutation in tumors, significant progresses were made in ovarian cancer. But due to poor sensitivity to conventional chemotherapy, effective therapeutic options for endometrial and cervical carcinoma are still unmet clinical needs. Immunotherapy showed remarkable progresses in treatment of melanoma, lung and renal malignancies in recent years. To explore potential use of biomarkers, our study aimed to assess PD-L1 expression on tumor cells and microsatellite instability (MSI) status in Chinese endometrial (EC) and cervical cancer (CC) populations.
Methods
160 endometrial and 197 cervical tumor samples collected in China between January 01, 2017 and April 15, 2020, were analyzed by a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab.
PD-L1 expression was accessed by IHC assay (SP263 or 22C3). We scored percentage of PD-L1 expression on tumor cells as TPS: TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%. MSI status was evaluated by targeted next-generation sequencing (NGS) covering 500 MSI loci.
Results
Median age of endometrial cancer patients was 58 years, while cervical cancer patients’ median age was 53 years. 2 (1.2%) individuals had tumors cells PD-L1 scores as TC3, 15 (9.4%) as TC2, 25 (15.6%) as TC1 and 118 (73.8%) as TC0 in EC patients; 16 (8.1%) individuals had tumors cells PD-L1 scores as TC3, 49 (24.9%) as TC2, 40 (20.3%) as TC1 and 92 (46.7%) as TC0 in CC patients. 39 (24.4%) endometrial cancer patients and 8 (4.1%) cervical cancer patients were MSI-H. 17 (43.6%) of MSI-H EC patients and 4 (50%) of MSI-H CC patients were TC1/2/3. TC1/2/3 was associated with MSI-H (P=0.0046) in EC patients, but no association was observed between TC1/2/3 and MSI-H (P=0.848) in CC patients.
Conclusions
The landscape of PD-L1 expression and microsatellite instability status among Chinese endometrial and cervical cancer populations in this study will further assist the utilization of these biomarkers to guide PD-1/PD-L1-related therapeutic strategies.
子宫内膜癌和宫颈癌患者PD-L1表达谱及微卫星不稳定性研究
背景
女性生殖系统恶性肿瘤是全球女性发病率和死亡率最高的疾病。随着对BRCA基因突变在肿瘤中的认识不断加深，卵巢癌的研究取得了重大进展。但由于对常规化疗的敏感性较差，子宫内膜癌和宫颈癌的有效治疗方案仍不能满足临床需要。近年来，免疫治疗在黑色素瘤、肺部和肾脏恶性肿瘤的治疗方面取得了显著进展。为了探索生物标记物的潜在应用，我们的研究旨在评估PD-L1在中国子宫内膜癌（EC）和宫颈癌（CC）人群中的肿瘤细胞PD-L1表达和微卫星不稳定性（MSI）状况。
方法
从2017年1月1日至2020年4月15日，收集了中国160个子宫内膜癌和197个宫颈肿瘤样本，由CAP（College of American Pathologists）和CLIA（Clinical Laboratory ImprovementAmendments）认证的实验室进行分析。
用IHC法（SP263或22C3）检测PD-L1的表达。我们将PD-L1在肿瘤细胞上的表达百分比作为TPS评分：TC3≥50%，TC2≥5%且<50%，TC1≥1%且<5%，TC0<1%。MSI状态是通过覆盖500个MSI基因座的二代测序（NGS）来评估的。
结果
子宫内膜癌患者的中位年龄为58岁，而宫颈癌患者的中位年龄为53岁。在子宫内膜癌患者中，2例患者（1.2%）肿瘤细胞PD-L1评分为TC3，15例（9.4%）为TC2，25例（15.6%）为TC1，118例（73.8%）为TC0；在宫颈内膜癌中，16例（8.1%）肿瘤细胞PD-L1评分为TC3，49例（24.9%）为TC2，40例（20.3%）为TC1，92例（46.7%）为TC0。39例子宫内膜癌（24.4%），8例宫颈癌（4.1%）患者为MSI-H。17例（43.6%）MSI-H的子宫内膜癌， 4例（50%）MSI-H的宫颈癌为TC1/2/3。在子宫内膜癌患者中，TC1/2/3与MSI-H相关（P=0.0046），但在宫颈癌患者中，TC1/2/3与MSI-H之间没有相关性（P=0.848）。
结论
本研究对中国人子宫内膜癌和宫颈癌人群PD-L1的表达和微卫星不稳定性的研究，将有助于这些生物标志物的应用，指导PD-1/PD-L1相关的治疗策略。
857P
Long-term survival outcomes in endometrial cancer patients having lymphadenectomy, sentinel node mapping followed by backup lymphadectomy and sentinel node mapping alone: A multi-institutional Italian experience
G. Bogani , F. Ghezzi , S. Ferrero , F. Raspagliesi
Background
Sentinel node mapping (SLNM) has replaced lymphadenectomy for staging surgery in apparent early-stage endometrial cancer (EC). Here, we evaluate long-term survival of three different approaches of nodal assessment in EC.
Methods
This is a multi-institutional retrospective study evaluating long-term outcomes (at least 3 years) of EC patients having lymphadenectomy, SLNM followed by lymphadenectomy and SLNM alone. In order to reduce possible confounding factors we applied a propensity-matched algorithm. Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazard models.
Results
Applying a propensity score matching algorithm we selected 180 patients having SLNM (90 SLNM vs. 90 SLNM followed by lymphadenectomy). Additionally, a control group of 180 patients having lymphadenectomy was selected using the same criteria. Overall, 10% of patients were diagnosed with positive nodes. Low volume disease was observed in 16 cases (5 micrometastasis and 11 isolated tumor cells). Patients having SLNM followed by lymphadenectomy had a higher possibility to be diagnosed with a stage IIIC disease in comparison to lymphadenectomy alone (p=0.02); while we did not observe difference in the diagnostic value of SLNM followed by lymphadenectomy and SLNM (p=0.389). Median follow-up time was 69 months (range, 7–206). The survival analysis comparing the three techniques did not show statistical differences in terms of disease-free (p=0.570, log-rank test) and overall survival (p=0.911, log-rank test). Similarly, they did not impact on survival outcomes after stratification by low, intermediate and high-risk patients.
Conclusions
Our study highlighted that SLNM provides similar long-term oncologic outcomes than lymphadenectomy. Further evidence is warranted to assess the prognostic value of low-volume disease detected by ultrastaging in patients following SLNM.
子宫内膜癌患者行淋巴结切除、前哨淋巴结定位及定位后切除的长期生存结局：意大利多机构经验
背景
前哨淋巴结定位（SLNM）已取代淋巴结切除术应用在在明显早期的子宫内膜癌（EC）的分期手术中。在这里，我们评估了三种不同的淋巴结评估方法在子宫内膜癌中的长期生存率。
方法
这是一项多机构的回顾性研究，评估了子宫内膜癌患者接受淋巴结切除、前哨淋巴结定位及前哨淋巴结定位后切除的长期预后（至少3年）。为了减少可能的混杂因素，我们采用了倾向性匹配算法。采用Kaplan-Meier和Cox比例风险模型评估生存结果。
结果
应用倾向性匹配评分算法，我们选择了180例SLNM患者（90例SLNM和90例SLNM术后淋巴结切除术）。此外，采用同样的标准选择180例淋巴结切除术的对照组。总体上，10%的患者被诊断为阳性淋巴结。低容量转移16例（微转移5例，孤立肿瘤细胞11例）。与单纯淋巴结切除术相比，SLNM行淋巴结切除术的患者诊断为IIIC期疾病的可能性更高（p=0.02）；但我们没有观察到SLNM后淋巴结切除术和SLNM在诊断价值上的差异（p=0.389）。中位随访时间为69个月（范围：7~206个月）。三种评估方案在DFS（p=0.570，log-ranktest）和OS（p=0.911，log-rank test）方面均没有统计学差异。同样，他们也不影响低、中、高风险分层后不同患者亚组的生存结局。
结论
我们的研究强调，SLNM提供了与淋巴结切除术相似的长期肿瘤学结局。目前仍需要更多的证据，评估SLNM超分期检测低容量转移的预后价值。
863P
A phase I study of mirvetuximab soravtansine (MIRV) and gemcitabine (G) in pts with selected FRα -positive solid tumours: Results in the endometrial cancer (EC) cohort
M.C.Cristea , P. Frankel , T. Synold , D.B. Stewart ,E. Wang , A. Jung , S. Wilczynski , M. Tran , G.E. Konecny , M. Eng , L. Kilpatrick ,Y-J. Chen , S. Glaser , E. Han , T.Dellinger , A. Hakim , S. Lee ,R.J. Morgan , L. Rodriguez , M. Wakabayashi
Background
Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, linked to the tubulin-disrupting maytansinoid DM4. MIRV has promising single agent activity in FRα-positive epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. Clinical data in other FRα-positive solid tumors has been limited. This study is evaluating MIRV and G in recurrent EOC, EC and triple negative breast cancer (TNBC). The recommended phase II dose (RP2D) reported at ASCO 2019, was established at DL3 (MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8) q21 days. Here we report the results in the EC cohort treated at the RP2D.
Methods
Pts with FRα-positive EC with ≤ 2 prior chemotherapy (CT) regimens are eligible. FRα positivity by immunohistochemistry was initially defined as ≥25% of cells with PS2+ staining intensity (low to high FRα levels) and was subsequently revised to ≥ 50% of cells with PS2+ (medium/high FRα levels, with high defined as ≥ 75% of cells with PS2+). The expansion cohort of 12 pts with FRα-positive EC treated at the RP2D pre-specified that ≥ 2 responders are required to declare the combination promising.
Results
From October 2017 to May 2020, 55 EC pts underwent FRα screening, with 4 results pending. Out of 51 EC pts with results, 12 pts (23.5%) have medium/high FRα levels with 5 pts (9.8%) have low FRα level. 5 EC pts were treated at the RP2D (1 too early and 4 evaluable for response of which 1 pt had medium FRα and 3 pts had low FRα). 2 of the 4 evaluable EC pts at the RP2D achieved a partial response (PR). 1 PR was observed on cycle 7 (the only medium FRα level pt) and the second PR was on cycle 3. One pt. had SD after 4 cycles and remains on treatment, and 1 pt progressed in the 1 cycle. Grade (G) 3-4 adverse events (AEs) in the 4 evaluable pts treated at the RP2D were infrequent and included: Gr 4 lymphopenia (1 pt), Gr 3 ANC/WBC/PLT (1 pt), and Gr 3 HTN and lymphopenia (1pt).
Conclusions
The combination of MIRV with G has promising clinical activity in FRα-positive EC. The regimen is tolerable with the expected treatment related AEs of these agents.
Mirvetuximab Soravtansine（MIRV）和吉西他滨（G）治疗经选择FRα阳性实体瘤的Ⅰ期研究：子宫内膜癌（EC）队列研究结果
背景
Mirvetuximabsoravtansine（MIRV）是一种由FRα结合抗体组成的ADC，其与微管蛋白干扰药物美登素DM4相连。MIRV在FRα阳性上皮性卵巢癌（EOC）中具有良好的单药活性（6 mg/kg），以矫正理想体重（AIBW）为基础，每21天静脉注射一次MIRV。其他FRα阳性实体瘤的临床资料有限。本研究旨在评估MIRV和G在复发性EOC、EC和三阴性乳腺癌（TNBC）中的作用。ASCO2019年报告的II期推荐剂量（RP2D）是DL3（MIRV 6 mg/kg AIBW IV，第1天和G 800 mg/m2 IV，第1，8天）每21天。在此，我们报告了在RP2D治疗的EC队列的结果。
方法
入组条件：FRα阳性且既往≤2线化疗（CT）方案的EC患者。免疫组化检测的FRα阳性最初定义为≥25%的PS2+染色强度（低至高FRα水平），随后修正为≥50%的PS2+细胞（中/高FRα水平，高FRα定义为≥75%的PS2+细胞）。在预先指定的12例FRα阳性EC患者的扩展队列中行RP2D治疗，定义≥2个应答者即为联合有效。
结果
从2017年10月到2020年5月，55例EC患者接受了FRα筛查，其中4例结果待定。在51例有结果的EC患者中，12例（23.5%）的FRα为中/高水平，5例（9.8%）的FRα为低水平。在RP2D治疗5例子宫内膜癌患者中（1例尚早，4例可评价疗效，其中1例为中度FRα，3例为低FRα）。在RP2D的4个可评估的患者中，有2例获得了部分反应（PR）。其中1例在第7个周期中观察到PR（唯一中等FRα水平患者），另外一例PR出现于第三个周期。此外，1例患者4个周期后SD，仍在治疗中；1例患者在第1个周期内进展。在RP2D治疗的4个可评估的患者中，3-4级不良事件（AEs）较少发生，主要为4级淋巴减少（1例）、3级ANC/WBC/PLT（1例）和3级HTN和淋巴减少（1例）。
结论
MIRV联合吉西他滨（G）治疗FRα阳性EC具有良好的临床应用价值。而对于相关不良事件可采取相应的治疗，因此该方案是可以耐受的。
864P
Phase II ofABTL0812, a pro-autophagic drug, in combination with paclitaxel and carboplatin(P/C) as first-line treatment in advanced/recurrent endometrial cancer
A. Leary , P. Estévez-García , R.Sabatier , L. Fariñas-Madrid , J.A. Pérez-Fidalgo , M. Romeo , M.P. BarretinaGinesta , M. Gil-Martin , E. Garralda , J. Rodon,J.M. Lizcano, P. Muñoz Guardiola, H. Pérez-Montoyo, M. Yeste-Velasco ,M. Cortal ,C. Domènech, J. Alfon, I.L. Ray-Coquard , A. Oaknin
Background
ABTL0812 induces cytotoxic autophagy-mediated cell death. It inhibits Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in endometrial cancer (EC) indicated efficacy as a single agent and synergy with chemotherapy. A phase I of ABTL0812 with P/C confirmed the safety of the triple combination.
Methods
A single-arm phase II study was designed where ABTL0812 was administered 1300 mg TID orally with P/C 175 mg/m / AUC5 D1 every 3 weeks, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients (pts) with advanced/recurrent EC except carcinosarcoma and leiomyosarcoma. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), duration of response (DOR), safety and tolerability according to CTCAE v4.03 and pharmacokinetics (PK). Target modulation was assessed by two pharmacodynamic (PD) markers: TRIB3 and CHOP (an ER-stress biomarker) in blood.
Results
42 pts received at least 1 dose of ABTL0812 and 34 were evaluable (median age: 67.9 years old; 15 advanced / 19 recurrent;23 endometrioid / 2 serous / 2 clear cell / 7 not determined -ND; 3 grade-1, 7 grade-2, 9 grade-3 / 15 ND). ORR was 66% (95% CI: 46-80%), DOR was 7.8 months (6.3-10.8) and PFS was 10.2 months (7.1-11.4). Most frequent hematological adverse events (AEs) were neutropenia (all grades 23.8%, grade≥3 14.3%), anemia (21.4%, 2.4%) and thrombocytopenia (9.5%,2.4%). Most frequent non-hematological AEs were nausea (47.6%, 2.4%), asthenia (45.2%, 0), vomiting (42.9%, 0), diarrhea(26.2%, 0), arthralgia and neurotoxicity (both 23.8%, 0). PK and PD analysis performed at 4 weeks showed that Cmax were 8.0/5.5 mg/L and t1/2 3.3/2.0 h for -/+-ABTL0812; TRIB3 and CHOP levels increased.
Conclusions
The combination of ABTL0812+P/C shows promising results with an acceptable safety and tolerability profile. These outcomes look promising compared with historical controls and warrant further investigation. PK and PD profiles indicate sustained target modulation.
促自噬药物ABTL0812，联合紫杉醇和卡铂（P/C）作为晚期/复发子宫内膜癌的一线治疗药物的2期试验
背景
ABTL0812具有细胞毒性，造成自噬性细胞死亡。它通过上调内源性Akt抑制剂TRIB3抑制Akt/mTOR轴，并诱导内质网应激（ER）。子宫内膜癌（EC）的临床前数据表明其作为单一药物的疗效，及其与化疗的协同作用。ABTL0812与P/C联合的1期试验确证了药物三联的安全性。
方法
研究设计了一项单臂II期试验，1300毫克ABTL0812口服tid，加每三周P/C 175mg/m/AUC5 D1，随后ABTL0812作为维持，直到疾病进展或出现不可接受的毒性。本研究纳入了除肉瘤和平滑肌瘤外的晚期/复发EC患者。主要终点为RECIST v.1.1定义的总有效率（ORR）。次要终点为无进展生存期（PFS）、反应持续时间（DOR）、安全性和耐受性（CTCAE v4.03）和药代动力学（PK）。通过血液中的两种药效学标记物TRIB3和CHOP（一种内质网应激生物标志物）来评估靶向调节。
结果
42例患者至少接受1次ABTL0812治疗，34例可评估（中位年龄：67.9岁；15例晚期/19例复发；23例子宫内膜样体/2例浆液性/2例透明细胞/7例未明确；3例1级，7例2级，9例3级/15 ND）。ORR为66%（95%CI:46-80%），DOR为7.8个月（6.3-10.8），PFS为10.2个月（7.1-11.4）。最常见的血液学不良事件（AEs）是中性粒细胞减少症（23.8%，≥3级为14.3%），贫血（21.4%，2.4%）和血小板减少症（9.5%，2.4%）。最常见的非血液学不良反应为恶心（47.6%，2.4%）、乏力（45.2%，0）、呕吐（42.9%，0）、腹泻（26.2%, 0），关节痛和神经毒性（均为23.8%，0）。对于-/+-ABTL0812，4周时进行的PK和PD分析显示Cmax为 8.0/5.5 mg/L和t1/23.3/2.0 h；TRIB3和CHOP增加。
结论
ABTL0812+P/C组合显示了良好的结果，安全性和耐受性良好。与历史对照相比，这些结果颇具前景，需更多研究证实。PK和PD结果显示了持续的靶点调控。
884TiP
AtTEnd/ENGOT-en7: A multicenter phase IIIdouble-blind randomized controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer
N. Colombo , Y. Antill , M.P. BarretinaGinesta , K. Harano , E. Hudson , F. Marmé , C. Marth , M. Rabaglio , A.A.Secord , R. Fossati, A. Roberto, F. Tettamanzi,E. Biagioli
Background
Prognosis of advanced/recurrent endometrial cancer (EC) is poor with median survival of 12-15 months for patients with measurable disease. Among the limited therapeutic options, the primary management is represented by chemotherapy with carboplatin and paclitaxel. EC is known to be one of the tumor types with highest mutation frequency. The two subgroups of ultra- and hyper-mutated EC, which harbor POLEand mismatch repair gene defects respectively, have shown to be associated with higher predicted neoantigen load, peri-tumoral T cell infiltration and high expression of PD-1 and PD-L1 proteins, making EC a good candidate for immune checkpoint inhibitor therapy. Preliminary data in EC have shown promising clinical evidence of tumor response to the PD-L1 targeting agent atezolizumab. This study aims at evaluating the efficacy of first-line atezolizumab versus placebo in combination with carboplatin and paclitaxel.
Trial design
This is a multicenter, phase III, double-blind, randomized trial in patients with newly diagnosed, advanced stage III/IV or recurrent EC. Patients are randomized in a 1:2 ratio into: i. control group receiving standard chemotherapy (175 mg/m paclitaxel plus AUC5/6 carboplatin) plus placebo IV every 21 days up to 6/8 cycles followed by placebo until progression; experimental group receiving standard chemotherapy (175 mg/m paclitaxel and AUC5/6 carboplatin) plus 1200 mg at ezolizumab IV every 21 days up to 6/8 cycles followed by atezolizumab until progression. Stratification factors are: histology, disease stage, microsatellite status, country of experimental site. The trial has two co-primary independent endpoints, PFS and OS. Secondary endpoints include ORR, duration of response, PFS2, quality of life, adverse events and compliance. Further exploratory endpoints relate to prognostic and predictive tumor biomarkers. The study is sponsored by the Italian MaNGO group and is involving sites from ENGOT and GCIG networks across Europe, Japan, Australia and New Zealand. As of May 18 2020, 182 out of 550 patients have been randomized.
Clinical trial identification NCT03603184.
ATHEAT/ENGOT-en7：阿替唑单抗联合紫杉醇和卡铂治疗晚期/复发性子宫内膜癌的多中心III期双盲随机对照试验
背景
晚期/复发性子宫内膜癌（EC）预后差，可测疾病患者的中位生存期为12-15个月。在有限的治疗方案中，主要的治疗方法是用卡铂和紫杉醇进行化疗。EC是突变频率最高的肿瘤类型之一。子宫内膜癌的2个亚型POLE强突变（ultramutated），微卫星不稳定超突变（hypermutated），分别具有POLE和错配修复基因缺陷，它们与较高的肿瘤新抗原负荷、肿瘤周围T细胞浸润以及PD-1和PD-L1高表达相关，这使得EC具有应用免疫检查点抑制剂的可能性。EC的初步数据显示肿瘤对PD-L1抑制剂阿替唑单抗有良好的临床反应。本研究旨在评估联合卡铂和紫杉醇，一线使用阿替唑单抗对比安慰剂的疗效。
试验设计
这是一个多中心、三期、双盲、随机试验，针对新诊断的晚期III/IV期或复发性EC。患者按1:2的比例随机分为：对照组，每21天接受标准化疗（175 mg/m紫杉醇+AUC5/6卡铂）加安慰剂静脉滴注，至6/8个周期，随后接受安慰剂直至病情进展；实验组接受标准化疗（175 mg/m紫杉醇和AUC5/6卡铂）加1200 mg阿替唑单抗静脉滴注/每21天，至6/8个周期，然后接受阿替唑单抗直至进展。分层因素有：组织学、疾病分期、微卫星状态、实验地点所在国。试验有两个主要独立终点，PFS和OS。次要终点包括ORR、反应持续时间、PFS2、生活质量、不良事件和依从性。更进一步的探索终点与预后，预测性肿瘤生物标志物相关。这项研究由意大利MaNGO赞助，研究中心来自欧洲、日本、澳大利亚和新西兰的ENGOT和GCIG组织。2020年5月18日，550例患者中的182例开始随机分组。临床试验编号NCT03603184。