Nivolumab保持积极的成果最新发现肝癌

StephenW

Nivolumab Maintains Positive Results in Latest HCC Findings                            Anita T. Shaffer @Shaffer1
                Published Online: Sunday, Sep 11, 2016
                           
                                                                                                     
                                            
                    
                                            
                    
                                            
                    
                                            
                    
                                            
                    
                                                            
                    

Bruno Sangro, MD, PhD

Nivolumab (Opdivo) continues to post “highly encouraging’” and durable responses in patients with advanced hepatocellular carcinoma (HCC) regardless of whether they had hepatitis B or C or whether they had received prior treatment with sorafenib (Nexavar), according to the lead investigator on the early-phase study.

The objective response rate (ORR) was 16% among 214 patients who participated in an expansion cohort of the CheckMate-040 study, Bruno Sangro, MD, PhD, reported at the at the 2016 International Liver Cancer Association conference.1 Among the 35 patients who responded, 33 had partial responses and 2 experienced a complete response. Another 111 patients had stable disease.

The interim findings are similar to efficacy and safety observations from the dose-escalation portion of the study reported at the 2016 ASCO Annual Meeting,2 although the follow-up period is much shorter than the 3-year timeframe in the first phase, said Sangro, who is director of the Liver Unit at Clinica Universidad de Navarra in Pamplona, Spain.

Sangro said the follow-up period is too short to draw conclusions about overall survival (OS). The OS rate for all patients was 82.5% at 6 months and 70.8% at 9 months.

“The 6-month and 9-month survival rates are not only highly encouraging but fit very well with the findings in the escalation cohort, in which the follow-up is much longer and in which 14.2-[month] median overall survival was reported at ASCO this year,” sand Sangro. “While these results are preliminary, the 9-month overall survival rate of 71% is certainly encouraging.”
In all, the expansion phase of the trial consisted of 4 groups of patients, all of whom received nivolumab at 3 mg/kg every 2 weeks: patients without hepatitis who had not received or were intolerant to sorafenib (n = 54); participants who had progressed after receiving sorafenib (n = 58); patients who were infected with hepatitis C (n = 51); and individuals who were infected with hepatitis B (n = 51).

In the 2 hepatitis cohorts, participants must have received prior sorafenib, become intolerant to it, or progressed during or after therapy with the agent. Many of the participants across all cohorts were heavily pretreated with therapies including surgical resection (58%), locoregional therapy (59%), and systemic therapy including sorafenib (73%).

The primary endpoint of the trial was ORR according to RECIST v1.1 criteria by blinded independent central review. Secondary endpoints included duration of response, time to response, time to progression, and OS.

During the study, patients received a median of 10 doses of nivolumab (range, 1-27) over a median time on treatment of 20 weeks, Sangro said. “Most of the patients who discontinued treatment did so because of progression,” he said. “Only a minority of 7% of the total population had to discontinue treatment because of study drug toxicity. Treatment was, by and large, very well tolerated.”

The most frequent symptomatic treatment-related adverse events (AEs) of any grades included fatigue (21%), pruritus (15%), and rash (12%). Treatment-related grade 3/4 AEs were reported in 39 patients (18%).

In analyzing response rates by cohort, Sangro said ORRs were similar across the groups. The ORR ranged from 12% for patients who had been infected with hepatitis B to 20% for uninfected patients who were sorafenib naïve or intolerant. “Etiology is not a major factor in defining the response to nivolumab therapy,” Sangro said.

He also said that the response rate did not differ by PD-L1 expression status, as assessed by immunohistochemistry on ≥1% versus <1% of tumor cells.

In terms of durability, Sangro indicated that responses were ongoing in 30 of 35 responders at the time of analysis in March, and the median duration of response had not yet been reached. He also said 29 of the patients responded within 3 months of beginning treatment.

As analysis continues on this group of patients, a phase III randomized trial of nivolumab versus sorafenib has been launched in the frontline setting.3 The trial, which is seeking to enroll 726 patients, has an estimated primary completion date of July 2017.

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References

StephenW

Nivolumab保持积极的成果最新发现肝癌
梅艳芳T.谢弗@ Shaffer1
在线发表时间：周日，2016年9月11日
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布鲁诺·桑格罗博士

布鲁诺·桑格罗博士
Nivolumab（Opdivo）继续张贴“非常令人鼓舞”“，并在晚期肝细胞癌（HCC），无论他们是否有乙型肝炎或丙型肝炎或他们是否收到了索拉非尼（多吉美）治疗前持续反应，根据铅研究者对早期阶段的研究。

客观缓解率（ORR）是其中214例谁参加的CheckMate-040研究的扩展队列16％，布鲁诺·桑格罗，博士，报道在2016国际肝癌协会conference.1其中35例谁回答，33例部分反应，2经历了一个完整的答复。另111例病情稳定。

临时结果类似于从在2016年ASCO年会上，2报告该研究的剂量递增部分的疗效和安全性意见虽然随访期是比在第一阶段的3年的时间内要短得多，所述桑格罗，谁是CLÍNICA大学纳瓦拉潘普洛纳，西班牙肝组主任。

桑格罗说，随访时间太短，得出总生存期（OS）的结论。所有患者的OS率分别为6个月82.5％和9个月70.8％。

“6个月和9个月的生存率不仅十分令人鼓舞，但身体非常好，在升级的队列研究结果，其中随访更长的时间，并在14.2- [月]中位总生存报告在ASCO今年以来，“沙桑格罗。 “虽然这些结果是初步的，71％的9个月的生存率肯定是鼓舞人心的。”

总之，审判的扩张阶段分为对照组患者中，所有的人在3毫克收到nivolumab / kg，每2周：患者无谁没有收到或不能容忍索拉非尼（N = 54）肝炎;谁曾接受索拉非尼（N = 58）后进展的参与者;谁是感染了丙型肝炎（51例）的患者;和谁被感染乙型肝炎（N = 51）的人。

在2肝炎同伙，参加者必须已经收到前索拉非尼，成为不耐受，或中或与代理治疗后进展。许多在所有队列的参与者被大量使用的疗法包括手术切除（58％），局部治疗（59％），以及全身治疗包括索拉非尼（73％）进行预处理。

该试验的主要终点根据独立蒙蔽中央审查RECIST v1.1的标准是ORR。次要终点包括响应的持续时间，时间到响应，进展时间，和OS。

在研究过程中，患者接受的10个剂量nivolumab的（范围1-27）在中位时间上治疗20周的中位数，桑格罗所述。 “大多数谁停止治疗，因为没有进展，以便患者，”他说。 “只有总人口的7％，少数不得不中断，因为研究药物毒性的治疗。治疗，总的来说，耐受性非常好。“

任何等级的最常见的对症治疗相关的不良事件（AE）包括疲乏（21％），皮肤瘙痒（15％）和皮疹（12％）。治疗相关的3/4级不良事件报告39例（18％）。

在通过队列分析响应率，桑格罗说ORRs是跨组相似。该ORR从12％不等的谁已感染乙肝20％为未感染的病人谁是索拉非尼天真或不耐受的患者。 “病因并非限定于nivolumab治疗的反应的一个主要因素，”桑格罗所述。

他还表示，响应速度并没有通过PD-L1表达状态不同，作为≥1％和<肿瘤细胞的1％，评估通过免疫组化。

在耐用性方面，桑格罗指出，在应对在分析时35应答30正在进行三月，而尚未达到响应时间中位数。他还表示，患者27 3个月，从治疗内作出回应。

随着分析继续在本组患者中，nivolumab与索拉非尼的III期随机试验在一线setting.3的试验，正在寻求招收726例患者已经启动，有2017年7月的估计主要完成日期。
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