Nivolumab继续促进肝癌的生存

StephenW

Nivolumab Continues to Boost Survival in Liver Cancer

Roxanne Nelson, BSN, RN
January 23, 2017

SAN FRANCISCO ― Immunotherapy is making inroads as a potential treatment for a number of cancer types, and the latest to add to the list is advanced hepatocellular carcinoma (HCC).

Early responses have been reported from the Checkmate 040 study, in which nivolumab (Opdivo, Bristol-Myers Squibb) was used as a single agent in advanced HCC. Its use resulted in objective responses and long-term survival in patients who had previously been treated with sorafenib (Nexavar, Onyx/Bayer), and "very importantly, also in sorafenib-naive patients," said lead study author Ignacio Melero, MD, of the Clinica Universidad de Navarra, Pamplona, Spain.

Dr Melero presented his findings here at the Gastrointestinal Cancers Symposium (GICS) 2017.

For patients with advanced HCC, the prognosis is poor. The multitargeted tyrosine kinase inhibitor sorafenib is currently the only approved systemic treatment for the disease, Dr Melero commented.

Patients who experience disease progression while taking sorafenib have few options, noted Dr Melero.

"Nivolumab provided early, stable, and durable responses," he said. "And these responses were observed irrespective of PD-L1 [programmed death ligand 1] expression on tumor cells."

Nine months after starting treatment, 71% of patients remain alive.

The overall response rate in patients who received nivolumab as second-line treatment was 18.6% (n = 27); three patients achieved a complete response.

The response rate was a little lower when nivolumab was used in the first-line setting. There were no complete responses, but 15 patients (21.7%) achieved a partial response.

Efficacy was not dependent on hepatitis infection status, and responses occurred in both infected and uninfected patients.

Escalation Leads to Expansion

The Checkmate 040 study was conducted in two phases.

"Because of the inflammation that often affects the liver, we were very afraid of precipitating hyperacute or fulminant hepatitis in these patients, and that was the reason that we undertook a very careful dose escalation," Dr Melero explained.

The dose escalation phase was conducted in 48 patients, who received primary pretreatment with sorafenib. These patients included those infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as patients who were uninfected.

Findings from the dose escalation phase in pretreated HCC patients were presented at the 2015 annual meeting of the American Society of Clinical Oncology and were reported by Medscape Medical News at that time.

Those early data showed an "unprecedented" overall response rate for a systemic therapy in advanced HCC. Eight of 42 (19%) evaluable patients responded to nivolumab (tumor reduction beyond 30%), including two with complete responses, the investigators reported at that time. The results compare favorably with those seen with sorafenib, which has a response rate in this setting of only 2%.

Owing to the efficacy and safety seen in the escalation phase, the study was extended into an expansion phase, with 214 patients being treated with nivolumab at the now standard dose of 3 mg/kg.

About half of patients were uninfected (n = 113). About 25% (n = 51) were infected with HBV, and 25% (n = 50) were infected with HCV.
The majority of patients (n = 145) had received prior sorafenib treatment and so were receiving nivolumab in the second-line setting; 69 patients were treatment naive.
The primary endpoint in the dose-expansion phase was objective response rate by RECIST v1.1. Secondary endpoints included duration of response and overall survival.
Among pretreated patients, stable disease was achieved in 45.5% (n = 66); 31.7% (n = 45) experienced disease progression. Similar results were seen for patients in the first-line setting; stable disease was achieved in 43.5% (n = 30) of patients, and 31.9% (n = 22) experienced disease progression on treatment.
When responses occurred, they tended to be very durable, Dr Melero pointed out. The time to response was 2.7 months. The duration of response, which was 17.1 months in the dose escalation phase, has not yet been reached in the current study.
"In regards to PD-L1, we found that there were responses regardless of PD-L1 status," he said. "There were compatible response rates in PD-L1-positive and PD-L1-negative tumors."
Safety was manageable and consistent across patient cohorts and was very similar to what has been observed in studies involving patients with other solid tumors. There were no new safety signals.
"Most of the grade 3 and 4 toxicities were lab abnormalities without clinical repercussions in the patients," Dr Melero said.
He added that a phase 3 study that is evaluating the use of nivolumab in treatment-naive patients with advanced HCC is ongoing.
Future Belongs to Immuno-Oncology
In a discussion of the paper, Milind Javle, MD, from the University of Texas MD Anderson Cancer Center, Houston, noted that the "study was impressive in the sense that the response rate was 19%, and the response was pretty brisk.
"There was similar efficacy whether it was given first- or second-line, and what is most impressive is that 71% of patients are still alive at 9 months," said Dr Javle. "This indicates that even if patients do progress, they survive for a reasonably long time."
From this study, one can say that checkpoint inhibitors may offer major clinical benefit, but only for a minority of patients, he noted.
Dr Javle emphasized that predictive markers for response in immuno-oncology are critical.
"Some are available in the clinic today, with the most popular one being PD-L1, although it was not predictive in the current study," he said.
Now the question is, where to go next?
There are ongoing first-line studies of nivolumab vs sorafenib and pembrolizumab vs sorafenib, but perhaps one can conceive a second-line study vs regorafenib (Stivarga, Bayer), Dr Javle commented.
Studies of combination strategies, such as with anti-PD-1/PD-L1 plus CTLA4 or with small molecule tyrosine kinase inhibitors, are also being considered, he explained. The role of immune-oncology in the adjuvant setting is also being explored.
The landscape of HCC has changed dramatically during the past 2 decades, with the advent of the HBV vaccine, sorafenib coming on the marketplace, and new effective therapies for HCV. "A second-line study for regorafenib was positive, but the future clearly belongs to immune-oncology," Dr Javle concluded.
"So clearly immune-oncology in HCC has come of age. Better predictors, immuno-oncology combinations, and application to other HCC settings are needed," he added.
The study was supported by Bristol-Meyers Squibb. Dr Melero has received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche; has served in a consulting/advisory role with AstraZeneca, Bayer, Bristol-Myers Squibb, Incyte, Merck Serono, MSD, and Roche; and has received research funding from Alligator Bioscience (Inst), Pfizer (Inst), and Tusk Therapeutics (Inst). Other coauthors also report relationships with industry. Dr Javle has disclosed no relevant financial relationships.
Gastrointestinal Cancers Symposium (GICS) 2017. Abstract 226, presented January 20, 2017.

StephenW

Nivolumab继续促进肝癌的生存

Roxanne Nelson，BSN，RN
2017年1月23日

SAN FRANCISCO - 免疫治疗正在作为一种潜在的治疗许多癌症类型，最新添加到列表中的是晚期肝细胞癌（HCC）。

早期反应已经从Checkmate 040研究报道，其中nivolumab（Opdivo，Bristol-Myers Squibb）用作晚期HCC中的单一药剂。该研究的作者Ignacio Melero博士说：“在索拉非尼（Nexavar，Onyx / Bayer）治疗的患者中，其使用导致客观反应和长期生存，”非常重要的是，的Navarra大学，潘普洛纳，西班牙。

Melero博士在这里的胃肠癌研讨会（GICS）上提出了他的发现。

对于晚期肝癌患者，预后较差。多靶点酪氨酸激酶抑制剂索拉非尼是目前唯一批准的该疾病的全身治疗，Melero博士评论道。

Melero博士指出，服用索拉非尼的患者发生疾病进展的可能性很少。

“Nivolumab提供早期，稳定和持久的反应，”他说。 “并且观察到这些反应，与肿瘤细胞上的PD-L1（程序性死亡配体1）表达无关。

开始治疗9个月后，71％的患者仍然存活。

接受nivolumab作为二线治疗的患者的总体反应率为18.6％（n = 27）; 3例患者达到完全缓解。

当nivolumab用于一线设置时，反应率略低。没有完全反应，但15例（21.7％）达到部分反应。

功效不依赖于肝炎感染状态，并且在感染和未感染患者中发生反应。

升级导致扩展

Checkmate 040研究分两个阶段进行。

Melero博士解释说：“由于通常影响肝脏的炎症，我们非常害怕这些患者发生超急性或暴发性肝炎，这是我们采取非常仔细的剂量增加的原因。

剂量递增期在48名患者中进行，他们接受用索拉非尼的初步预处理。这些患者包括感染乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）的患者，以及未感染的患者。

在预处理的HCC患者的剂量递增阶段的结果在美国临床肿瘤学会的2015年年会上提出，并且当时被Medscape Medical News报道。

这些早期数据显示，对于晚期肝癌的全身治疗，“前所未有”的总体反应率。 42例中有8例（19％）可评估的患者对nivolumab的反应（肿瘤减少超过30％），包括两例具有完全反应，研究者当时报告。结果与索拉非尼的结果相当，索拉非尼在这种情况下的反应率仅为2％。

由于在升级阶段中观察到的功效和安全性，将该研究扩展到扩增阶段，其中214名患者用nivolumab以3mg / kg的标准剂量治疗。

约一半的患者未感染（n = 113）。约25％（n = 51）感染HBV，25％（n = 50）感染HCV。

大多数患者（n = 145）先前接受了索拉菲尼治疗，因此在二线设置中接受了nivolumab; 69例患者接受了原初治疗。

剂量扩张期的主要终点是RECIST v1.1的客观反应率。次要终点包括反应持续时间和总生存期。

（N = 45）经历疾病进展。在一线设置的患者中观察到类似的结果;稳定的疾病达到45.5％（n = 66）; 31.7％= 30）和31.9％（n = 22）的患者在治疗中经历疾病进展。

在当前研究中，在剂量递增阶段中的反应时间为17.1个月，尚未达到。回应的时间，往往是非常耐用的，Melero博士指出。反应时间为2.7个月。

“关于PD-L1，我们发现无论PD-L1状态如何，都有反应，”他说。 “PD-L1阳性和PD-L1阴性肿瘤有兼容的反应率。

安全性是可控的并且在患者队列中是一致的，并且与在涉及其他实体瘤患者的研究中观察到的非常相似。没有新的安全信号。

“大多数3级和4级毒性是实验室异常，没有患者的临床反应，”Melero博士说。

他补充说，正在评估nivolumab在具有晚期HCC的初治患者中的使用的3期研究正在进行。

未来属于免疫肿瘤学

在论文的讨论中，来自德克萨斯大学MD安德森癌症中心（University of Texas MD Anderson Cancer Center，Houston）的Milind Javle博士指出，“研究结果令人印象深刻，回应率为19％，反应相当热烈。

“无论是第一线还是第二线，都有类似的疗效，最令人印象深刻的是，71％的患者在9个月时还活着，”Javle博士说。 “这表明，即使病人做进展，他们生存了相当长的时间。

从这项研究，可以说，检查点抑制剂可能提供主要的临床益处，但只有少数患者，他指出。

Javle博士强调，免疫肿瘤学反应的预测标志物至关重要。

“一些在今天的诊所，最受欢迎的一个是PD-L1，虽然它不是在本研究中的预测，”他说。

现在的问题是，下一步去哪里？

目前有关于nivolumab vs索拉非尼和pembrolizumab与索拉非尼的一线研究，但也许有人可以设想对regorafenib（Stivarga，Bayer）的二线研究，Javle博士评论道。

他解释说，还考虑了组合策略的研究，如与抗PD-1 / PD-L1加CTLA4或与小分子酪氨酸激酶抑制剂。免疫肿瘤学在佐剂设置中的作用也正在被探索。

在过去二十年中，随着HBV疫苗，索拉非尼进入市场以及新的HCV有效治疗的出现，HCC的景观发生了巨大变化。 “对regorafenib的二线研究是积极的，但未来的愿景对免疫肿瘤学，”Javle博士总结。

＆Quot;显然，HCC的免疫肿瘤已经成熟。更好的预测因子，免疫肿瘤学组合和应用于其他HCC设置是需要的，他加了。

该研究由Bristol-Meyers Squibb支持。 Melero博士从AstraZeneca，Bayer，Bristol-Myers Squibb，Incyte，Merck Serono，MSD和Roche获得了酬金;曾在AstraZeneca，Bayer，Bristol-Myers Squibb，Incyte，Merck Serono，MSD和Roche担任顾问/咨询职务;并已从Alligator Bioscience（Inst），Pfizer（Inst）和Tusk Therapeutics（Inst）获得研究资金。其他合作者也报告与行业的关系。 Javle博士没有披露任何相关的财务关系。

Gastrointestinal Cancers Symposium（GICS）2017。摘要226，2017年1月20日提交。