Qin Angel, Rengan Ramesh, Lee Sylvia, Santana-Davila Rafael, Goulart Bernardo H L, Martins Renato, Baik Christina, Kalemkerian Gregory P, Hassan Khaled A, Schneider Bryan J, Hayman James A, Jolly Shruti, Hearn Jason, Lawrence Theodore S, Towlerton Andrea M H, Tewari Muneesh, Thomas Dafydd, Zhao Lili, Brown Noah, Frankel Timothy L, Warren Edus H, Ramnath Nithya
Department of Medicine, Hematology-Oncology, University of Michigan, Ann Arbor, Michigan.
Department of Radiation Oncology, University of Washington, Seattle, Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center.
Int J Radiat Oncol Biol Phys. 2020 Sep 1;108(1):170-177. doi: 10.1016/j.ijrobp.2019.10.047. Epub 2019 Nov 19.
Preclinical data and subset analyses from immunotherapy clinical trials indicate that prior radiation therapy was associated with better progression-free survival and overall survival when combined with immune checkpoint inhibitors in patients with non-small cell lung cancer. We present a prospective study of hypofractionated image guided radiation therapy (HIGRT) to a single site of metastatic disease concurrently with atezolizumab in patients with metastatic non-small cell lung cancer.
Patients meeting eligibility criteria received 1200 mg of atezolizumab intravenously every 3 weeks with concurrent 3- or 5-fraction HIGRT starting no later than the second cycle. The 3-fraction regimen employed a minimum of 8 Gy per fraction compared with 6 Gy for the 5-fraction regimen. Imaging was obtained every 12 weeks to assess response.
From October 2015 to February 2017, 12 patients were enrolled in the study (median age 64; range, 55-77 years). The best response by the Response Evaluation in Solid Tumors criteria was partial response in 3 and stable disease in 3, for a disease control rate of 50%. Five patients had a grade 3 immune-related adverse event, including choreoretinitis (n = 1), pneumonitis (n = 1), transaminitis (n = 1), fatigue (n = 1), and peripheral neuropathy (n = 1). The median progression-free survival was 2.3 months, and the median overall survival was 6.9 months (range, 0.4-not reached). There was no clear association between peripheral blood T cell repertoire characteristics at baseline, PD-L1, or tumor mutations and response or outcome. One long-term survivor exhibited oligoclonal T cell populations in a baseline tumor biopsy that were consistently detected in peripheral blood over the entire course of the study.
HIGRT plus atezolizumab resulted in an overall response rate of 25% and disease control rate of 50% in this pilot study. The incidence of grade 3 adverse events was similar to that of atezolizumab alone. Alhough it was a pilot study with limited sample size, the results generated hypotheses worthy of further investigation.
临床前数据以及免疫疗法临床试验的亚组分析表明，在非小细胞肺癌患者中，与免疫检查点抑制剂联合使用时，既往放疗与更好的无进展生存期和总生存期相关。我们开展了一项前瞻性研究，对转移性疾病的单个部位进行大分割影像引导放射治疗（HIGRT），同时对转移性非小细胞肺癌患者使用阿特珠单抗。
符合入选标准的患者每3周静脉注射1200mg阿特珠单抗，同时进行3或5次分割的HIGRT，开始时间不晚于第二个周期。3次分割方案每次分割至少8Gy，而5次分割方案每次分割为6Gy。每12周进行一次成像以评估反应。
2015年10月至2017年2月，12名患者入组本研究（中位年龄64岁；范围55 - 77岁）。根据实体瘤疗效评价标准，最佳反应为3例部分缓解，3例病情稳定，疾病控制率为50%。5例患者发生3级免疫相关不良事件，包括舞蹈性视网膜病变（n = 1）、肺炎（n = 1）、转氨酶升高（n = 1）、疲劳（n = 1）和周围神经病变（n = 1）。中位无进展生存期为2.3个月，中位总生存期为六个月9个月（范围0.4 - 未达到）。基线外周血T细胞库特征、PD - L1或肿瘤突变与反应或结局之间无明显关联。一名长期存活者在基线肿瘤活检中表现出寡克隆T细胞群体，在研究的整个过程中，外周血中持续检测到这些细胞群体。
在这项初步研究中，HIGRT联合阿特珠单抗导致总缓解率为25%，疾病控制率为50%。3级不良事件的发生率与单独使用阿特珠单抗相似。尽管这是一项样本量有限的初步研究，但结果产生了值得进一步研究的假设。
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