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标题: I / II期Opdivo（nivolumab）试验表明施贵宝公司的PD-1免疫检查点 [打印本页]
作者: StephenW    时间: 2015-5-30 10:40     标题: I / II期Opdivo（nivolumab）试验表明施贵宝公司的PD-1免疫检查点

Friday, May 29, 2015                  Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb’s PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers       Squibb Company (NYSE:BMY)todayannounced results from       an interim analysis of CA209-040, a Phase I/II dose-ranging trial       evaluating the safety and anti-tumor activity of Opdivo (nivolumab)       in previously-treated patients with hepatocellular carcinoma (HCC) or       advanced liver cancer. Initial findings demonstrated that the estimated       survival rate in evaluable patients (n=47) was 62% at 12 months. Results       also show the safety profile of Opdivo is generally consistent       with that previously-reported for Opdivo in other tumor types.       These data will be featured today, May 29, during the 51st Annual       Meeting of the American Society of Clinical Oncology (ASCO) press       briefing at 1:00 – 2:00 p.m. CDT and presented on Saturday, May 30 from       8:27 a.m. – 8:39 a.m. CDT (Late Breaking Abstract #101).   

“Hepatocellular carcinoma is an aggressive and fatal cancer, comprising       90 percent of all liver cancer in adults worldwide with limited       therapeutic options for patients with advanced stage disease; no       treatment advances have been made for patients who fail to respond or       progress on the current standard of care,” said Anthony B. El-Khoueiry,       MD, lead study author and associate professor of clinical medicine and       phase I program director at the University of Southern California Norris       Comprehensive Cancer Center. “These preliminary data are encouraging and       support the ongoing evaluation of nivolumab in this patient population,       as they show promising preliminary survival data, and durable partial or       complete response in one out of five nivolumab-treated patients, with       many others experiencing stable disease.”   

More than 700,000 people around the world are diagnosed with HCC each       year with a majority of all HCC cases caused by infection with the       hepatitis B virus (HBV) or hepatitis C virus (HCV), making HBV/HCV the       most common risk factor for liver cancer worldwide. Patients with       advanced HCC receiving the current standard of care have a median       overall survival of less than 1 year. For patients who have relapsed or       have disease progression, median survival with best supportive care is       approximately 7 to 8 months.   

“Bristol-Myers Squibb’s experience in hepatitis and Immuno-Oncology make       us poised as leaders to advance Opdivo into additional studies of       hepatocellular carcinoma,” said Michael Giordano, senior vice president,       Head of Development, Oncology, Bristol-Myers Squibb. “Opdivo has       demonstrated improvements in survival in a number of different tumor       types. We are excited that this trial has shown the potential that this       may extend to advanced liver cancer and hope to confirm these findings       in future trials.”   

About the CA209-040   
CA209-040 is a Phase I/II dose-ranging trial that evaluated the safety       and anti-tumor activity of Opdivo in patients with HCC, the       majority of whom had received prior treatment. The trial included 47 HCC       patients who were enrolled into one of three treatment arms depending on       whether or not they were infected with HCV or HBV. Patients enrolled in       the trial received Opdivo doses ranging from 0.1 – 10 mg/kg       intravenously every 2 weeks for up to 2 years. The primary objective was       safety, tolerability, dose limiting toxicities, and maximum tolerated       dose. Anti-tumor activity was a secondary objective (using RECIST 1.1       criteria), and overall survival was an exploratory objective.   
As of this interim analysis, 62% of patients in the study were still       alive after 12 months. Eight (19%) patients (of 42 evaluable patients)       achieved a complete or partial response, meaning that the size of their       tumors measured at baseline decreased by 30–100% with Opdivo       treatment. In patients with response, duration of response ranged from       more than 1.4 – 12.5 months. Seventeen patients remained on study       treatment and 30 discontinued treatment due to progressive disease       (n=26), complete response (n=2), or adverse events (n=2).   

CA209-040 is the first trial to characterize the safety profile of Opdivo       monotherapy in patients with HCC, including those with HCV and HBV       infections. In the trial, safety and tolerability were       well-characterized, with the frequency and intensity of       treatment-related adverse events (AEs) being consistent across Opdivo       dose levels. The majority of side effects were mild to moderate in       nature with abnormal liver enzymes (19% AST and 15% ALT), rash (17%) and       elevation of amylase (15%) and lipase (17%) being the most common; the       abnormal liver enzymes and elevated amylase and lipase were not       accompanied by any significant clinical symptoms. Grade 3–4       treatment-related AEs were infrequent (19%). There were no       treatment-related deaths reported.   

About Opdivo   
Bristol-Myers Squibb has a broad, global development program to study Opdivo       in multiple tumor types consisting of more than 50 trials – as       monotherapy or in combination with other therapies – in which more than       8,000 patients have been enrolled worldwide.   

Opdivo became the first PD-1 immune checkpoint inhibitor to       receive regulatory approval anywhere in the world on July 4, 2014 when       Ono Pharmaceutical Co. announced that it received manufacturing and       marketing approval in Japan for the treatment of patients with       unresectable melanoma. In the U.S., the U.S. Food and Drug       Administration (FDA) granted its first approval for Opdivo for       the treatment of patients with unresectable or metastatic melanoma and       disease progression following Yervoy (ipilimumab) and, if BRAF       V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo       received its second FDA approval for the treatment of patients with       metastatic squamous non-small cell lung cancer (NSCLC) with progression       on or after platinum-based chemotherapy.

Read complete press release here







Posted byHCV Advocateat4:54 PMNo comments:
作者: StephenW    时间: 2015-5-30 10:41

周五，2015年5月29日
I / II期Opdivo（nivolumab）试验表明施贵宝公司的PD-1免疫检查点抑制剂是第一次证明抗肿瘤活性肝癌患者

    中期业绩报告显示先前治疗的患者Opdivo的良好的安全性，耐用响应
    62％在12个月生存率在这个中期分析观察
    肝细胞癌是世界各地的癌症相关死亡的第二最常见的原因，并保持的显著未满足的医疗需要的区域
    肝癌患者谁有复发或有疾病进展，下面护理标准，有一个中位生存期与最佳支持治疗的〜7〜8个月


新泽西州普林斯顿 - （BUSINESS WIRE） - 施贵宝公司（NYSE：BMY）今天宣布，从CA209-040的中期分析，一个阶段的结果I / II剂量范围试验，评估的安全性和抗肿瘤活性的Opdivo（nivolumab）先前治疗的患者与肝细胞癌（HCC）或肝癌晚期。初步调查结果显示，在评估的患者（n = 47）的估计存活率为62％，在12个月。结果还表明Opdivo的安全性方面是与在其他肿瘤类型的先前报告的Opdivo基本一致。这些数据将在今天精选，5月29日，临床肿瘤学会（ASCO）新闻发布会的美国社会的第51届会议于1:00时 - 下午2:00 CDT并提交上周六，5月30日8:27 - 上午08时39分CDT（晚破摘要＃101）。

“肝癌是一个积极的和致命的癌症，包括90％的成年人在全球拥有有限的治疗选择患者的晚期疾病的所有肝癌;没有治疗已经取得进展的谁不响应或照顾的现行标准进展的患者，“安东尼·埃尔 - Khoueiry，MD，研究的主要作者和临床医学和一期项目主任在大学副教授南加州诺里斯综合癌症中心。 “这些初步的数据是令人鼓舞的，支持nivolumab的持续评估在该患者人群，因为他们表现出希望的初步​​存活数据，并在五分之一的nivolumab治疗的患者持久的部分或完全缓解，与许多人经历病情稳定。”

世界各地的70多万人，每年被诊断为肝癌与大多数与乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）感染引起的肝癌所有病例，使HBV / HCV肝最常见的危险因素全世界的癌症。晚期肝癌接受护理的现行标准有不足1年的中位总生存期。对于谁有复发或有疾病进展，中位生存期与最佳支持治疗的患者大约是7〜8个月。

“百时美施贵宝公司在肝炎和经验免疫肿瘤让我们蓄势作为领导者提前进入Opdivo肝癌的进一步研究，”佐丹奴迈克尔高级副总裁，发展，肿瘤学，施贵宝公司的负责人说。 “Opdivo已经证明改善生存在许多不同的肿瘤类型。我们很高兴这项试验已表明潜在的，这可能扩展到中晚期肝癌，并希望以确认今后的审判这些发现。“

关于CA209-040
CA209-040是I / II期剂量范围试验，评价Opdivo的安全性和抗肿瘤活性在HCC患者，多数曾收到过现有的治疗。该试验包括谁被纳入三个方案之一的治疗取决于他们是否不被感染HCV或HBV 47肝癌患者。患者参加了试验获得Opdivo剂量范围为0.1 - 10毫克/公斤静脉注射，每2周长达2年。的主要目的是安全性，耐受性，剂量限制性毒性，和最大耐受剂量。抗肿瘤活性的次要目标（使用RECIST 1.1标准），和总生存期是一个探索性的目标。
作为这一中期分析，患者在研究中62％的人仍然存活12个月后。八（19％）患者（42可评估患者）实现了完全或部分缓解，这意味着在基线测量他们的肿瘤的大小减少了30-100％与Opdivo治疗。 12.5个月 - 患者的反应，反应的持续时间超过1.4不等。 17名患者留在研究治疗和30停止治疗，由于进行性疾病（N = 26），完全缓解（2例），或不良事件（N = 2）。

CA209-040是Opdivo单一疗法的安全性的特征在HCC患者，包括那些与HCV和HBV感染的第一个试验。在试验中，安全性和耐受性良好的特点，与治疗相关的不良事件（AE）是跨越Opdivo剂量水平一致的频率和强度。大多数的副作用是轻度异常肝酶（19％AST和15％，ALT），皮疹（17％）和淀粉酶（15％）和脂肪酶（17％）是最常见的标高性质，中度;异常肝酶和升高的淀粉酶和脂肪酶并没有伴随任何显著临床症状。 3-4级治疗相关的AEs是罕见（19％）。目前还没有报道治疗相关的死亡。

关于Opdivo
百时美施贵宝拥有广泛的全球发展计划，研究Opdivo多种肿瘤类型包括50多个试验 - 单药或与其他疗法联合 - 其中超过8000名患者参加了世界各地。

Opdivo成为第一个PD-1免疫检查点抑制剂，在世界任何地方获得监管部门的批准于2014年7月4日当小野制药有限公司宣布，该公司获得生产和销售许可在日本用于治疗不能手术切除的黑色素瘤的治疗。在美国，美国食品和药物管理局（FDA）以下Yervoy（易普利姆玛），如果BRAF V600突变阳性，一个BRAF抑制剂授予其第一批准Opdivo用于治疗不能切除或转移性黑素瘤和疾病进展的治疗。在2015年3月4日，Opdivo接到其第二FDA批准用于治疗转移性鳞状非小细胞肺癌（NSCLC）的治疗进展或以后铂为基础的化疗。

在这里阅读完整的新闻发布
发贴者HCV提倡在下午4时54分没有评论：
作者: StephenW    时间: 2015-5-30 10:43

这是一个振奋的消息. nivolumab, 在理论上，也可以治疗HBV.
作者: StephenW    时间: 2015-5-30 10:53

Nivolumab shows promise for advanced hepatocellular carcinoma
May 29, 2015

   

CHICAGO — Nivolumab appeared safe and effective for the treatment of patients with advanced hepatocellular carcinoma, according to interim study results presented at the ASCO Annual Meeting.

The responses observed with nivolumab (Opdivo, Bristol-Myers Squibb) — a programmed cell death-1 (PD-1) antibody — also appeared durable, results showed.

“This is a worldwide problem, with 780,000 people diagnosed with liver cancer annually,” Anthony B. El-Khoueiry, MD, associate professor of clinical medicine and phase 1 program director at the University of South California Norris Comprehensive Cancer Center, said during a press conference. “For patients with advanced disease, who are the majority of patients we see, sorafenib (Nexavar; Bayer, Onyx) is the only FDA-approved systemic treatment, with an average survival of less than 11 months. After failure of sorafenib, there is no current standard of care.”

El-Khoueiry and colleagues evaluated data from 47 patients with advanced hepatocellular carcinoma who had a Child-Pugh score of 5 or 6 and an ECOG performance status of 0 or 1. Seventy-five percent of patients had undergone prior systemic therapy, and 68% had received sorafenib.

Researchers divided patients into three cohorts. One included patients with hepatitis C (n = 12), a second included patients with hepatitis B (n = 11), and a third consisted of uninfected patients (n = 24).

“The reason patients were treated in separate cohorts was to ensure that nivolumab was safe in all these groups of patients,” El-Khoueiry said. “The dose was escalated separately in each group.”

Patients received 0.1 mg/kg to 10 mg/kg IV nivolumab in parallel dose-escalation cohorts for up to 2 years.

Safety served as the study’s primary endpoint. Antitumor activity — assessed using modified RECIST criteria — served as the secondary endpoint.

Nivolumab appeared well tolerated in patients with ongoing hepatitis B and C infections, and researchers observed no safety concerns related to flares of hepatitis B infection or worsening viral infection.

Most adverse events were mild, El-Khoueiry said. Sixty-eight percent of patients experienced a drug-related adverse event, and 19% experienced grade 3 or grade 4 events. The most commonly reported adverse events included aspartate aminotransferase increase (19%); rash (17%); elevation of alanine aminotransferase (15%), lipase (17%) and amylase (15%); and pruritus (13%).

The most common grade 3 or grade 4 adverse events included aspartate aminotransferase increase (11%), alanine aminotransferase increase (9%) and lipase increase (9%).

One patient who received the 10-mg/kg dose experienced a dose-limiting toxicity; however, researchers did not define the maximum tolerated dose in any cohort.

Of 42 patients evaluable for response, 21 were uninfected and 21 were viral infected. Eight patients achieved objective tumor shrinkage beyond 30%, which equated to an objective response rate of 19%.

“To put this into context, the response rate with the standard of care currently, sorafenib, is 2% to 3%,” El-Khoueiry said.

Two patients — both uninfected — achieved a complete response, with responses ongoing past 12 months. Six patients, five of whom were viral infected, achieved a partial response.

Of the eight total responders, six had an ongoing response at the time of the analysis, and 50% of responses lasted longer than 12 months.

Forty-eight percent of patients experienced stalled tumor growth, and the longest duration of tumor stabilization has extended beyond 17 months.

Sixty-two percent of patients achieved 12-month OS. The 1-year OS rate among patients who have already received sorafenib typically is only 30%, El-Khoueiry said.

“We are encouraged to see that nivolumab was safe overall, and the response rate as well as preliminary survival data look quite promising,” El-Khoueiry said in a press release. “While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer.”

An expansion part of the study is ongoing to confirm these findings, El-Khoueiry said. – by Alexandra Todak

Reference:

El-Khoueiry AB, et al. Abstract LBA101. Presented at: ASCO Annual Meeting. May 29-June 2, 2015; Chicago.

作者: StephenW    时间: 2015-5-30 10:55

Nivolumab显示诺言为晚期肝癌
2015年5月29日

   

芝加哥 - Nivolumab出现安全有效的治疗晚期肝癌的治疗，根据在ASCO年会上提出的中期研究成果。

一个程序性细胞死亡1（PD-1）抗体 - - 与nivolumab（Opdivo，施贵宝）观察到的答复也出现耐用，结果显示。

“这是一个世界性的难题，与78万人，每年确诊为肝癌，”安东尼·埃尔 - Khoueiry医师，临床医学和1期项目主任在南加州诺里斯综合癌症中心的副教授，在一个说新闻发布会。 “对于晚期患者，谁是广大患者，我们看到，索拉非尼（多吉美，拜耳，玛瑙）是唯一获得FDA批准的全身治疗，用不到11个月，平均生存期。索拉非尼失败后，有护理没有现行标准。“

埃尔 - Khoueiry和他的同事从47例晚期肝癌谁了Child-Pugh评分5或6和0或1的患者百分之七十五曾接受全身治疗的ECOG评分和68％的数据进行评估收到了索拉非尼。

研究人员将患者分为3组。其中包括丙型肝炎患者（N = 12），第二包括乙肝患者（N = 11），第三包括未感染患者（n = 24）。

“之​​所以患者在不同的队列处理是确保nivolumab是安全的所有这些群体的患者，”厄尔尼诺 - Khoueiry说。 “剂量是各组中分别升级”。

患者接受0.1毫克/公斤至10毫克/千克IV nivolumab并联剂量递增队列长达2年。

安全担当了研究的主要终点。抗肿瘤活性 - 使用改良RECIST标准评估 - 担任次要终点。

Nivolumab出现很好的耐受性的患者与正在进行乙型和丙型肝炎的感染，以及研究人员观察到相关的乙型肝炎感染或恶化病毒感染耀斑没有安全问题。

大部分不良事件为轻度，埃尔 - Khoueiry说。患者的百分之六十八经历了与毒品有关的不良事件，19％经历了3级或4级事件。最常见的不良反应包括谷草转氨酶升高（19％）;皮疹（17％）;丙氨酸氨基转移酶（15％），脂肪酶（17％）和淀粉酶（15％）的正视图;和瘙痒（13％）。

最常见的3级或4级不良反应包括谷草转氨酶升高（11％），丙氨酸氨基转移酶升高（9％）和脂肪的增加（9％）。

谁收到了10毫克/公斤的剂量一个病人经历了剂量限制性毒性;然而，研究人员并没有限定在任何队列的最大耐受剂量。

42例患者可评价的反应，21人感染，21人感染病毒。八名病人超过30％，这等同于19％的客观缓解率达到客观的肿瘤缩小。

“为了把这个变成背景下，反应速度与护理的标准目前，索拉非尼，是2％〜3％，”厄尔尼诺 - Khoueiry说。

两名病人 - 无论是未感染 - 实现了完全缓解，与正在进行的反应过去12个月。六名病人，五人是病毒感染，取得了部分缓解。

八个总应答器，六有在分析的时间持续的反应，并响应50％的持续时间超过12个月。

患者四十八个％的经历停滞肿瘤生长和肿瘤稳定的最长持续时间延长到17个月。

患者的百分之六十二实现了12个月的OS。其中已经收到索拉非尼的患者谁在1年OS率通常只有30％，埃尔 - Khoueiry说。

“我们感到鼓舞地看到，nivolumab是安全的全局性，响应速度以及初步的生存数据看起来相当有前途的，”厄尔尼诺 - Khoueiry在一份新闻稿中说。 “虽然我们需要验证更多的研究早期信号，这是与免疫抑制剂检查站将免疫治疗在肝癌的治疗作用的第一个标志之一。”

这项研究的一个扩展的一部分正在进行确认这些发现，埃尔 - Khoueiry说。 - 亚历山德拉Todak

参考：

埃尔 - Khoueiry AB，等。摘要LBA101。发表在：ASCO年会上。 5月29日至6月2日，2015;芝加哥。
作者: 中国先生ws    时间: 2015-5-30 14:39

这个不是已经上市了吗？
作者: StephenW    时间: 2015-5-30 14:43

回复 中国先生ws 的帖子

是, FDA批准用于黑色素瘤.
作者: 中国先生ws    时间: 2015-5-30 14:48

回复 StephenW 的帖子

那现在的意思是可能对乙肝也有效果 从新做实验？
作者: StephenW    时间: 2015-5-30 15:00

回复 中国先生ws 的帖子

不是, 现在做肝癌实验. 很多肝癌患者也有乙型肝炎病毒.
作者: hchu    时间: 2015-5-30 16:17

[ASCO2015]重磅研究：Nivolumab治疗晚期HCC安全性和抗肿瘤活性
医脉通 2015-05-30
2015年ASCO年会于5月29日—6月2日在美国芝加哥召开。芝加哥时间5月30日上午8:27-8:39在科学临床研讨会专场上，Anthony B. El-Khoueiry（Southern California Norris大学综合癌症中心I期项目主任，临床医学副教授）发表一项CA209-040研究：晚期肝细胞癌（HCC）患者nivolumab的I/II期安全性和抗肿瘤活性。医脉通整理如下：
一项I/II期研究结果表明，nivolumab治疗晚期肝癌是安全有效的。根据I期研究部分的结果，42名接受评估的患者有8名对抗-PD-1抗体产生应答，肿瘤缩小了30%。更重要的是，响应是持久的，有4例患者超过12个月。12个月时的总存活率是62%。
晚期肝癌患者对新的治疗特别需要。目前只有一种FDA批准的晚期肝癌治疗，多靶点酪氨酸激酶抑制剂，索拉非尼。然而，只有2%的患者对索拉非尼出现客观肿瘤缓解（超过30%的缩小），平均总生存期是10~11个月。
“我们很高兴的发现nivolumab总体上是安全的，缓解率以及初步的生存数据看上去相当有前途，”研究主要作者Anthony B. El-Khoueiry（Southern California Norris大学综合癌症中心I期项目主任，临床医学副教授）说。“但是我们需要在更大型的研究中验证这一早期信号，这是免疫检查点抑制剂免疫治疗在肝癌治疗中发挥作用的信号之一。”
2015年美国约有35660名患者诊断为肝癌，但是这一疾病在非洲和东南亚部分地区更为常见。肝癌是世界范围内癌症死亡的主要原因，每年有超过600000人死亡。
入组研究的患者有75%曾经接受系统性治疗，包括68%的患者接受索拉非尼。Nivolumab静脉注射给药，每两周1次，长达两年。
总缓解率是19%，8例患者出现客观肿瘤缩小超过30%，两例患者表现完全缓解。反应是持久的，50%的患者持续超过12个月，大多数患者继续治疗。此外，在48%的患者中肿瘤稳定（肿瘤生长停滞），最长的病例持续超过17个月。
Nivolumab是安全的，且耐受性良好，即使是在乙型或丙型肝炎感染的患者中。具体而言，没有任何与乙型肝炎感染或恶化病毒感染相关的安全性问题。大部分不良反应是轻度至中度肝酶异常，皮疹，淀粉酶和脂肪酶升高是最常见的；肝酶异常，淀粉酶和脂肪酶升高没有伴随任何显著的临床症状。
El-Khoueiry认为早期试验的研究结果为肝癌患者的一类新药打开了一扇大门。“虽然这些结果是初步的，限制在小部分患者中，但他们仍然很高兴，更多nivolumab和其他免疫治疗方法的研究为晚期肝癌患者提供强有力的证据，”他说。
这项研究接受了施贵宝公司的资助。
ASCO观点：
PD-1免疫治疗在难治性疾病中继续呈现新突破。事实上，这种药物会阻止晚期肝癌进展数个月，甚至一年，对患者来说是个好消息。然而，为了认识这种方法的全部影响，还需要开展更大型的试验。
——ASCO专家Lynn Schuchter, MD, FASCO

摘要简介：
肝细胞癌中PD-L1过表达会有较差预后。Nivolumab（一种完全人类IgG4单克隆抗体PD-1抑制剂）的安全性和初步抗肿瘤效力，在HCC患者中以多递增剂量形式开展I/II期研究进行评估。
方法：病理证实的晚期HCC，Child-Pugh（CP）评分≤B7，进展性病变（PD），对索拉非尼不耐受，或拒绝索拉非尼的患者入组。剂量递增以病因为基础在平行队列中进行：无活动性肝炎病毒感染或病毒感染的HCC患者。患者接受nivolumab 0.1-10mg/kg静脉注射，长达两年。主要终点是安全性。次要终点包括应用mRECIST标准的抗肿瘤活性，药代动力学，和免疫原性。
结果：研究纳入了41例CP评分为5（n=35）或6（n=6），ECOG评分为0（n=26）或1（n=15）的患者，71%的患者肝外转移和/或门静脉侵犯，77%之前使用过索拉非尼。由于PD（n=17），完全缓解（CR；n=2），药物相关不良事件（AEs；n=2）和非药物相关AEs（n=2），18例患者仍在研究中，23例患者停止治疗。
不同级别药物相关AEs发生在29例患者中（71%；17%的为3/4级），出现谷草转氨酶（AST）增加和皮疹（各占17%），丙氨酸氨基转移酶（ALT）和脂肪酶增加（各占12%）的患者≥10%。≥5%的3级和4级AEs是AST增加（12%），ALT增加（10%），和脂肪酶增加（5%）。一例未感染患者发生剂量限制性毒性是10mg/kg；在任一队列中没有定义最大耐受剂量。
39例患者中的缓解评估情况是：2例CR（5%），7例部分缓解（PR；18%）。CR的缓解持续时间是14~17+个月，PR的持续缓解时间是＜1~8+个月，病情稳定（SD）的时间是1.5~17个月。6个月时的总存活率是72%。
结论：根据所有的剂量水平和HCC队列情况，Nivolumab具有可管理的不良反应范围，并能带来持续的缓解，6个月的总存活率良好。最新的安全性，抗肿瘤活性，和生物标志物数据不久会被提交。
作者: hchu    时间: 2015-5-30 16:23

Nivolumab三期临床提前终止，PD-1抑制剂治疗肺癌倒计时
来源：美中药源 2015-01-13
今天，百时美施贵宝（BMS）的PD-1抑制剂Opdivo（nivolumab）治疗非小细胞肺癌的一个3期临床被提前终止。这个代号为CheckMate-017的3期临床头对头比较Opdivo和多西他赛治疗之前接受过治疗的，鳞状的晚期非小细胞肺癌的疗效和安全性。因为一个独立的数据监测委员会评估Opdivo治疗组的总生存期明显优于多西他赛对照组，达到预期的实验终点，施贵宝决定终止该临床实验。
一个随机的、双盲的、有标准疗法对照的晚期临床实验提前终止通常发生在两种情况：一种是治疗组的疗效和安全性远远优于对照组，不需要按照预定设计方案完成整个实验也可以获得统计学明显区分，另一种是对照组的临床结果远不如预期。遗憾的是实验被提前终止的多数原因往往是后者。
当然例外也时有发生。药源今年6月份曾报道，施贵宝的PD-1抑制剂nivolumab因在一个黑色素瘤的三期临床中明显改进患者的总生存期而被提前终止。今天施贵宝再爆惊喜，在一个头对头比较Opdivo（nivolumab）和多西他赛的一个3期非小细胞肺癌临床实验中，Opdivo治疗组的总生存期明显优于多西他赛对照组。但是施贵宝目前还没有披露这个实验的详细数据。施贵宝计划完成CheckMate-017临床数据的全面评估。因为非小细胞肺癌市场远远高于黑色素瘤，即使鳞癌的全球市场总额也有30亿美元。所以受此振奋消息的鼓舞，施贵宝股票大幅上涨，最高涨幅高达6%至63.75美元，创14年以来最高。

著名免疫学家，癌症研究所的CEO和学术事务总监Jill O’Donnell-Tormey教授最近在接受福布斯采访时评述，随着免疫疗法的长足进步，人类越来越接近治愈癌症。如果说2014年是癌症免疫疗法获得重大突破的年份，2015将会是免疫疗法走向丰收，成为主流抗癌疗法的一年。按照IMS医疗信息研究所的数据，全球抗肿瘤领域总共有374个中晚期临床实验，其中25-30%是免疫疗法。目前免疫疗法进展最快的有免疫哨卡（如PD-1、PD-L1）抑制剂，主要用于治疗固体肿瘤，和过继T细胞疗法（包括CAR-T和TCR）主要治疗血液肿瘤。
目前获得美国FDA批准上市的PD-1抑制剂有默克的Keytruda（通用名：pembrolizumab）和施贵宝的Opdivo，二者都曾获得过FDA突破性药物称号。虽然pembrolizumab率先在美国上市，但在非小细胞肺癌领域Opdivo稍微领先，而且FDA批准Opdivo用于治疗晚期黑色素瘤比预计的评审时间提前了3个月。Opdivo的一个非鳞癌3期临床实验估计年中会有结果报道。当然默克在非小细胞肺癌领域也不甘落后，而且其终场发挥能力也有目共睹，默克今天也报道Keytruda预计今年中期提交非小细胞肺癌的sBLA。所以施贵宝要想保证在非小细胞肺癌领域的优势还要继续给力。当然无论是谁胜出受惠的还是患者，免疫哨卡抑制剂的应答人群目前虽然大约只有30%，和其它疗法的联合使用有望进一步扩大战果，治愈癌症已经不再只是一个梦想。(生物谷Bioon.com)
作者: MP4    时间: 2015-5-30 16:51

好，很好
作者: 9病成医    时间: 2015-5-30 17:03

今天央视新闻报道，外国专家使用处理过的疱疹病毒，治疗黑色素瘤取得成功。
作者: StephenW    时间: 2015-5-30 18:30

回复 9病成医 的帖子

是的. Nivolumab是单克隆抗体(monoclonal antibody).
作者: 战天斗hbv    时间: 2015-5-30 20:35

StephenW 发表于 2015-5-30 18:30
回复 9病成医 的帖子

是的. Nivolumab是单克隆抗体(monoclonal antibody).

我说个外行话、这个药我看治疗黑色素瘤、怎么看起来像birinapant？？？？
作者: StephenW    时间: 2015-5-30 20:53

回复 战天斗hbv 的帖子


乙肝患者的T细胞(T cell)被“耗尽(exhausted)”，也就是说，很多PD1（细胞程序性死亡）的表达。
作者: StephenW    时间: 2015-5-30 20:59

www.natap.org

Nivolumab targets a protein called the programmed death-1 (PD-1) receptor. The PD-1 pathway plays an important role in controlling the immune system to prevent inadvertent immune cell activation and autoimmune disease.

There continues to be a buzz about immunotherapy, and particularly the programmed death (PD) inhibitors, such as nivolumab (Opdivo, Bristol-Myers Squibb Company) and pembrolizumab (Keytruda, Merck & Co, Inc). Both these drugs have already been launched, but there are similar drugs coming through the pipeline, including MPDL3280A (Genentech/Roche), MEDI4736 and MED10680 (Medimmune Inc), avelumab (Merck Serono), pidilizumab (CureTech), and others…...http://www.medscape.com/viewarticle/845163

Immunotherapy for Genitourinary Cancers Still in Infancy - ......http://www.cancernetwork.com/asc ... ncers-still-infancy

Immunotherapies at ASCO….May 27, 2015…...http://www.onclive.com/conferenc ... ultiple-Tumor-Types…….Findings from large, late-stage clinical trials in melanoma, non–small cell lung cancer (NSCLC), and several hematologic malignances are expected to rank among the most clinically significant research findings presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, according to industry analysts.

"Liver cancer can be added to the tumor types that have responded to the immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb)…..The programmed death-1 (PD-1)”   

Opdivo (nivolumab) First PD-1 Inhibitor to Demonstrate Superior Overall Survival Versus Standard of Care (docetaxel) in Previously-Treated Non-Squamous Non-Small Cell Lung Cancer in Pivotal Phase III Trial......http://news.bms.com/press-releas ... =635685709624226643
Bristol-Myers Squibb to Present Data at 2015 American Society of Clinical Oncology (ASCO) Annual Meeting that Demonstrate the Promise of its Broad Immuno-Oncology Portfolio Across Solid Tumors and Blood Cancers Including Multiple Myeloma……...http://asco2015.bms.com/news/new ... yeloma/default.aspx
Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma…….http://www.nejm.org/doi/full/10.1056/NEJMoa1414428…..
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Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb’s PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma

Interim results show favorable safety profile of Opdivo, and durable responses in previously-treated patients

Overall survival rate of 62% at 12 months observed at this interim analysis

Hepatocellular carcinoma is the second most frequent cause of cancer-related death worldwide and remains an area of significant unmet medical need

Patients with hepatocellular carcinoma who have relapsed or have disease progression, following standard of care, have a median survival with best supportive care of ~7 to 8 months
Friday, May 29, 2015 2:02 pm EDT

"Bristol-Myers Squibb’s experience in hepatitis and Immuno-Oncology make us poised as leaders to advance Opdivo into additional studies of hepatocellular carcinoma"

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced results from an interim analysis of CA209-040, a Phase I/II dose-ranging trial evaluating the safety and anti-tumor activity of Opdivo (nivolumab) in previously-treated patients with hepatocellular carcinoma (HCC) or advanced liver cancer. Initial findings demonstrated that the estimated survival rate in evaluable patients (n=47) was 62% at 12 months. Results also show the safety profile of Opdivo is generally consistent with that previously-reported for Opdivo in other tumor types. These data will be featured today, May 29, during the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) press briefing at 1:00 – 2:00 p.m. CDT and presented on Saturday, May 30 from 8:27 a.m. – 8:39 a.m. CDT (Late Breaking Abstract #101).

“Hepatocellular carcinoma is an aggressive and fatal cancer, comprising 90 percent of all liver cancer in adults worldwide with limited therapeutic options for patients with advanced stage disease; no treatment advances have been made for patients who fail to respond or progress on the current standard of care,” said Anthony B. El-Khoueiry, MD, lead study author and associate professor of clinical medicine and phase I program director at the University of Southern California Norris Comprehensive Cancer Center. “These preliminary data are encouraging and support the ongoing evaluation of nivolumab in this patient population, as they show promising preliminary survival data, and durable partial or complete response in one out of five nivolumab-treated patients, with many others experiencing stable disease.”

More than 700,000 people around the world are diagnosed with HCC each year with a majority of all HCC cases caused by infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV), making HBV/HCV the most common risk factor for liver cancer worldwide. Patients with advanced HCC receiving the current standard of care have a median overall survival of less than 1 year. For patients who have relapsed or have disease progression, median survival with best supportive care is approximately 7 to 8 months.

“Bristol-Myers Squibb’s experience in hepatitis and Immuno-Oncology make us poised as leaders to advance Opdivo into additional studies of hepatocellular carcinoma,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “Opdivo has demonstrated improvements in survival in a number of different tumor types. We are excited that this trial has shown the potential that this may extend to advanced liver cancer and hope to confirm these findings in future trials.”

About the CA209-040

CA209-040 is a Phase I/II dose-ranging trial that evaluated the safety and anti-tumor activity of Opdivo in patients with HCC, the majority of whom had received prior treatment. The trial included 47 HCC patients who were enrolled into one of three treatment arms depending on whether or not they were infected with HCV or HBV. Patients enrolled in the trial received Opdivo doses ranging from 0.1 – 10 mg/kg intravenously every 2 weeks for up to 2 years. The primary objective was safety, tolerability, dose limiting toxicities, and maximum tolerated dose. Anti-tumor activity was a secondary objective (using RECIST 1.1 criteria), and overall survival was an exploratory objective.

As of this interim analysis, 62% of patients in the study were still alive after 12 months. Eight (19%) patients (of 42 evaluable patients) achieved a complete or partial response, meaning that the size of their tumors measured at baseline decreased by 30–100% with Opdivo treatment. In patients with response, duration of response ranged from more than 1.4 – 12.5 months. Seventeen patients remained on study treatment and 30 discontinued treatment due to progressive disease (n=26), complete response (n=2), or adverse events (n=2).

CA209-040 is the first trial to characterize the safety profile of Opdivo monotherapy in patients with HCC, including those with HCV and HBV infections. In the trial, safety and tolerability were well-characterized, with the frequency and intensity of treatment-related adverse events (AEs) being consistent across Opdivo dose levels. The majority of side effects were mild to moderate in nature with abnormal liver enzymes (19% AST and 15% ALT), rash (17%) and elevation of amylase (15%) and lipase (17%) being the most common; the abnormal liver enzymes and elevated amylase and lipase were not accompanied by any significant clinical symptoms. Grade 3–4 treatment-related AEs were infrequent (19%). There were no treatment-related deaths reported.

About Opdivo

Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 8,000 patients have been enrolled worldwide.

Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. In the U.S., the U.S. Food and Drug Administration (FDA) granted its first approval for Opdivo for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (ipilimumab) and, if BRAF V600 mutation positive, a BRAF inhibitor. On March 4, 2015, Opdivo received its second FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

    Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 1 or Trial 3. In Trial 1, pneumonitis, including interstitial lung disease, occurred in 3.4% (9/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Immune-mediated pneumonitis occurred in 2.2% (6/268) of patients receiving OPDIVO; one with Grade 3 and five with Grade 2. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including, five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

    In Trial 1, diarrhea or colitis occurred in 21% (57/268) of patients receiving OPDIVO and 18% (18/102) of patients receiving chemotherapy. Immune-mediated colitis occurred in 2.2% (6/268) of patients receiving OPDIVO; five with Grade 3 and one with Grade 2. In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

    In Trial 1, there was an increased incidence of liver test abnormalities in the OPDIVO-treated group as compared to the chemotherapy-treated group, with increases in AST (28% vs 12%), alkaline phosphatase (22% vs 13%), ALT (16% vs 5%), and total bilirubin (9% vs 0). Immune-mediated hepatitis occurred in 1.1% (3/268) of patients receiving OPDIVO; two with Grade 3 and one with Grade 2. In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

    In Trial 1, there was an increased incidence of elevated creatinine in the OPDIVO-treated group as compared to the chemotherapy-treated group (13% vs 9%). Grade 2 or 3 immune-mediated nephritis or renal dysfunction occurred in 0.7% (2/268) of patients. In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

    In Trial 1, Grade 1 or 2 hypothyroidism occurred in 8% (21/268) of patients receiving OPDIVO and none of the 102 patients receiving chemotherapy. Grade 1 or 2 hyperthyroidism occurred in 3% (8/268) of patients receiving OPDIVO and 1% (1/102) of patients receiving chemotherapy. In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients, including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

    In Trial 1 and 3 (n=385), the following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

    Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

    It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

    In Trial 1, serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.
    In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

    The most common adverse reactions (≥20%) reported with OPDIVO in Trial 1 were rash (21%) and in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see U.S. Full Prescribing Information for OPDIVO.

Immuno-Oncology at Bristol-Myers Squibb

Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as Immuno-Oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining Immuno-Oncology agents that target different pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of Immuno-Oncology, with the goal of changing survival expectations and the way patients live with cancer.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol-Myers Squibb, visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995 regarding the research, development and commercialization of pharmaceutical products. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could delay, divert or change any of them, and could cause actual outcomes and results to differ materially from current expectations. No forward-looking statement can be guaranteed. Among other risks, there can be no guarantee Opdivo will receive regulatory approval for an additional indication in hepatocellular carcinoma or advanced liver cancer. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Bristol-Myers Squibb's business, particularly those identified in the cautionary factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K for the year ended December 31, 2014 in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

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Media:
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or
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作者: StephenW    时间: 2015-5-30 21:00

Study Opens Door for Nivolumab in HCC

May 29, 2015

Anita T. Shaffer  

http://www.onclive.com/conferenc ... or-Nivolumab-in-HCC

Nivolumab (Opdivo) generated antitumor responses in nearly 20% of patients with advanced hepatocellular carcinoma (HCC) in a small study that suggests a promising role for the immunotherapy agent in a malignancy with dismal outcomes,1 researchers said at the 2015 ASCO Annual Meeting.

Eight of 42 evaluable patients who participated in the phase I/II study achieved a complete (n = 2) or partial (n = 6) response, as defined by RECIST criteria, lead investigator Anthony B. El-Khoueiry, MD, said during a press briefing. El-Khoueiry is an associate professor of clinical medicine and the phase I program director at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.

Notably, El-Khoueiry said, the responses were durable, extending beyond 9 months in 7 of the 8 responders. Tumor growth stabilized in 48% of patients, with the longest duration extending beyond 17 months. Additionally, 62% of patients in the study were still surviving with HCC at 12 months.

The study is the first to demonstrate that a PD-1 inhibitor can be effective in patients with HCC and, even though the study cohort was small, the results compare favorably with existing treatment options, El-Khoueiry indicated. He said the next step in the research is an expansion phase of the trial that will evaluate the drug in a larger group of patients.2

El-Khoueiry noted that sorafenib, which inhibits VEGFR and other kinases, is the only FDA-approved systemic therapy for patients with advanced HCC, with an average overall survival of 7 months to 11 months. “The response rate with the standard of care, which is sorafenib, is 2% to 3%,” he said. "In the setting of patients who have already been treated with sorafenib it’s about 30% who are usually alive at 12 months.”

There is a pressing need for new therapies for patients with HCC, most of whom present with advanced disease, El-Khoueiry indicated. He said HCC is the second most frequent cause of cancer-related death worldwide, and that approximately 780,000 new cases are diagnosed annually.

Patients Stratified by Viral Status

As of mid-March 2015, the CA209-040 study, as it is labeled, enrolled 47 patients with advanced HCC with Child-Pugh scores ≤B7 whose disease progressed after sorafenib treatment or who were intolerant of sorafenib. Overall, 75% of the patients in the study had previously undergone systemic treatment, including 68% who had received sorafenib.

Participants were then divided into three treatment groups depending on whether they had been infected with either hepatitis B (n = 11) or hepatitis C (n = 12), which are risk factors for HCC, or showed no signs of either viral strain (n = 24).

Nivolumab was administered intravenously at doses ranging from 0.1 mg/kg to 10 mg/kg every 2 weeks for up to 2 years.

El-Khoueiry said no maximum-tolerated dose was identified. He also said responses occurred regardless of hepatitis infection status.

In the area of safety signals, treatment-related adverse events (AEs) of any grade were reported in 68% of the total patient population (N = 47), chiefly increases in aspartate aminotransferase (AST), lipase, alanine aminotransferase (ALT), and amylase. Rash of any grade was reported in 17% of patients and pruritis was observed in 13% of participants, although no cases of either AE fell into the grade 3/4 category.  Grade 3/4 events were reported in 19% of participants, including increases in AST, ALT, and lipase.

“The safety profile of nivolumab in this study is generally consistent with that previously reported with nivolumab in other types of tumors,” said El-Khoueiry, adding that there were no treatment-related deaths.

Looking Forward

Lynn M. Schuchter, MD, FASCO, who served as moderator of the press briefing, placed the study of nivolumab in HCC in the context of immunotherapy advances across a broad range of malignancies. “These are cancers that we previously never thought about using immunotherapy for,” said Schuchter, chief of the division of hematology/oncology at Penn Medicine in Philadelphia, the University of Pennsylvania’s health system.

Currently, the FDA has approved nivolumab for the treatment of patients with unresectable or metastatic melanoma and for individuals with metastatic squamous non–small cell lung cancer.

El-Khoueiry said more study is needed to assess what role nivolumab might play in the treatment paradigm for HCC, as well as whether immunotherapies can be safely and effectively combined with other drugs. He said preclinical studies in mice suggest that pretreatment with sorafenib might enhance the chance of responding to anti-PD-1 therapy.

The expansion phase of the CA209-040 study is seeking to recruit approximately 400 patients into three cohorts stratified by hepatitis viral status, with an estimated completion date of July 2018.2 Primary endpoints include the incidence of worst adverse events and clinical laboratory test abnormalities.

References

1. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015 (suppl; abstr LBA101).
2. NIH Clinical Trials Registry. www.ClinicalTrails.gov. Identifier: NCT01658878

-------------------
作者: StephenW    时间: 2015-5-30 21:01

Add Liver Cancer to Nivolumab's List of Victims

Nick Mulcahy
May 29, 2015

http://www.medscape.com/viewarticle/845641

CHICAGO — Liver cancer can be added to the tumor types that have responded to the immunotherapy nivolumab (Opdivo, Bristol-Myers Squibb).

The programmed death-1 (PD-1) inhibitor demonstrated an unprecedented overall response rate for a systemic therapy in advanced liver cancer, according to phase 1/2 data presented here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

However, the results are early, the sample size is small, and the patient population had relatively high liver function, experts caution.

Nevertheless, eight of 42 (19%) evaluable patients responded to nivolumab (tumor reduction beyond 30%), including two with complete responses, reported lead study author Anthony B. El-Khoueiry, MD, from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.

The results compare favorably with the only systemic treatment approved by the US Food and Drug Administration for advanced liver cancer, sorafenib (Nexavar, Onyx/Bayer), which is a multitargeted tyrosine kinase inhibitor. The response rate with sorafenib in this setting is only 2%.

In the study, nivolumab was given intravenously every 2 weeks for up to 2 years.

Notably, responses to nivolumab have been durable in six of eight responders, and have surpassed 12 months in four patients.

Also, 20 (48%) of the patients had stable disease, with the longest lasting 17 months.

The overall survival rate at 12 months was 62% with nivolumab. The average overall survival rate at 12 months is about 30% with sorafenib, Dr El-Khoueiry said during a press briefing.

He also gave a big-picture perspective of the results.

"While we have to verify this early signal in larger studies, this is one of the first signs that immunotherapy with immune checkpoint inhibitors will have a role in the treatment of liver cancer," he said in a press statement.

Another medical oncologist echoed this perspective.

"PD-1 immunotherapies continue to break new ground in diseases where nothing else seems to work well. The fact that this drug might stop advanced liver cancer in its tracks for months, even a year, is great news for patients." said ASCO expert Lynn Schuchter, MD, a medical oncologist at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

PD-1 immunotherapies continue to break new ground.


Larger trials are needed to understand the full impact of immunotherapy in liver cancer, she added.

Closer Look: Child–Pugh Score

All the study patients had histologically confirmed advanced hepatocellular carcinoma (HCC) and a Child–Pugh score of B7 or below.

The exclusion of patients with higher Child–Pugh scores is important, said Arturo Loaiza-Bonilla, MD, who treats liver cancer patients at Penn and was asked for comment.

Essentially, the patients in the nivolumab study are Child–Pugh A, and thus "more fit and healthier," he told Medscape Medical News in an email.

Child–Pugh A patients have a better prognosis than other liver cancer patients.

The study is also unusual in that it required a confirmatory tissue biopsy of the liver. "Currently, most of the diagnosis of HCC is made with imaging studies and AFP levels," said Dr Loaiza-Bonilla.

Tissue biopsy is preferable, he explained, because it allows molecular and biomarker assessment, which are needed to move the field forward and eventually aid patient treatment selection.

Liver cancer is the second leading cause of cancer death worldwide, said Dr El-Khoueiry.

In this study, the population was largely pretreated, with 75% of the enrolled patients having received previous systemic therapy, including 68% who had received sorafenib.

The 47 patients were a mix of those infected with hepatitis B or C (n = 23) and those uninfected (n = 24).

The primary end point of the study was safety, and nivolumab was "safe and well tolerated" even in patients with ongoing hepatitis B or C infections, Dr El-Khoueiry reported.

There have not been any safety concerns related to flares of hepatitis B infection or worsening viral infection, according to meeting press materials.

Drug-related adverse events of any grade occurred in 68%, and 19% were grade 3/4.

Grade 3 and 4 adverse events that affected at least 5% of patients were aspartate aminotransferase increase (12%), alanine aminotransferase increase (10%), and lipase increase (5%).

Abnormal liver enzymes and elevated amylase and lipase of any grade occurred in less than 20% of patients; these were not accompanied by any significant clinical symptoms, Dr El-Khoueiry observed.

A dose-limiting toxicity occurred in an uninfected patient at 10 mg/kg, but no maximum tolerated dose was defined in any cohort in the dose-escalation study.

Nivolumab is currently approved in the United States for the treatment of non-small cell lung cancer and melanoma.

These new findings indicate that a new class of drugs works in liver cancer. The results "provide strong justification for more studies of nivolumab and other immunotherapy approaches for patients with advanced liver cancer," Dr El-Khoueiry said.

This study was funded by Bristol-Myers Squibb. Dr El-Khoueiry reports financial ties to multiple pharmaceutical companies, including Bristol-Myers Squibb. Some of his coauthors report financial relationships with pharmaceutical companies, and one is an employee of Bristol-Myers Squibb. Dr Schuchter reports receiving research funding from multiple pharmaceuticals, including Bristol-Myers Squibb.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA101. Presented May 30, 2015.

---------------------------

作者: StephenW    时间: 2015-5-30 21:03

Monoclonal antibody nivolumab improves survival rates of melanoma patients
Published on May 29, 2015 at 4:42 AM

http://www.news-medical.net/news ... anoma-patients.aspx

The monoclonal antibody nivolumab has shown promise as a therapeutic agent, particularly by improving the survival rates of melanoma patients. Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center will be presenting data from a retrospective analysis of the safety of nivolumab in 4 ongoing phase I-III studies in melanoma patients at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago.

Nivolumab targets a protein called the programmed death-1 (PD-1) receptor. The PD-1 pathway plays an important role in controlling the immune system to prevent inadvertent immune cell activation and autoimmune disease. PD-1 is found on immune cells called T cells, while its ligand PD-L1 is expressed on antigen presenting cells. Binding of PD-L1 to PD-1 inhibits the replication and activity of immune cells and prevents an immune response. Melanoma cells express high levels of PD-L1 to avoid immune detection and improve their survival potential.

The Moffitt team and their collaborators analyzed safety data from 576 patients who received at least one dose of nivolumab. They report that drug-related adverse events were primarily low-grade. The most common adverse events included fatigue (25 percent), pruritus (17 percent), diarrhea (13 percent), and rash (13 percent). Grade 3/4 adverse events occurred in 10 percent of the patients, and prior treatment with the CTLA-4 inhibitor ipilimumab did not affect the incidence of subsequent adverse events with nivolumab.

The adverse events that occurred during nivolumab treatment were manageable. Immunomodulatory (IM) drugs were administered to resolve toxicity to 166 out of 474 patients on the phase III studies, with 114 patients receiving corticosteroids. Resolution of symptoms was dependent on the type of adverse event, with a median time of resolution of 3 weeks for hepatic adverse events and 29 weeks for skin adverse events. Only 1 patient out of 21 who had a select grade 3/4 adverse event did not have resolution following IM treatment.

Importantly, treatment with IM agents did not affect response rates; 44 percent of patients who received an IM for an adverse event responded to therapy, while 36 percent of patients who did not receive an IM responded.

The safety analysis of nivolumab in melanoma patients will be presented during a poster discussion session on Monday, June 1, 4:45 to 6 p.m. in room S100bc. There will also be a poster session on Monday, June 1, 1:15 to 4:45 p.m. in S Hall A.
Source:

H. Lee Moffitt Cancer Center & Research Institute
作者: StephenW    时间: 2015-5-30 21:04

Bristol's Opdivo cuts risk of lung cancer death for some

http://www.reuters.com/article/2 ... USL1N0YK29N20150529

By Deena Beasley

Chicago May 29 (Reuters) - Bristol-Myers Squibb Co's drug, Opdivo, improved survival in a trial of patients with the most common form of lung cancer, but it did not work in patients who tested negative for a specific protein in their tumors, leading to a nearly 7 percent sell-off in the company's shares on Friday.

The Phase III trial found that Opdivo, part of a new class of drugs that harness the immune system to fight cancer, reduced by 27 percent the risk of death from advanced non-squamous non-small cell lung cancer (NSCLC), compared with chemotherapy. The benefit reached 60 percent for patients with the highest levels of the PD-L1 protein.

"Opdivo did not work in PD-L1 negative patients," said Amit Roy, an analyst at research group Foveal. "That is nearly half of the non-squamous patients."

He said many investors had expected that the drug might be effective regardless of PD-L1 levels, but the results indicate regulators would likely restrict usage to patients who test positive for the protein.

The Bristol drug was approved by U.S. regulators in December to treat advanced melanoma and competes with Keytruda from Merck & Co Inc. The current approvals for both drugs do not require testing patients for PD-L1.

Investors have been keeping a close eye on Opdivo's performance in lung cancer, the most common form of the disease worldwide, and a far larger market. Opdivo was cleared in March to treat the less-common squamous type of NSCLC. Between 85 percent and 90 percent of all lung cancers are NSCLC, and more than two-thirds of those are the non-squamous type, according to the American Cancer Society.

Bristol shares fell $4.55, or 6.6 percent, to close at $64.60 on the New York Stock Exchange.

This latest trial, presented at the annual meeting of the American Society of Clinical Oncology, involved 582 previously treated patients with non-squamous NSCLC.

"This marks the end of the chemotherapy era in second-line treatment of lung cancer," said Fouad Namouni, who oversees Opdivo development at Bristol-Myers.

He said the company is talking with the Food and Drug Administration about applying to expand approval for Opdivo, or nivolumab, to include advanced non-squamous NSCLC. Bristol is also studying Opdivo on its own and in combination with another immunotherapy called Yervoy as an initial treatment for lung cancer.

The trial results showed median overall survival of 12.2 months for the Opdivo group compared with 9.4 months for patients treated with docetaxel. For the subgroup of patients with high levels of PD-L1, which is used by tumors to evade the body's defenses, median survival exceeded 17 months with Opdivo, compared with 9 months for chemotherapy patients.

One in 10 Opdivo patients in the trial experienced serious side effects, compared with more than half of patients in the chemotherapy group.

Roy said eventual use of rival immunotherapy drugs being developed by Roche Holding AG, AstraZeneca Plc and Pfizer Inc will also likely be restricted based on biomarker levels.

The ASCO conference also featured results from an early-stage study of Opdivo showing that 19 percent of patients with advanced liver cancer responded to the antibody with tumor shrinkage of more than 30 percent.

Researchers said that compares with a response rate of just 2 percent for Nexavar, the only currently approved systemic treatment for advanced liver cancer. Nexavar is produced by subsidiaries of Bayer AG and Amgen Inc (Editing by Andre Grenon)
Nivolumab (Opdivo) generated antitumor responses in nearly 20% of patients with advanced hepatocellular carcinoma (HCC) in a small study that suggests a promising role for the immunotherapy agent in a malignancy with dismal outcomes,1 researchers said at the 2015 ASCO Annual Meeting.

Eight of 42 evaluable patients who participated in the phase I/II study achieved a complete (n = 2) or partial (n = 6) response, as defined by RECIST criteria, lead investigator Anthony B. El-Khoueiry, MD, said during a press briefing. El-Khoueiry is an associate professor of clinical medicine and the phase I program director at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles.

Notably, El-Khoueiry said, the responses were durable, extending beyond 9 months in 7 of the 8 responders. Tumor growth stabilized in 48% of patients, with the longest duration extending beyond 17 months. Additionally, 62% of patients in the study were still surviving with HCC at 12 months.

The study is the first to demonstrate that a PD-1 inhibitor can be effective in patients with HCC and, even though the study cohort was small, the results compare favorably with existing treatment options, El-Khoueiry indicated. He said the next step in the research is an expansion phase of the trial that will evaluate the drug in a larger group of patients.2

El-Khoueiry noted that sorafenib, which inhibits VEGFR and other kinases, is the only FDA-approved systemic therapy for patients with advanced HCC, with an average overall survival of 7 months to 11 months. “The response rate with the standard of care, which is sorafenib, is 2% to 3%,” he said. "In the setting of patients who have already been treated with sorafenib it’s about 30% who are usually alive at 12 months.”

There is a pressing need for new therapies for patients with HCC, most of whom present with advanced disease, El-Khoueiry indicated. He said HCC is the second most frequent cause of cancer-related death worldwide, and that approximately 780,000 new cases are diagnosed annually.
Patients Stratified by Viral Status
As of mid-March 2015, the CA209-040 study, as it is labeled, enrolled 47 patients with advanced HCC with Child-Pugh scores ≤B7 whose disease progressed after sorafenib treatment or who were intolerant of sorafenib. Overall, 75% of the patients in the study had previously undergone systemic treatment, including 68% who had received sorafenib.

Participants were then divided into three treatment groups depending on whether they had been infected with either hepatitis B (n = 11) or hepatitis C (n = 12), which are risk factors for HCC, or showed no signs of either viral strain (n = 24).

Nivolumab was administered intravenously at doses ranging from 0.1 mg/kg to 10 mg/kg every 2 weeks for up to 2 years.

El-Khoueiry said no maximum-tolerated dose was identified. He also said responses occurred regardless of hepatitis infection status.

In the area of safety signals, treatment-related adverse events (AEs) of any grade were reported in 68% of the total patient population (N = 47), chiefly increases in aspartate aminotransferase (AST), lipase, alanine aminotransferase (ALT), and amylase. Rash of any grade was reported in 17% of patients and pruritis was observed in 13% of participants, although no cases of either AE fell into the grade 3/4 category.  Grade 3/4 events were reported in 19% of participants, including increases in AST, ALT, and lipase.

“The safety profile of nivolumab in this study is generally consistent with that previously reported with nivolumab in other types of tumors,” said El-Khoueiry, adding that there were no treatment-related deaths.
Looking Forward
Lynn M. Schuchter, MD, FASCO, who served as moderator of the press briefing, placed the study of nivolumab in HCC in the context of immunotherapy advances across a broad range of malignancies. “These are cancers that we previously never thought about using immunotherapy for,” said Schuchter, chief of the division of hematology/oncology at Penn Medicine in Philadelphia, the University of Pennsylvania’s health system.

Currently, the FDA has approved nivolumab for the treatment of patients with unresectable or metastatic melanoma and for individuals with metastatic squamous non–small cell lung cancer.

El-Khoueiry said more study is needed to assess what role nivolumab might play in the treatment paradigm for HCC, as well as whether immunotherapies can be safely and effectively combined with other drugs. He said preclinical studies in mice suggest that pretreatment with sorafenib might enhance the chance of responding to anti-PD-1 therapy.

The expansion phase of the CA209-040 study is seeking to recruit approximately 400 patients into three cohorts stratified by hepatitis viral status, with an estimated completion date of July 2018.2 Primary endpoints include the incidence of worst adverse events and clinical laboratory test abnormalities.
References
1. El-Khoueiry AB, Melero I, Crocenzi TS, et al. Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol. 2015 (suppl; abstr LBA101).
2. NIH Clinical Trials Registry. www.ClinicalTrails.gov. Identifier: NCT01658878
- See more at: http://www.onclive.com/conferenc ... thash.LkTehYFz.dpuf
作者: 战天斗hbv    时间: 2015-5-30 21:20

StephenW 发表于 2015-5-30 20:53
回复 战天斗hbv 的帖子

那就是和birinapant一个路子嘛
作者: StephenW    时间: 2015-5-30 21:22

本帖最后由 StephenW 于 2015-5-30 21:23 编辑

回复 战天斗hbv 的帖子

birinapant是细胞凋亡(apoptosis), 完全不同.
作者: 战天斗hbv    时间: 2015-5-30 21:50

StephenW 发表于 2015-5-30 21:22
回复 战天斗hbv 的帖子

birinapant是细胞凋亡(apoptosis), 完全不同.

哦、谢谢解答！已经是我完全不懂的领域了、
这个药已经上市、治疗HBV到底行不行、岂不是公司早就知道了、想知道效果的渴望是肯定的、这种渴望实现起来是容易的、毕竟是上市的药物、不知道我表达的清楚不、所以我肤浅的认为、公司肯定知道对于HBV的效果、简直就是必然知道
作者: 战天斗hbv    时间: 2015-5-30 21:56

Nivolumab是安全的，且耐受性良好，即使是在乙型或丙型肝炎感染的患者中。具体而言，没有任何与乙型肝炎感染或恶化病毒感染相关的安全性问题。大部分不良反应是轻度至中度肝酶异常，皮疹，淀粉酶和脂肪酶升高是最常见的；肝酶异常，淀粉酶和脂肪酶升高没有伴随任何显著的临床症状。


看新闻稿子的意思是已经在HBVER上试过了、要是有效果、早就油炸锅了、我个人不看好
作者: hao2014    时间: 2015-5-31 11:29

完全赞同，在这个牛皮漫天的时代，没消息等于坏消息，当然了，估计还是有点作用的
作者: zgct    时间: 2015-5-31 23:36

很好！发现乙肝新药的思路方向非常有价值



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