Johns Hopkins Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD.
University of Washington, Seattle Cancer Care Alliance, Seattle, WA.
J Clin Oncol. 2020 Aug 1;38(22):2476-2487. doi: 10.1200/JCO.20.00201. Epub 2020 Apr 23.
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC.
In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies.
Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation.
Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
默克尔细胞癌（MCC）是一种罕见的侵袭性皮肤癌，通常由默克尔细胞多瘤病毒（MCPyV）驱动。程序性死亡受体 1（PD-1）/程序性死亡配体 1（PD-L1）免疫抑制途径在 MCC 中常被上调，晚期转移性 MCC 常对 PD-1 阻断有反应。我们报告了首例在可切除 MCC 的新辅助治疗中使用抗 PD-1 的试验。
在病毒相关癌症类型的 I/II 期 CheckMate 358 研究中，可切除 MCC 患者接受nivolumab 240 mg 静脉注射，第 1 天和第 15 天各 1 次。第 29 天进行手术。通过影像学和显微镜评估肿瘤消退情况。在预处理肿瘤活检中评估肿瘤 MCPyV 状态、PD-L1 表达和肿瘤突变负担（TMB）。
39 例美国癌症联合委员会（AJCC）分期 IIA-IV 期可切除 MCC 患者接受了至少 1 次 nivolumab 剂量治疗。由于肿瘤进展（n=1）或不良事件（n=2），有 3 例患者（7.7%）未进行手术。18 例患者（46.2%）出现任何级别的治疗相关不良事件，3 例患者（7.7%）出现 3-4 级事件，无意外毒性。在 36 例接受手术的患者中，17 例（47.2%）达到病理完全缓解（pCR）。在 33 例影像学可评估且接受手术的患者中，18 例（54.5%）肿瘤缩小≥30%。无论肿瘤 MCPyV、PD-L1 或 TMB 状态如何，均观察到应答。在中位随访 20.3 个月时，中位无复发生存（RFS）和总生存未达到。RFS 与手术时的 pCR 和影像学反应显著相关。在观察期间，无 pCR 患者发生肿瘤复发。
MCC 患者在手术前约 4 周接受 nivolumab 治疗通常是可以耐受的，可诱导约一半治疗患者达到 pCR 和影像学肿瘤消退。这些早期反应标志物显著预测 RFS 改善。需要进一步研究这些有前景的发现。
