Background

Merkel cell carcinoma is among the most aggressive and lethal of primary skin cancers, with a high rate of distant metastasis. Anti-programmed death receptor 1 (anti-PD-1) and programmed death ligand 1 (PD-L1) monotherapy is currently standard of care for unresectable, recurrent, or metastatic Merkel cell carcinoma. We assessed treatment with combined nivolumab plus ipilimumab, with or without stereotactic body radiotherapy (SBRT) in patients with advanced Merkel cell carcinoma as a first-line therapy or following previous treatment with anti-PD-1 and PD-L1 monotherapy.

Methods

In this randomised, open label, phase 2 trial, we randomly assigned adults from two cancer sites in the USA (one in Florida and one in Ohio) to group A (combined nivolumab and ipilimumab) or group B (combined nivolumab and ipilimumab plus SBRT) in a 1:1 ratio. Eligible patients were aged at least 18 years with histologically proven advanced stage (unresectable, recurrent, or stage IV) Merkel cell carcinoma, a minimum of two tumour lesions measureable by CT, MRI or clinical exam, and tumour tissue available for exploratory biomarker analysis. Patients were stratified by previous immune-checkpoint inhibitor (ICI) status to receive nivolumab 240 mg intravenously every 2 weeks plus ipilimumab 1 mg/kg intravenously every 6 weeks (group A) or the same schedule of combined nivolumab and ipilimumab with the addition of SBRT to at least one tumour site (24 Gy in three fractions at week 2; group B). Patients had to have at least two measurable sites of disease so one non-irradiated site could be followed for response. The primary endpoint was objective response rate (ORR) in all randomly assigned patients who received at least one dose of combined nivolumab and ipilimumab. ORR was defined as the proportion of patients with a complete response or partial response per immune-related Response Evaluation Criteria in Solid Tumours. Response was assessed every 12 weeks. Safety was assessed in all patients. This trial is registered with ClinicalTrials.gov, NCT03071406.

Findings

50 patients (25 in both group A and group B) were enrolled between March 14, 2017, and Dec 21, 2021, including 24 ICI-naive patients (13 [52%] of 25 group A patients and 11 [44%] of 25 group B patients]) and 26 patients with previous ICI (12 [48%] of 25 group A patients and 14 [56%] of 25 group B patients]). One patient in group B did not receive SBRT due to concerns about excess toxicity. Median follow-up was 14·6 months (IQR 9·1–26·5). Two patients in group B were excluded from the analysis of the primary endpoint because the target lesions were irradiated and so the patients were deemed non-evaluable. Of the ICI-naive patients, 22 (100%) of 22 (95% CI 82–100) had an objective response, including nine (41% [95% CI 21–63]) with complete response. Of the patients who had previously had ICI exposure, eight (31%) of 26 patients (95% CI 15–52) had an objective response and four (15% [5–36]) had a complete response. No significant differences in ORR were observed between groups A (18 [72%] of 25 patients) and B (12 [52%] of 23 patients; p=0·26). Grade 3 or 4 treatment-related adverse events were observed in 10 (40%) of 25 patients in group A and 8 (32%) of 25 patients in group B.

Interpretation

First-line combined nivolumab and ipilimumab in patients with advanced Merkel cell carcinoma showed a high ORR with durable responses and an expected safety profile. Combined nivolumab and ipilimumab also showed clinical benefit in patients with previous anti-PD-1 and PD-L1 treatment. Addition of SBRT did not improve efficacy of combined nivolumab and ipilimumab. The combination of nivolumab and ipilimumab represents a new first-line and salvage therapeutic option for advanced Merkel cell carcinoma.

Funding

Bristol Myers Squibb Rare Population Malignancy Program.

中文翻译：

---

联合纳武单抗和易普利姆玛联合或不联合立体定向全身放射治疗治疗晚期默克尔细胞癌：一项随机、开放标签的 2 期试验

背景

默克尔细胞癌是最具侵袭性和致命性的原发性皮肤癌之一，具有很高的远处转移率。抗程序性死亡受体 1（抗 PD-1）和程序性死亡配体 1 (PD-L1) 单一疗法目前是不可切除、复发或转移性默克尔细胞癌的标准治疗方法。我们评估了晚期 Merkel 细胞癌患者的纳武单抗加伊匹单抗联合治疗，联合或不联合立体定向放射治疗 (SBRT) 作为一线治疗或在既往接受抗 PD-1 和 PD-L1 单一疗法治疗后的治疗。

方法

在这项随机、开放标签、2 期试验中，我们将来自美国两个癌症地点（一个在佛罗里达州，一个在俄亥俄州）的成年人随机分配到 A 组（纳武单抗和伊匹单抗联合治疗）或 B 组（纳武单抗和伊匹单抗联合治疗加 SBRT） ）按 1:1 的比例。符合条件的患者年龄至少 18 岁，患有组织学证明的晚期（不可切除、复发或 IV 期）默克尔细胞癌，至少有两个可通过 CT、MRI 或临床检查测量的肿瘤病灶，并且肿瘤组织可用于探索性生物标志物分析。根据既往免疫检查点抑制剂 (ICI) 状态对患者进行分层，接受每 2 周静脉注射 240 mg 纳武单抗加每 6 周静脉注射 1 mg/kg 伊匹单抗（A 组）或接受纳武单抗和伊匹单抗联合治疗加 SBRT 的相同方案至少一个肿瘤部位（第 2 周分 3 次 24 Gy；B 组）。患者必须至少有两个可测量的疾病部位，以便可以跟踪一个未照射部位的反应。主要终点是所有随机分配的接受至少一剂纳武单抗和伊匹单抗联合治疗的患者的客观缓解率 (ORR)。ORR 定义为根据实体瘤免疫相关反应评估标准获得完全缓解或部分缓解的患者比例。每 12 周评估一次疗效。对所有患者进行安全性评估。该试验已在 ClinicalTrials.gov 注册，NCT03071406。

发现

2017年3月14日至2021年12月21日期间入组了50名患者（A组和B组各25名），其中包括24名未接受过ICI治疗的患者（25名A组患者中的13名[52%]，以及25名A组患者中的11名[44%]）。 25 名 B 组患者]）和 26 名既往有 ICI 的患者（25 名 A 组患者中的 12 名 [48%] 和 25 名 B 组患者中的 14 名 [56%]）。B 组中的一名患者由于担心过度毒性而没有接受 SBRT。中位随访时间为 14·6 个月 (IQR 9·1–26·5)。B 组中的两名患者被排除在主要终点分析之外，因为目标病灶受到了照射，因此患者被认为不可评估。在未接受 ICI 治疗的患者中，22 名 (95% CI 82–100) 患者中有 22 名 (100%) 获得客观缓解，其中 9 名 (41% [95% CI 21–63]) 获得完全缓解。在之前接受过 ICI 暴露的患者中，26 名患者 (95% CI 15-52) 中的 8 名 (31%) 出现客观缓解，4 名 (15% [5-36]) 出现完全缓解。A 组（25 名患者中的 18 名 [72%]）和 B 组（23 名患者中的 12 名 [52%]；p=0·26）之间没有观察到 ORR 存在显着差异。A 组 25 名患者中有 10 名患者（40%）观察到 3 级或 4 级治疗相关不良事件，B 组 25 名患者中有 8 名患者（32%）出现 3 级或 4 级治疗相关不良事件。

解释

一线联合纳武单抗和伊匹单抗治疗晚期默克尔细胞癌患者显示出高 ORR、持久反应和预期的安全性。纳武单抗和易普利姆玛联合治疗也对既往接受过抗 PD-1 和 PD-L1 治疗的患者显示出临床益处。添加 SBRT 并没有提高纳武单抗和伊匹单抗联合治疗的疗效。纳武单抗和易普利姆玛的组合代表了晚期默克尔细胞癌的新一线和挽救治疗选择。

资金

百时美施贵宝罕见人群恶性肿瘤计划。