Ahmadzada Tamkin, Cooper Wendy A, Holmes Mikaela, Mahar Annabelle, Westman Helen, Gill Anthony J, Nordman Ina, Yip Po Yee, Pal Abhijit, Zielinski Rob, Pavlakis Nick, Nagrial Adnan, Daneshvar Dariush, Brungs Daniel, Karikios Deme, Aleksova Vesna, Burn Juliet, Asher Rebecca, Grau Georges E, Hosseini-Beheshti Elham, Reid Glen, Clarke Stephen, Kao Steven
Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
Tissue Pathology and Diagnostic Oncology, New South Wales Health Pathology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
JTO Clin Res Rep. 2020 Jul 16;1(4):100075. doi: 10.1016/j.jtocrr.2020.100075. eCollection 2020 Nov.
We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab.
Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples.
A total of 98 patients were included with a median age of 70 years (range, 46-91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6-6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6-13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, < 0.01). Baseline platelet count of less than or equal to 400 × 10/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, = 0.05; median OS: 10 mo versus 4 mo, = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 ( = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor ( < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate.
Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment.
我们研究了帕博利珠单抗在澳大利亚真实世界间皮瘤患者中的疗效和毒性。我们旨在确定有助于选择可能从帕博利珠单抗治疗中获益的患者的临床因素和预测生物标志物。
纳入作为新南威尔士州保险与护理赔偿计划一部分接受帕博利珠单抗治疗的间皮瘤患者。回顾性收集临床信息。使用存档的福尔马林固定石蜡包埋肿瘤样本检测肿瘤生物标志物，如程序性死亡配体1（PD-L1）、BAP1和CD3阳性（CD3+）肿瘤浸润淋巴细胞（TILs）。
共纳入98例患者，中位年龄70岁（范围46 - 91岁）；92%为男性；76%为上皮样亚型；21%的东部肿瘤协作组（ECOG）体能状态为0。94例患者将帕博利珠单抗用作二线或后续治疗，4例患者用作一线治疗。总体缓解率为18%，疾病控制率为56%。中位无进展生存期（PFS）为4.8个月（95%置信区间：3.6 - 6.2），中位总生存期（OS）为9.5个月（95%置信区间：6.6 - 13.7）。27%的患者发生免疫相关不良事件，其中9例（9%）为3级或更高等级。在多变量分析中，与较长PFS独立相关的因素包括基线ECOG状态为0（中位PFS：12个月对4个月，P < 0.01）和PD-L1肿瘤比例评分大于或等于1%（中位PFS：6个月对4个月，P < 0.01）。基线血小板计数小于或等于400×10⁹/L与较长的PFS和OS独立相关（中位PFS：6个月对2个月，P = 0.05；中位OS：10个月对4个月，P = 0.01），而未进行预处理地塞米松与OS独立相关，但与PFS无关（中位OS：10个月对3个月，P = 0.01）。基线ECOG状态为0（P = 0.02）和肿瘤中CD3+ TILs大于或等于5%（P < 0.01）的患者缓解几率更高。PD-L1表达、BAP1缺失和基质中的CD3+ TILs与总体缓解率无显著相关性。
免疫疗法是间皮瘤患者的合理治疗选择。我们的结果在缓解方面与其他研究帕博利珠单抗治疗间皮瘤的临床试验相当。良好的体能状态评估仍然是患者预后最可靠的预测指标。肿瘤中的CD3+ TILs可能有助于选择可能对帕博利珠单抗有反应的患者，而诸如PD-L1表达、基线血小板计数和未进行预处理地塞米松等因素可能有助于预测帕博利珠单抗治疗的生存结果。
