美国H Lee Moffitt癌症中心和研究所Sungjune Kim团队研究了联合纳武单抗和伊匹单抗，与立体定向体放疗治疗晚期默克尔细胞癌的疗效与安全性。2022年9月11日，《柳叶刀》杂志发表了这一成果。

默克尔细胞癌是原发性皮肤癌中最具侵袭性和致死性的一种，具有较高的远端转移率。抗程序性死亡受体1（抗PD-1）和程序性死亡配体1（PD-L1）单药治疗目前是不可切除、复发或转移性默克尔细胞癌的标准治疗。研究组评估了联合使用纳武单抗和伊匹单抗，同时使用或不使用立体定向体放射治疗（SBRT）作为一线治疗，或紧随着先前的抗PD-1和PD-L1单药治疗对晚期默克尔细胞癌患者的疗效。

在这项随机、开放标签、2期临床试验中，研究组将来自美国两个癌症中心（一个在佛罗里达州，一个在俄亥俄州）的成年人随机分为A组（联合使用纳武单抗和伊匹单抗）或B组（联合使用纳武单抗和伊匹单抗加SBRT），比例为1:1。符合条件的患者年龄至少为18岁，患有经组织学证实的晚期（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或临床检测的肿瘤病变，其肿瘤组织可用于探索性生物标志物分析。

根据先前的免疫检查点抑制剂（ICI）状态对患者进行分层，每2周静脉注射纳武单抗240 mg，每6周静脉注射伊匹单抗1 mg/kg（A组），或采用相同的方案，在至少一个肿瘤部位添加SBRT（第2周24 Gy；B组）。患者必须至少有两个可测量的肿瘤部位，以便跟踪一个非照射部位的反应。

主要终点是所有随机分配的至少接受一剂联合纳武单抗和伊匹单抗患者的客观缓解率（ORR）。ORR定义为实体瘤中根据免疫相关缓解评价标准完全缓解或部分缓解的患者比例。每12周评估一次缓解。对所有患者进行安全性评估。

2017年3月14日至2021年12月21日，研究组共招募了50名患者（A组和B组各25名），包括24名初始ICI的患者（25名A组患者中有13名[52%]、25名B组患者中有11名[44%]）和26名既往接受过ICI的患者（25位A组患者中有12名[48%]、25位B组患者中有14名[56%]）。B组的一名患者因担心过度毒性而未接受SBRT。

中位随访时间为14.6个月。B组中的两名患者被排除在主要终点分析之外，由于靶病变受到照射，患者被认为不可评估。在初次ICI患者中，22例（100%）全部客观缓解，包括9例（41%）完全缓解。在既往接受过ICI的患者中，26名患者中有8名（31%）客观缓解，4名（15%）完全缓解。

在A组（25名患者中有18名[72%]）和B组（23名患者中的12名[52%]）之间未观察到ORR的显著差异。A组25名患者中有10名（40%）观察到3级或4级治疗相关不良事件，B组25例患者中有8名（32%）。

研究结果表明，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，具有持久的缓解和预期的安全性。在先前抗PD-1和PD-L1治疗的患者中，纳武单抗和伊匹单抗联合应用也显示出临床益处。SBRT的添加并没有改善联合纳武单抗和伊匹单抗的疗效。纳武单抗和伊匹单抗的联合治疗为晚期默克尔细胞癌提供了一种新的一线和挽救治疗选择。

附：英文原文

Title: Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Author: Sungjune Kim, Evan Wuthrick, Dukagjin Blakaj, Zeynep Eroglu, Claire Verschraegen, Ram Thapa, Matthew Mills, Khaled Dibs, Casey Liveringhouse, Jeffery Russell, Jimmy J Caudell, Ahmad Tarhini, Joseph Markowitz, Kari Kendra, Richard Wu, Dung-Tsa Chen, Anders Berglund, Lauren Michael, Mia Aoki, Min-Hsuan Wang, Imene Hamaidi, Pingyan Cheng, Janis de la Iglesia, Robbert J Slebos, Christine H Chung, Todd C Knepper, Carlos M Moran-Segura, Jonathan V Nguyen, Bradford A Perez, Trevor Rose, Louis Harrison, Jane L Messina, Vernon K Sondak, Kenneth Y Tsai, Nikhil I Khushalani, Andrew S Brohl

Issue&Volume: 2022-09-11

Abstract:

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.

DOI: 10.1016/S0140-6736(22)01659-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01659-2/fulltext