与Nivolumab一起使用的SIRT证明了HCC的积极安全性和耐受性结果

StephenW

SIRT Administered With Nivolumab Demonstrates Positive Safety, Tolerability Results in HCC
October 3, 2020
Tony Berberabe, MPH
Page Number: 24

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Findings from the NASIR-HCC phase 2 clinical trial demonstrated the safety and tolerability of nivolumab administered with selective internal radiation therapy containing yttrium-90 resin in patients who were ineligible for transarterial chemoembolization.

Bruno Sangro, MD, PhD

Findings from the NASIR-HCC (hepatocellular carcinoma) phase 2 clinical trial (NCT03380130) demonstrated the safety and tolerability of nivolumab (Opdivo) administered with selective internal radiation therapy (SIRT) containing yttrium-90 resin in patients who were ineligible for transarterial chemoembolization (TACE).1

“NASIR-HCC combined these 2 therapies for the treatment of patients who were not candidates for locoregional therapy,” said senior author Bruno Sangro, MD, PhD, director of the Liver Unit at Clínica Universidad de Navarra and a professor of medicine at the Clínica Universidad de Navarra School of Medicine in Pamplona, Spain, during his presentation of the data at the International Liver Cancer Association (ILCA) 2020 Virtual Conference.

After a median follow-up of nearly 16 months, 11% of patients reported a complete response and 26.2% had a partial response. The objective response rate (ORR) in 42 patients was 38.1%, and the disease control rate (DCR) was 81.0% (TABLE).1 Investigators reported that median time to progression was 9.0 months (95% CI, 7.84-10.15) and median overall survival (OS) was 20.69 months (95% CI, 17.38-24.01), with a 12-month OS rate of 73.7% and an 18-month OS rate of 61.3%.

Patients with intermediate-stage or advanced-stage HCC have limited therapeutic options, but the mainstay of treatment is intraarterial therapies, Sangro said. Nivolumab stimulates T-cell activity by blocking the PD-1 receptor and has shown significant antitumor activity for advanced-stage HCC. It is also approved in several countries, including the United States, as a second-line therapy.2

The trial was carried out in 9 academic hospitals in Spain. Eligible patients for NASIR-HCC had to have an unequivocal diagnosis of unresectable HCC confirmed by histology or imaging. Patients had to be ineligible for chemoembolization because of a single tumor larger than 5 cm, multiple tumors in the Barcelona Clinic Liver Cancer–B2 substage, or 90% of unilobar tumors with segmental or lobar portal vein thrombosis.

Initially, patients received SIR-Spheres that contained Y90 resin microspheres and 3 weeks later, they received 240 mg of nivolumab every 2 weeks. The primary end point was safety, and the secondary end point was antitumor activity as determined by ORR, DCR, duration of response, time to progression, progression-free survival, and progression pattern by RECIST 1.1. Exploratory end points included OS, albumin-bilirubin grade, and biomarkers, which were not discussed in the presentation.

Sangro reported that 54 patients were screened, with 43 patients evaluated to receive SIRT. Forty-two patients were treated with SIRT, and 41 patients received at least 1 dose of nivolumab.

Median age of patients was 65 years (range, 49-79). Prior treatments included TACE (21.4%), resection (16.7%), ablation (14.3%), and sorafenib (Nexavar; 11.9%). Nine patients (21.4%) had hepatitis C virus etiology, and 1 patient (2.4%) had hepatitis B virus. Thirty-two (76.2%) patients were uninfected.

Regarding SIRT treatment characteristics, the majority of patients had either 1 or 2 macroaggregated albumin injection sites, with 38.1% having 1 site and 50.0% having 2 sites. Only 11.9% of patients had 3 injection sites.

Sangro said that 15 patients (35.7%) completed treatment with nivolumab. “Ten patients continued on nivolumab after the study because they experienced disease control or objective remissions,” he added.

The main reasons for nivolumab discontinuation were tumor progression (40.5%) or toxicity (11.9%). Out of 26 events of progression, intrahepatic progression was reported in 53.5% of patients and extrahepatic progression was reported in 38.5%; 7.7% had both patterns of progression.

Regarding safety, the majority of adverse effects (AEs) of any causality were grade 1 (67.4%) or 2 (23.4%) in severity. Sangro said that 6.3% of patients temporarily discontinued nivolumab treatment as a result of AEs, but the majority (93.7%) took no action.

Thirty-eight percent of patients reported all-grade treatment-related AEs (TRAEs), and 11.9% reported grade 3 or 4 TRAEs. One (2.3%) patient reported a TRAE impeding nivolumab administration, and 1 patient had a TRAE leading to permanent discontinuation of nivolumab. Five (11.9%) patients required systemic steroids.

Immune-mediated AEs were typical of those observed in studies involving single-arm anti– PD-1 therapies, Sangro said.

“In this phase 2 trial, patients with HCC treated with resin microspheres and nivolumab showed a favorable safety profile with no signs of synergistic toxicity,” said Sangro. “Importantly, encouraging efficacy data were observed that warrant further evaluation in controlled trials.”

References:

1. De La Torre M, Matilla A, Varela M, et al. Nivolumab after selective internal radiation therapy using sir spheres resin microspheres in patients with hepatocellular carcinoma: the NASIR HCC trial. Presented at: International Liver Cancer Association 2020 Virtual Conference; September 11-13, 2020.

2. FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib. FDA. September 22, 2017. Accessed September 15, 2020. https://bit.ly/3moHi4q

StephenW

与Nivolumab一起使用的SIRT证明了HCC的积极安全性和耐受性结果
2020年10月3日
MPH的Tony Berberabe
页码：24

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来自NASIR-HCC 2期临床试验的结果表明，对于不适合经动脉化学栓塞治疗的患者，应用含yttrium-90树脂的选择性内部放射疗法联合应用nivolumab的安全性和耐受性。

医学博士Bruno Sangro

NASIR-HCC（肝细胞癌）2期临床试验（NCT03380130）的结果表明，对于不适合经动脉化学栓塞治疗的患者，应用含yttrium-90树脂的选择性内部放射治疗（SIRT）的nivolumab（Opdivo）的安全性和耐受性（ TACE）.1

“ NASIR-HCC结合了这两种疗法来治疗那些不适合局部治疗的患者，”资深作者Bruno Sangro医学博士，克利尼察大学纳瓦拉大学肝脏科主任，克利尼察大学的医学教授说。西班牙潘普洛纳的纳瓦拉大学医学院在国际肝癌协会（ILCA）2020虚拟会议上介绍数据时。

中位随访近16个月后，11％的患者报告完全缓解，26.2％的患者部分缓解。 42例患者的客观缓解率（ORR）为38.1％，疾病控制率（DCR）为81.0％（表）。1研究人员报告，进展时间的中位数为9.0个月（95％CI，7.84-10.15），而中位总体生存期（OS）为20.69个月（95％CI，17.38-24.01），其中12个月OS率为73.7％，18个月OS为61.3％。

Sangro说，中晚期肝癌患者的治疗选择有限，但是治疗的主要手段是动脉内治疗。 Nivolumab通过阻断PD-1受体刺激T细胞活性，并已显示出对晚期HCC具有显着的抗肿瘤活性。它也被包括美国在内的多个国家批准为二线治疗药物。 2

该试验在西班牙的9家学术医院中进行。符合条件的NASIR-HCC患者必须通过组织学或影像学明确诊断为不可切除的HCC。患者必须不符合化学栓塞治疗的资格，因为单个肿瘤大于5厘米，巴塞罗那临床肝癌B2期为多个肿瘤，或90％的单节肿瘤伴节段性或大叶门静脉血栓形成。

最初，患者接受包含Y90树脂微球的SIR-Spheres，3周后，每2周接受240 mg的nivolumab。主要终点是安全性，次要终点是通过ORR，DCR，反应持续时间，进展时间，无进展生存期和RECIST 1.1确定的进展模式确定的抗肿瘤活性。探索性终点包括OS，白蛋白-胆红素等级和生物标记物，本演示文稿中未讨论。

Sangro报告称，对54例患者进行了筛查，其中43例接受了SIRT评估。 SIRT治疗了42例患者，41例患者接受了至少1剂nivolumab。

患者的中位年龄为65岁（范围49-79）。先前的治疗包括TACE（21.4％），切除术（16.7％），消融（14.3％）和索拉非尼（Nexavar; 11.9％）。 9名患者（21.4％）患有丙型肝炎病毒病因，1名患者（2.4％）患有乙型肝炎病毒。未感染的有32名（76.2％）患者。

关于SIRT的治疗特征，大多数患者有1个或2个大白蛋白注射位点，其中38.1％的患者有1个位点，50.0％的患者有2个位点。只有11.9％的患者有3个注射部位。

Sangro说，有15名患者（35.7％）完成了nivolumab的治疗。他补充说：“研究结束后，十名患者继续接受nivolumab治疗，因为他们经历了疾病控制或客观缓解。”

尼古鲁单抗停药的主要原因是肿瘤进展（40.5％）或毒性（11.9％）。在26种进展事件中，有53.5％的患者报告了肝内进展，有38.5％的患者报告了肝外进展。 7.7％的人都有两种发展模式。

关于安全性，任何因果关系的不良反应（AE）的严重程度均为1级（67.4％）或2级（23.4％）。 Sangro说，有6.3％的患者因AE暂时停用了nivolumab治疗，但大多数患者（93.7％）没有采取任何行动。

38％的患者报告了所有级别的治疗相关AE（TRAE），而11.9％的患者报告了3或4级TRAE。 1名（2.3％）患者报告了TRAE阻碍了nivolumab的给药，而1名患者的TRAE导致了nivolumab的永久停用。五名（11.9％）患者需要全身性激素治疗。

Sangro说，在涉及单臂抗PD-1治疗的研究中观察到的典型的免疫介导AE。
尼古鲁单抗停药的主要原因是肿瘤进展（40.5％）或毒性（11.9％）。在26种进展事件中，有53.5％的患者报告了肝内进展，有38.5％的患者报告了肝外进展。 7.7％的人都有两种发展模式。

关于安全性，任何因果关系的不良反应（AE）的严重程度均为1级（67.4％）或2级（23.4％）。 Sangro说，有6.3％的患者因AE暂时停用了nivolumab治疗，但大多数患者（93.7％）没有采取任何行动。

38％的患者报告了所有级别的治疗相关AE（TRAE），而11.9％的患者报告了3或4级TRAE。 1名（2.3％）患者报告了TRAE阻碍了nivolumab的给药，而1名患者的TRAE导致了nivolumab的永久停用。五名（11.9％）患者需要全身性激素治疗。

Sangro说，在涉及单臂抗PD-1治疗的研究中观察到的典型的免疫介导AE。

Sangro说：“在2期临床试验中，用树脂微球和nivolumab治疗的HCC患者显示出良好的安全性，没有协同毒性的迹象。” “重要的是，观察到令人鼓舞的疗效数据，值得在对照试验中进行进一步评估。”

参考文献：

1. De La Torre M，Matilla A，Varela M等。在肝细胞癌患者中使用Sir spheres树脂微球进行选择性内部放射治疗后的Nivolumab：NASIR HCC试验。演讲者：国际肝癌协会2020虚拟会议； 2020年9月11日至13日。

2. FDA批准nivolumab加快批准先前用索拉非尼治疗的HCC。 FDA。 2017年9月22日。访问2020年9月15日。https://bit.ly/3moHi4q