Nivolumab ORR在第一阶段存在波动I / II肝癌研究

StephenW

Nivolumab ORR Fluctuates in Phase I/II HCC Study
Published Online: Jul 06,2016

Treatment with the PD-1 inhibitor nivolumab (Opdivo) demonstrated an objective response rate (ORR) of 9% as a second-line therapy for patients with hepatocellular carcinoma (HCC), according to updated results from the phase I/II CheckMate-040 study presented at the 2016 ASCO Annual Meeting.

In previous findings from the study, the ORR was 19%; however, for the latest update, the investigators cautioned that data were preliminary and so they may have underestimated the response rate. In the study, responses were frequently delayed, with a complete response occurring after 24 months of treatment. When considering those with stable disease, the disease control rate was 65%.

“The updated nivolumab in HCC data are still very encouraging. The disease control rate was 65%, and there were 3 complete responses,” said Kabir Mody, MD, from the Mayo Clinic.

The phase I/II study explored ascending doses of nivolumab ranging from 0.1 mg/kg to 10 mg/kg every 2 weeks for up to 2 years. All patients enrolled had Child-Pugh class A disease. The primary endpoint was ORR by RECIST criteria. Secondary outcome measures focused on overall survival (OS), progression-free survival, and biomarker assessments.

In an expansion cohort, nivolumab was administered at 3 mg/kg across 4 groups, including those uninfected by hepatitis who were sorafenib naïve/intolerant, those uninfected following progression on sorafenib, those with hepatitis C virus (HCV) infection, and those with hepatitis B virus (HBV) infection.

Overall, 206 patients were enrolled in the study, 65% with extrahepatic metastasis and 7% with vascular invasion. Most patients had received prior sorafenib (64%).

Of enrolled patients, 91 had ≥18 weeks of follow-up and were evaluable for response. For those who responded to treatment, the median duration of response was 17 months (range, 6-24). Stable responses occurred as late as 12 to 18 months following the initiation of treatment. Overall, PD-L1 status did not appear to impact response rates. The 6-month OS rate was 69% (95% CI, 0.43-0.85).

For uninfected, sorafenib-naïve or intolerant patients (n = 22), the ORR was 14%. In those who progressed on prior sorafenib and were uninfected (n = 27), the ORR was 7%. In the HCV-infected (n = 21) and HBV-infected (n = 21) patients, the ORRs were 14% and 0%, respectively.

Across all cohorts of the trial, patients received 5 to 6 doses of nivolumab (range, 1-19). Half of patients experienced a treatment-related adverse event (AE), with the most frequent events being fatigue (17%) and pruritus (12%). Grade 3/4 treatment-related AEs were seen in 14% of patients, with the most common being ALT and AST increases (3% each).

In the frontline setting, nivolumab is being compared with sorafenib for patients with HCC in a phase III study. The primary endpoints are time to progression and OS. The study hopes to enroll 726 patients with an estimated completion date of July 2017 (NCT02576509).
REFERENCE

    Sangro B, Melero I, Ya TC, et al. Safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of dose-expansion cohorts from the phase 1/2 CheckMate-040 study. J Clin Oncol. 2016;34 (suppl; abstr 4078).


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StephenW

Nivolumab ORR在第一阶段存在波动I / II肝癌研究
在线发表时间：七月06,2016

用PD-1抑制剂nivolumab（Opdivo）治疗证明了9％的客观响应率（ORR），为二线治疗患者的肝细胞癌（HCC），根据从I / II期的CheckMate-040更新的结果研究发表在2016年ASCO年会。

在从研究以前的研究结果，ORR为19％;然而，最新的更新，研究人员提醒说，数据是初步的，因此他们可能低估了反应速度。在这项研究中，反应被频繁延迟，治疗24个月后发生完全反应。当考虑那些具有稳定的疾病，疾病控制率为65％。

“在HCC数据更新nivolumab仍然是非常令人鼓舞的。疾病控制率为65％，并有3个完整的反应，“卡比尔么医师，梅奥诊所说。

在I / II期研究探讨提升剂量nivolumab从0.1毫克/千克至10毫克/公斤，每2周长达2年。入选所有患者Child-Pugh分级A类疾病。主要终点是ORR由RECIST标准。次要结果指标集中在总生存期（OS），无进展生存期，和生物标志物的评估。

在膨胀的队列，nivolumab混合物在3毫克/千克跨越4组给药，包括那些由肝炎未感染谁是索拉非尼天真/不耐，索拉非尼的那些未感染以下进展，那些与丙型肝炎病毒（HCV）感染，和那些与肝炎乙型肝炎病毒（HBV）感染。

总体而言，206例患者被纳入研究，65％的肝外转移和血管浸润7％。大多数患者接受索拉非尼前（64％）。

参加试验的患者中，有91周≥18随访和评价疗效。对于那些谁对治疗有反应，反应时间中位数为17个月（6-24）。稳定的响应处理开始以下发生迟12至18个月。总体而言，PD-L1的状态并未以影响反应率。 6个月的OS率为69％（95％CI，0.43-0.85）。

对于未感染，索拉非尼天真或不能耐受的患者（n = 22），ORR为14％。在那些谁进步了事先索拉非尼并未感染（N = 27），ORR为7％。在HCV感染（21例）和HBV感染（21例）的患者，所述ORRs分别为14％和0％。

在整个审判的所有同伙，患者接受5〜6剂nivolumab（范围：1-19）。一半的患者经历了治疗相关的不良事件（AE），最频繁的事件是疲劳（17％）和瘙痒（12％）。 3/4级治疗相关的AEs主要出现在14％的患者，最常见的是ALT和AST增加（各3％）。

在一线设置，nivolumab正与在III期研究索拉非尼对HCC患者进行比较。主要终点是疾病进展时间和OS。这项研究希望招收726例2017年7月（NCT02576509）的预计完成日期。
参考

    桑格罗B，Melero我，雅TC等。安全性和晚期肝癌（HCC）患者（分）nivolumab（NIVO）的抗肿瘤活性：从相1/2的CheckMate-040研究的剂量扩大同伙中期分析。 Ĵ临床Oncol。 2016年，34（增刊; abstr 4078）。


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