Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors
Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors
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DOI：
10.1200/jco.2017.76.2229
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发表时间：
2018-06-01
影响因子：
45.3
通讯作者：
Chmura, Steven J.
中科院分区：
文献类型：
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作者：
Luke, Jason J.;Lemons, Jeffrey M.;Chmura, Steven J.
目的立体定向体部放射治疗（SBRT）可通过刺激机体固有免疫和获得性免疫来增强免疫治疗反应。多部位SBRT是治疗转移性疾病的新兴范例。抗PD-1治疗结果可能会随着疾病负担的降低而改善。在这种情况下，我们进行了一项I期研究，以评估pembrolizumab与多位点SBRT在转移性实体瘤患者中的安全性。Patients and MethodsPatients progressing on standard treatment received SBRT to two to four metastases.并非所有转移灶都被靶向，> 65 mL的转移灶被部分照射。SBRT剂量因研究中心而异，范围为30 - 50戈伊，分3 - 5次给药，如果观察到过量的剂量限制性毒性，则预先确定剂量递减。在SBRT完成后7天内开始Pembrolizumab治疗。前和后SBRT活检标本进行了分析，在一个子集的患者，以量化干扰素诱导的基因expression.ResultsA共79例患者参加;三名患者没有接受任何治疗，三名患者只接受SBRT。纳入分析的患者接受SBRT和至少一个周期的帕博利珠单抗治疗。大多数（94.5%）患者接受SBRT治疗2个转移灶。毒性的中位随访时间为5.5个月（四分位距，3.3至8.1个月）。6例患者出现剂量限制性毒性，未降低放射剂量。在68例接受影像学随访的患者中，总体客观缓解率为13.2%。中位总生存期为9.6个月（95% CI，6.5个月至未确定），中位无进展生存期为3.1个月（95% CI，2.9至3.4个月）。SBRT后肿瘤活检标本中干扰素相关基因的表达与非照射肿瘤反应显着相关。结论多位点SBRT后联合帕博利珠单抗耐受性良好，毒性可接受。探索多位点SBRT和PD-1联合免疫治疗的临床获益和预测生物标志物的其他研究是必要的。(C)2018年美国临床肿瘤学会
PurposeStereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors.Patients and MethodsPatients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon--induced gene expression.ResultsA total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced dose-limiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-associated genes from post-SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response.ConclusionMultisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1-directed immunotherapy are warranted. (C) 2018 by American Society of Clinical Oncology