整理：大叔
来源：大叔快评
Nivolumab针对晚期肝癌设计的checkmate-040是一项特别意义的phaseI研究，赋予剂量爬坡和扩展研究两项功能，借力FDA对临床研究药物评审的灵活性，checkmate-040设计分为2个部分，以索拉非尼治疗进展后的二线患者为主，兼备部分一线初次治疗的患者。Checkmate-040结果已经分别在ASCO、ESMO、ESMO ASIA陆续报道过多次，此次在2017 ASCO-GI是最新版本，为了让大家get到重点，还是要介绍一下研究设计。
Checkmate-040研究设计：
第一部分：剂量爬坡组（48例）起始剂量0.1mg/kg，最大剂量 10mg/kg。无肝炎病毒感染23例；丙肝感染（HCV）10例；乙肝感染（HBV）15例。其中2线37例（索拉非尼治疗后），1线11例（未经索拉非尼治疗）。
第二部分：扩展组（214例），确定剂量为3mg/kg（nivolumab先期研究大多数采用的body-weight 剂量，目前nivolumab的研究更多采用240mg 固定剂量flat dose）
2017年ASCO-GI口头报告由来自西班牙的Ignacio Melero 教授呈现，香港中文大学的Thomas Yau 教授为第三作者。题目还是老样子，Nivolumab在晚期肝细胞癌患者中的剂量爬升和剂量扩展CheckMate-040研究。
患者基线特征：
总病例数262例，其中剂量扩展组214例，剂量爬升组48例。值得关注的是亚裔患者119例，占45%；索拉非尼治疗后的患者182例，占69%；未经索拉非尼治疗的患者63例，占24%。
研究结果：
ORR用了两个评判标准，经典的RECIST1.1 和mRECIST，分别由研究者评估和独立中心盲法评估BICR（blinded- independent central review），很显然BICR更客观，最大可能避免评估的主观偏差。以mRECIST评判的总体ORR分别为21.6%（剂量爬升组），18.6%（剂量扩展组），在二线是不错的结果。其中69例1线患者ORR为21.7% byRECIST 1.1。
索拉非尼治疗后的2线患者ORR、OS分析的数据库截至到2016年8月8日，剂量爬升组OS 15.0个月（5.-22.2），剂量扩展组OS 13.2个月（13.2-NR）。
索拉非尼治疗后的2线患者OS
安全性：
剂量扩展组214例患者中，与治疗相关的AE，Grade 3/4 为19% （40例），Grade All 74%（159例）。
剂量扩展组AEs
结论：
1. Nivolumab的安全性可管理，2个组别一致，与其他肿瘤中观察的副反应一致，没有发现新的安全性问题。
2. Nivolumab在索拉非尼治疗和未经索拉非尼治疗的患者中均体现有获益的ORR和长期的生存获益。
3. Nivolumab单药治疗体现早期、稳定和持久的应答，与HCV和HBV是否感染无关，与肿瘤细胞PD-L1表达无关。
【大叔点评】
1. 一项262例样本的单臂临床研究，以2线患者为主（69%），69例一线患者表现出21%的ORR，期待正在进行的PhaseIII checkmate-459不久将来的印证。
2. BMS有可能用这项研究的结果申请nivolumab晚期肝癌2线的适应症
3. 拜耳瑞戈非尼的晚期肝癌2线三期临床研究结果已经在Lancet发表，入组573例患者，2:1随机分组，OS为10.6个月 vs 7.8个月（安慰剂）。2017年1月6日获得FDA优先审评资格。
特此致谢，图片均来自Vivian Li 和 Linda Xu
2017年1月21日 大叔
Phase I/II CheckMate 040 Study Suggests Nivolumab Is Active and Well Tolerated As First- or Second-Line HCC Monotherapy; Phase III Analyses Underway
Interim results of the large phase I/II CheckMate 040 study of nivolumab indicate that the anti–PD-1 antibody is both active and well tolerated when given as monotherapy to patients with advanced hepatocellular carcinoma (HCC; Abstract 226). The study included 262 patients with unselected PD-L1 tumors—182 of whom had received sorafenib and 80 of whom were treatment naive. Confirmed objective response rate (ORR) in the dose-expansion group reached 18.6% or better, and upwards of 70% of these patients survived to 9 months.
Ignacio Melero, MD, of the Clinica Universidad de Navarra, in Spain, presented the findings on behalf of his co-investigators.
Many patients with HCC present with advanced disease, leading to a poor prognosis. The current standard of care for these individuals is the multikinase inhibitor sorafenib. However, no standard exists for those whose disease progresses on this agent.
The current findings suggest that nivolumab immunotherapy holds the potential to enhance the therapeutic armamentarium for HCC as it has already done for melanoma, non–small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, and Hodgkin lymphoma.
CheckMate 040 was a dose-escalation and -expansion study conducted in 262 patients with advanced HCC who were not suitable for surgical resection. Hepatitis B virus or hepatitis C virus infection was allowed, as was one prior line of treatment, typically sorafenib. Patients were evaluated based on treatment-naive or sorafenib-experienced status to inform future analyses.
Following confirmation of safety and tolerability in the dose-escalation phase, all patients in the dose-expansion phase received intravenous nivolumab 3 mg/kg every 2 weeks until progressive disease or intractable toxicity set in.
The ORR among 145 sorafenib-experienced patients in the dose-expansion phase of the trial reached 18.6%, largely consisting of partial responses (16.6%). The addition of another 45.5% of patients with stable disease bumped the disease control rate to 64.1%. Notably, responses were observed regardless of whether patients had hepatitis B virus infection, hepatitis C virus infection, or no viral hepatitis infection, and regardless of PD-L1 expression on tumor cells.
Of the patients who demonstrated an objective response to nivolumab in the dose-expansion phase, the median time to response was 2.7 months, and the median duration of response has not yet been reached.
Median overall survival (OS) in the sorafenib-experienced group has also not yet been reached for those in the dose-expansion phase, but it extended to 15.0 months for the 37 individuals in the dose-escalation phase. Dr. Melero remarked that “stabilization of disease is a driver of survival,” as illustrated by the data showing that 82% of patients receiving nivolumab 3 mg/kg survived to 6 months and 71% survived to 9 months.
Findings similar to those in the treatment-experienced cohort were observed in the smaller cohort of 69 patients who were treatment naive. In the dose-expansion phase, the ORR reached 21.7%, the disease control rate reached 65.2%, 6-month OS reached 87%, and 9-month OS reached 77%.
Dr. Melero said that the toxicity profile of nivolumab in patients with HCC appeared similar to that observed in other tumor types, with no new concerning safety signals. Among patients in the dose-expansion phase, treatment-related adverse events occurred in 74% of patients. However, only 19% of these events reached grade 3 or 4 severity, and no grade 5 events occurred. The most common grade 3/4 treatment-related adverse events that arose consisted of increased levels of aspartate aminotransferase (4%) and alanine aminotransferase (2%), with no evidence of clinical repercussions.
Rounding out the efficacy and safety findings, Dr. Melero also presented data showing that measures of patient-reported quality of life held steady throughout 25 weeks of assessment. No clinically meaningful differences were observed from baseline to any time point or between the first- and second-line cohorts.
“One can say from this study that checkpoint inhibitors may offer major clinical benefit but for a minority of patients,” discussant Milind M. Javle, MD, of The University of Texas MD Anderson Cancer Center, said in his critique of the CheckMate 040 findings. “Clearly, predictive biomarkers for immuno-oncology are critical.”
Although PD-L1 expression was not predictive in the current study, Dr. Javle suggested several other biomarkers that may hold value for enriching the population of patients who stand to gain from nivolumab.
Still, Dr. Javle acknowledged that immunotherapies represent the latest and greatest advance in the changing HCC landscape. “Immuno-oncology in HCC has come of age,” he said. “Better predictors, immuno-oncology combinations, and application to other HCC settings are needed.”
One that note, Dr. Melero did indicate that the phase III CheckMate 459 trial is currently underway and aims to compare nivolumab and sorafenib as first-line therapy in patients with advanced HCC.
Nivolumab dose escalation and expansion in patients with advanced hepatocellular carcinoma (HCC): The CheckMate 040 study.
Abstract:
Background: HCC diagnosed at advanced stages has a poor prognosis. Patients who progress on sorafenib have few options. Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 (PD-1), has demonstrated clinical and survival benefit in a number of tumor types. Here we report updated interim analyses of safety, efficacy, and exploratory biomarkers in patients with advanced HCC treated with nivolumab in the CheckMate 040 study (NCT01658878). Methods: Patients enrolled had advanced HCC with or without hepatitis C or B virus (HCV or HBV) infection. Prior sorafenib was allowed. Phase 1 dose-escalation evaluated nivolumab (0.1–10 mg/kg) Q2W. Phase 2 dose-expansion was initiated in 4 cohorts: sorafenib naïve/intolerant, sorafenib progressors, HCV infected, and HBV infected. All cohorts received nivolumab 3 mg/kg Q2W. The primary endpoint in the dose-escalation phase was safety/tolerability, and the primary endpoint in the dose-expansion phase was objective response rate (ORR) by RECIST v1.1 (central review). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and overall survival (OS). Biomarkers within pre-treatment tumors were assessed. Results: Across dose escalation and expansion phases, 262 patients have been treated. Grade 3/4 treatment-related adverse events occurred in 20%. No maximum tolerated dose was reached during dose escalation (n = 48). The ORR (investigator-assessed) was 20% (95% CI 15–26) in 214 patients treated in the dose expansion phase with a median DoR of 9.9 months; DCR was 64% (95% CI 58–71). Responses were observed across etiologies and regardless of tumor PD-L1 expression. ORRs of 23% (95% CI 13–36) and 21% (95% CI 11–34) were observed in the uninfected sorafenib-naive and -treated patients, respectively. The 9-month overall survival rate in the expansion phase was 74% (95% CI 67–79). Association between immune-cell biomarkers and clinical outcomes will be presented. Conclusions: In this heavily pretreated population, responses to nivolumab were durable with encouraging overall survival. Safety was manageable and consistent with that observed in other solid tumors with no new safety signals. Clinical trial information: NCT01658878
参考文献：
2017 ASCO GI Abs
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