索拉非尼治疗晚期肝癌后Pembrolizumab有希望

StephenW

Pembrolizumab Promising After Sorafenib in Advanced HCC                            Wayne Kuznar
                Published: Saturday, Jan 20, 2018
                           
                                                                                                     
                                            
                    
                                            
                    
                                            
                    
                                            
                    
                                            
                    
                                       
                    

Andrew X. Zhu, MD, PhD

Treatment with the PD-1 inhibitor pembrolizumab (Keytruda) elicited promising progression-free survival (PFS) and overall survival (OS) results in patients with advanced hepatocellular carcinoma (HCC) who received previous treatment with sorafenib, according to phase II findings presented at the 2018 Gastrointestinal Cancers Symposium.

Of 105 patients enrolled in the single-arm, open-label phase II KEYNOTE-224 study, the objective response rate with pembrolizumab was 16.3% (95% CI, 9.8%-24.9%), with 1 complete response (CR). The median PFS was 4.8 months (95% CI, 3.4-6.6) and the median OS has not been reached. The 6-month PFS and OS rates were 43.1% and 77.9%, respectively. Treatment remained ongoing in 23 patients, reported lead investigator Andrew X. Zhu, MD, PhD.

“With the availability of various options in the treatment of refractory HCC, I think what our data are showing is that single-agent pembrolizumab is showing very impressive antitumor activity as evidenced by the response rate of 16.3%, but also a decent PFS in this population,” said Zhu, Professor of Medicine, Harvard Medical School, and Director, Liver Cancer Research, Massachusetts General Hospital Cancer Center, Boston.

Sorafenib is standard first-line therapy for advanced HCC, with regorafenib (Stivarga) and nivolumab (Opdivo) being the only approved second-line options in selected patients with HCC. Regorafenib was approved based on an improvement in OS in a phase III study while nivolumab was granted an accelerated approval based on response data in a phase I/II study. The phase III KEYNOTE-240 is currently assessing pembrolizumab for pretreated patients with HCC, with a primary endpoint of OS (NCT02702401).

“We think that this agent may become another potential option depending on an ongoing phase III trial,” Zhu said. “If that’s the case, this could be a new agent that we can consider for combination strategies but also looking at biomarkers of response to this class of drugs. More options are good for our patients.” Adding to this, he said that biomarker analysis will be conducted on tissue samples obtained from KEYNOTE-224.

In the phase II study, the efficacy and safety of pembrolizumab monotherapy was assessed in patients with Child Pugh class A advanced HCC who experienced radiographic progression of disease while receiving treatment with sorafenib, or were intolerant to sorafenib, and had a predicted life expectancy >3 months. Of the 105 patients enrolled, 104 were treated with pembrolizumab, 200 mg every 3 weeks for 2 years or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. Response was assessed every 9 weeks per RECIST v1.1 criteria.

Median patient age was 68 years, 21.2% were positive for hepatitis B virus (HBV), and 26.0% were positive for hepatitis C virus (HCV). Some 79.8% discontinued sorafenib for disease progression and 20.2% for intolerance. Extrahepatic disease was present in 63.5%.

In addition to the ORR of 16.3%, the disease control rate was 61.5% (95% CI, 51.5%-70.9%). Best overall response was a partial response in 15.4%, CR in 1.0%, and stable disease in 45.2%. In the responders, the median time to response was 2.1 months. Some 94% of responders were estimated to have a response duration ≥6 months, and the median duration of response was 8.2 months (range, 2.3+ to 8.3+). Responses were observed in patients with HBV or HCV infection and in uninfected patients.

The rate of treatment-related adverse events (TRAEs) of any grade was 73.1%. The most common TRAEs of any grade were pruritus (21.2%), fatigue (12.5%), increased aspartate aminotransferase (9.6%), and diarrhea (9.6%). Overall, 25.0% of patients had grade ≥3 TRAEs and there was 1 treatment-related death from ulcerative esophagitis. There were no flares of HCV or HBV. Immune-mediated hepatitis occurred in 3 patients (2.9%).

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Zhu AX, Finn RS, Cattan S, et al. KEYNOTE-224: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Presented at: 2018 Gastrointestinal Cancers Symposium; January 18-20, 2018; San Francisco, Calif. Abstract 209.

StephenW

索拉非尼治疗晚期肝癌后Pembrolizumab有希望
韦恩库兹纳尔
发布时间：2018年1月20日，星期六
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朱伟安博士
Andrew X. Zhu医学博士
依据PD-1抑制剂pembrolizumab（Keytruda）的治疗，在接受索拉非尼治疗的晚期肝细胞癌（HCC）患者中引发了有希望的无进展生存（PFS）和总生存期（OS） 2018年胃肠癌研讨会。

在单臂开放性II期KEYNOTE-224研究中，105名患者中，pembrolizumab的客观有效率为16.3％（95％可信区间，9.8％-24.9％中位PFS为4.8个月（95％CI，3.4 -6.6），中位OS​​尚未达到，6个月的PFS和OS率分别为43.1％和77.9％，报告的主要研究人员Andrew X. Zhu博士，治疗仍在进行中的23名患者。

“由于治疗难治性HCC的各种方案的可用性，我认为我们的数据显示，单药pembrolizumab显示非常令人印象深刻的抗肿瘤活性，如16.3％的反应率所证实的，但在该群体中也有体面的PFS ，“哈佛医学院医学教授，麻省综合医院癌症中心肝癌研究主任朱说。

索拉非尼是晚期HCC的标准一线治疗方案，瑞格非尼（Stivarga）和nivolumab（Opdivo）是唯一被批准用于HCC患者的二线治疗方案。 Regorafenib在III期研究中基于OS的改善被批准，而nivolumab在I / II期研究的基础上获得了响应数据的加速批准。 III期KEYNOTE-240目前正在评估pembrolizumab治疗HCC的预治疗患者，主要终点为OS（NCT02702401）。

朱镕基说：“根据正在进行的第三阶段试验，我们认为该代理商可能成为另一个潜在的选择。 “如果是这种情况，这可能是一个新的代理，我们可以考虑的组合策略，但也看到生物标志物的响应更多，他说，生物标志物分析将进行组织样本从KEYNOTE - 224获得。

在II期研究中，评估了Pembrolizumab单药治疗对Child-Pugh A级晚期HCC患者的疗效和安全性，这些患者在接受索拉非尼治疗时经历了疾病的放射学进展，或者对索拉非尼不耐受，且预期寿命预期值> 3 105名患者中有104名患者接受了pembrolizumab治疗，每3周200mg治疗2年，或直到疾病进展，毒副作用，撤回同意或研究者决定。每RECIST v1.1标准每9周评估一次响应。

中位患者为68岁，乙肝病毒（HBV）阳性21.2％，丙型肝炎病毒（HCV）阳性26.0％。大约79.8％的患者因疾病恶化而停用索拉非尼，20.2％的患者不耐受。肝外疾病占63.5％。

ORR为16.3％，疾病控制率为61.5％（95％CI，51.5％-70.9％）。最好的总体反应是15.4％，CR在1.0％，稳定的疾病在45.2％。在回应者中，回应的中位时间为2.1个月。约94％的反应者估计有≥6个月的反应持续时间，中位反应持续时间为8.2个月（范围2.3 + 8.3+）。在HBV或HCV感染患者和未感染患者中观察到。

任何级别的治疗相关不良事件（TRAEs）的发生率为73.1％。任何级别最常见的TRAEs为瘙痒（21.2％），疲劳（12.5％），天冬氨酸转氨酶％增加）。总体而言，25.0％的患者≥3级TRAE，并且有1例与溃疡性食管炎相关的死亡。没有丙型肝炎病毒或乙型肝炎的火焰。发生在3名患者（2.9％）的免疫介质。
Zhu AX，Finn RS，Cattan S等人KEYNOTE-224：以前用索拉非尼治疗的晚期肝细胞癌患者的Pembrolizumab。提交于：2018年胃肠癌研讨会; 2018年1月18 - 20日;旧金山，加利福尼亚州摘要209。