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首页 » 百时美施贵宝 » 重磅!百时美免疫组合Opdivo+Yervoy一线治疗黑色素瘤获巨大成功

重磅!百时美免疫组合Opdivo+Yervoy一线治疗黑色素瘤获巨大成功

来源:生物谷 2015-04-21 10:03

2015年4月21日讯 /生物谷BIOON/ --百时美施贵宝(BMS)近日公布了备受业界关注的免疫组合疗法Opdivo+Yervoy用于黑色素瘤一线治疗的积极顶线数据。与Yervoy单药疗法相比,Opdivo+Yervoy组合疗法取得了非常高的客观缓解率(61% vs 11%),完全缓解率22%,疾病恶化或死亡风险降低60%,疗效之强劲在黑色素瘤治疗领域前所未有。业界认为,该方案将为晚期黑色素瘤提供一个极其重要的一线治疗选择,再次证明了不同免疫疗法的组合方案在肿瘤临床治疗中的巨大潜力。

此次公布的名为CheckMate-069的II期研究,在初治晚期黑色素瘤患者中开展,包括BRAF野生型和BRAF突变型黑色素瘤,评估了PD-1免疫疗法Opdivo(nivolumab)与Yervoy(ipilimumab)的组合疗法相对于Yervoy单药疗法用于初治晚期不可切除性(3-4阶段)黑色素瘤一线治疗的疗效和安全性。数据显示,针对BRAF野生型黑色素瘤,Opdivo+Yervoy方案取得了更高的客观缓解率(ORR=61%,n=44/72),与Yervoy单药(ORR=11%,n=4/37)相比具有统计学显著差异(p<0.001),达到了研究的主要终点;同时,Opdivo+Yervoy治疗组有22%(n=16)患者实现完全缓解,Yervoy单药组为0%;中位无进展生存期(PFS)数据尚未获得。

针对BRAF突变型黑色素瘤,Opdivo+Yervoy方案也取得了相似的结果,中位无进展生存期(PFS:8.5个月 vs 2.7个月),疾病恶化或死亡风险降低60%。此外,客观缓解率(ORR)独立于PD-L1状态:PD-L1阳性肿瘤中ORR为58%,PD-L1阴性肿瘤中ORR为55%。该研究中,安全性与既往评估Opdivo+Yervoy方案的相关研究一致,主要包括3-4级结肠炎(17%)、腹泻(11%)、丙氨酸转氨酶升高(11%)。

这些数据已提交至4月18-22日举行的2015年美国癌症研究协会(AACR)年会上。同时,相关结果也将发表于《新英格兰医学杂志》(NEJM)。

哈佛医学院达纳-法伯癌症研究所 (Dana-Farber Cancer Institute)医学副教授F.Stephen Hodi医师对该项研究给予了非常高的评价,他表示,这些疗效数据在晚期黑色素瘤临床治疗中前所未有,Opdivo+Yervoy方案所取得的高缓解率在其他免疫肿瘤学制剂临床研究中也未见报道,CheckMate-069研究证实了该方案在转移性黑色素瘤的治疗潜力,有望为该群体提供一个非常重要的一线治疗选择。

Opdivo和Yervoy均属于肿瘤免疫疗法,通过靶向免疫系统中特定的调控元件,利用人体自身的免疫系统对抗肿瘤。Opdivo能够结合至活化T细胞上表达的免疫检查点受体PD-L1,阻断该通路使免疫系统攻击肿瘤。Opdivo于2014年12月获FDA加速批准,用于治疗无法手术切除或已经出现转移且对其它药物无应答的晚期黑色素瘤患者。

Yervoy能够有效阻断细胞毒性T淋巴细胞相关抗原4(CTLA-4)。CTLA-4是一种T细胞活化的负调控因子,Yervoy与CTLA-4结合后,能阻断CTLA-4与其配体CD80/CD86的相互作用。而阻断CTLA-4已被证明能够增强T细胞的活化和增殖。Yervoy在黑色素瘤患者中的疗效作用机制,是间接通过T细胞介导的抗肿瘤免疫反应。Yervoy于2011年3月获FDA批准用于不能手术切除或转移性黑色素瘤,目前该药已获全球40多个国家批准。

关于黑色素瘤:

黑色素瘤(melanoma)是一种高度恶性肿瘤,复发率和死亡率非常高。根据其原位特性(厚度、溃烂)、是否已扩散至淋巴结、远处转移程度,黑色素瘤可分为5级(0-4阶段)。3阶段黑色素瘤已到达区域性淋巴结,但尚未扩散到远端淋巴结或机体其他部位(转移),需要外科手术切除原发肿瘤及所涉及的淋巴结。3阶段黑色素瘤复发风险很高,总存活率一直很低;许多患者会在治疗后5年内复发,其中近90%复发病例发生于高复发风险人群。一旦病情复发,存活率将非常低,历史数据为11%-20%。(生物谷Bioon.com)

英文原文:First Randomized Study Evaluating Opdivo (nivolumab)+Yervoy (ipilimumab) Regimen Demonstrates Superior Efficacy Versus Yervoy Alone in Patients with Previously Untreated Advanced Melanoma

Opdivo+Yervoy regimen achieves objective response rate of 61%, including a 22% complete response rate, in previously untreated, advanced melanoma patients with BRAF wild-type mutation status

Opdivo+Yervoy regimen decreased risk of melanoma progression or death compared to Yervoy alone by 60%, based upon hazard ratio of 0.4; median progression-free survival for the regimen not reached with a minimum follow-up of 11 months

Safety profile of the Opdivo+Yervoy regimen from this trial (CheckMate -069) was consistent with previously-reported studies

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb Company (NYSE:BMY) today announced positive results from a Phase II trial (CheckMate -069), evaluating the Opdivo (nivolumab)+Yervoy (ipilimumab) regimen versus Yervoy alone in patients with previously untreated advanced melanoma. Patients with BRAF wild-type mutation status treated with the Opdivo+Yervoy regimen experienced a higher objective response rate (ORR) of 61% (n=44/72) – the primary study endpoint – compared to 11% (n=4/37) for patients administered Yervoy monotherapy (P<0.001). Complete responses were also reported in 22% (n=16) of patients with BRAF wild-type mutation status administered the Opdivo+Yervoy regimen and in no patients who received Yervoy monotherapy. Similar results were also observed in BRAF mutation-positive patients. The safety profile was consistent with previously-reported studies evaluating the Opdivo+Yervoy regimen and included grade 3-4 colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%).

These data will be presented today at the American Association for Cancer Research (AACR) Annual Meeting and featured during a press briefing at 8:30 AM EDT [Abstract #2860]. The results will also be published in The New England Journal of Medicine (NEJM).

“These data are unprecedented in advanced melanoma, showing efficacy results that have not previously been observed with Immuno-Oncology agents,” said F. Stephen Hodi, M.D., Associate Professor of Medicine, Dana-Farber Cancer Institute and an author of the NEJM manuscript. “With the Opdivo+Yervoy regimen, we observed much higher response rates which were sustained, as well as significant reduction in tumor burden than with Yervoy. These responses seen in CheckMate -069 demonstrate the potential of this regimen in patients with metastatic melanoma.”

Melanoma is the most serious form of skin cancer and strikes adults of all ages. While melanoma represents less than 5% of skin cancers, it results in most deaths. The CheckMate -069 trial is the first randomized study reporting outcomes in the first-line setting for advanced melanoma patients treated with a regimen of immune checkpoint inhibitors compared to Yervoy. The efficacy and safety results of CheckMate -069 are consistent with the Phase Ib dose-ranging trial (CheckMate -004), which evaluated the safety and activity of the regimen in patients with advanced melanoma.

“The CheckMate -069 results reinforce our belief that the future lies in the combination of Immuno-Oncology agents, including Opdivo and Yervoy, that can leverage the immune system in order to offer cancer patients options with greater efficacy beyond current treatment approaches,” said Michael Giordano, senior vice president, Head of Development, Oncology. “Our strategy has always been to build upon the success achieved with Yervoy. In 2011, long-term survival for metastatic melanoma patients was unheard of, but the introduction of Yervoy has helped to make this a reality for some patients. Now we are building on this success with Opdivo, which was the first PD-1 inhibitor to demonstrate an improved survival benefit.”

About CheckMate -069

CheckMate -069 is a Phase II double-blind, randomized study that evaluated the Opdivo+Yervoy regimen in patients with previously untreated unresectable Stage 3 and 4 melanoma. The study included patients with both BRAF wild-type and BRAF mutation-positive melanoma.

The trial enrolled 142 patients who were randomized to receive either the Opdivo+Yervoy (n=95) regimen or Yervoy (n=47) monotherapy. Randomization was stratified by BRAF mutation status (V600 wild-type tumors versus BRAF mutation-positive tumors as assessed by an FDA-approved test). Patients in the Opdivo+Yervoy regimen group received 1 mg/kg of Opdivo plus 3 mg/kg of Yervoy every 3 weeks for 4 doses followed by 3 mg/kg of Opdivo per every 2 weeks until progression or unacceptable toxic effects. In the Yervoy monotherapy group, patients were treated with the same dosing schedule plus matching placebo.

The primary endpoint was ORR in patients with BRAF wild-type tumors. Secondary endpoints included progression-free survival (PFS) in BRAF wild type patients and ORR and PFS in BRAF V600 mutation-positive patients, along with safety.

Along with higher ORR and more complete responses, the regimen decreased risk of progression for BRAF mutant and wild-type patients (hazard ratios = 0.4 [95% CI: 0.23, 0.68; P<0.001] and 0.38 [95% CI: 0.15, 1.00], respectively), representing a 60-62% reduction of risk of progression or death. In BRAF wild-type patients, median PFS was not reached. In BRAF mutation-positive patients, median PFS was 8.5 months for the regimen and 2.7 months for Yervoy alone. In addition, ORR was independent of PD-L1 status: 58% among patients with PD-L1 positive tumors and 55% among those with and PD-L1 negative tumors. The minimum follow-up period after randomization was 11 months.

CheckMate -069 is the first randomized study to characterize the safety profile of the Opdivo+Yervoy regimen versus Yervoy monotherapy. The safety profile was consistent with that previously reported for the Opdivo+Yervoy regimen. The treatment-related adverse event rate was similar (91% for the Opdivo+Yervoy regimen versus 93% for Yervoy monotherapy). The incidence of grade 3/4 adverse events (drug-related AEs) was higher with the Opdivo+Yervoy regimen (54%) compared to 24% of patients who received Yervoy monotherapy and managed using established safety guidelines and the majority (approximately 80%) improved or resolved with appropriate monitoring and use of corticosteroids. The most common grade 3/4 AEs with the Opdivo+Yervoy regimen were colitis (17%), diarrhea (11%), and increased alanine aminotransferase (11%). The Opdivo+Yervoy regimen was discontinued due to adverse events in 47% of patients versus 17% for Yervoy monotherapy. Of those patients who discontinued due to adverse events, 68% continued to experience a complete or partial response. There were three drug-related deaths associated with the Opdivo+Yervoy regimen.

About Opdivo and Yervoy

Cancer cells may exploit “regulatory” pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo and Yervoy are both monoclonal antibodies and immune checkpoint inhibitors that target separate, distinct checkpoint pathways. Inhibition of these immune checkpoint pathways results in enhanced T cell function greater than the effects of either antibody alone.

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. Recently, on March 5, 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.

In the European Union, the European Medicines Agency (EMA) has validated for review the Marketing Authorization Application for Opdivo in advanced melanoma. The application has also been granted accelerated assessment by the EMA’s Committee for Medicinal Products for Human Use (CHMP). The EMA also validated for review the MAA for Opdivo in NSCLC.

On March 25, 2011, the FDA approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is now approved in more than 40 countries.

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 7,000 patients have been enrolled worldwide.

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