解读 Lenvatinib 在 HCC 中的新的和以前的试验结果

StephenW

解读 Lenvatinib 在 HCC 中的新的和以前的试验结果
2022 年 10 月 27 日
有针对性的肿瘤学人员

在现场虚拟活动中，医学博士 Ghassan K. Abou-Alfa 讨论了 lenvatinib 与 sorafenib 的 REFLECT 试验以及 lenvatinib/pembrolizumab 与 lenvatinib 在肝细胞癌患者中的 LEAP-002 试验的结果。
人物形象

Ghassan K. Abou-Alfa，医学博士，工商管理硕士

医学肿瘤学家

纪念斯隆凯特琳癌症中心

纽约州纽约

Targeted OncologyTM：哪些数据支持使用乐伐替尼 (Lenvima) 治疗 HCC 患者？

GHASSAN K. ABOU-AL​​FA，医学博士，工商管理硕士：REFLECT 研究 [NCT01761266] 研究了索拉非尼 [Nexavar] 与 lenvatinib。 [设计]是标准的，这项研究没有什么特别之处。 Child-Pugh 评分为 A 的患者在一线接受治疗，[并具有] 适当的全身治疗资格。患者被随机分配到乐伐替尼组或索拉非尼组。主要终点是总生存期[OS]。有趣的是，患者按地区、血管受累程度或疾病程度、体能状态和体重进行分层。

这是一项寻找非劣效性的研究。 [目标是] 看到 2 条 Kaplan-Meier 曲线相互拥抱，这正是我们所拥有的，lenvatinib 的中位 OS 为 13.6 个月，而索拉非尼的中位 OS 为 12.3 个月。 [几乎] 与 0.92 [95% CI, 0.79-1.06] 的风险比完全没有区别，接近 1，正是您想要的。1

有趣的是，本研究中乐伐替尼的无进展生存期 [PFS] 是索拉非尼的 3 倍。最重要的是，该益处针对所有患者，与他们在不同人口统计方面的疾病无关。但更重要的是，即使通过局部晚期疾病，它有时也可能使患者受益。巴塞罗那诊所肝癌 [BCLC]-B 期疾病的患者表现非常好。这是一个非常重要的信息，因为并非所有 BCLC-B 期患者都会接受栓塞治疗。

本研究中的患者在进展后的二线治疗中接受了哪些治疗？

在研究后的 lenvatinib 组中，大约三分之一的人接受了索拉非尼 [或其他治疗]，而其他人没有接受任何治疗。但对于索拉非尼，这是所有这些疗法的早期阶段，因此 12% 的人仍然使用索拉非尼 [因为] 没有其他选择。当我们没有其他任何东西时，我们通过保持索拉非尼来减缓疾病。我们不再这样做了，因为我们有选择。患者在乐伐替尼之后可能已经厌倦了索拉非尼，但当时还没有免疫疗法。

HCC 患者的 3 期 LEAP-002 试验 (NCT03713593) 的结果是什么？

这是一项非常简单的研究；这是第一行。我们将乐伐替尼确立为 [在 REFLECT 试验中] 的护理标准。该试验研究了 lenvatinib 加 pembrolizumab [Keytruda]（一种 TKI 加免疫检查点抑制剂的组合）与 lenvatinib 加安慰剂的比较。这是一项随机、盲法研究……主要终点是 OS。该研究有相同的标准要求。

这是在巴黎举行的 2022 年欧洲医学肿瘤学会大会 [2022 年 9 月] 上提出的。2 患者人群的中位年龄约为 66 岁，接近 50% 的患者患有乙型肝炎，约 20% 患有丙型肝炎，大约 78%（与我们在每项研究中看到的情况相似）是 BCLC-C，即患有转移性疾病，其余的是 BCLC-B，即局部晚期疾病。

结果显示，乐伐替尼加派姆单抗的中位 OS 为 21.2 个月，单药乐伐替尼为 19.0 个月。2 风险比为 0.84，[表明] 2 个结果之间没有 [显着] 差异 [95% CI, 0.708- 0.997; P = .0227]。对使用 lenvatinib/pembrolizumab 组合的所有兴奋和期待都没有实现。但更有趣的是，单药乐伐替尼的中位 OS 为 19.0 个月，[出乎意料地高]。尽管乐伐替尼/派姆单抗组有[轻微的]改善，但归根结底，乐伐替尼也一样好。

乐伐替尼/派姆单抗的 ORR [按 RECIST 1.1] 分别为 26% 和 17%，单独使用乐伐替尼。 [双臂] 的疾病稳定率相当高。根据修改后的 RECIST 标准，您正在研究 [治疗诱导的肿瘤] 坏死，乐伐替尼/派姆单抗的 ORR 为 40%，而乐伐替尼为 34%。将派姆单抗添加到乐伐替尼有[一些改善]，但与单药乐伐替尼相比差异不大。

这些患者在疾病进展后接受了哪些治疗？

在乐伐替尼/派姆单抗组中，约 14% 接受了免疫治疗，然后在乐伐替尼/安慰剂组中，22% 接受了免疫治疗。 这不是一个庞大的患者数量。 您可能会争辩说，仅乐伐替尼的中位 OS 为 19.0 个月，因为之后每个人都接受了派姆单抗或 [其他免疫疗法]。 但只有大约 20% 的人明白这一点。

StephenW

Interpreting Results From New and Previous Trials of Lenvatinib in HCC
October 27, 2022
Targeted Oncology Staff

During a live virtual event, Ghassan K. Abou-Alfa, MD, discussed the results of the REFLECT trial of lenvatinib versus sorafenib and the LEAP-002 trial of lenvatinib/pembrolizumab versus lenvatinib in patients with hepatocellular carcinoma.
figure image

Ghassan K. Abou-Alfa, MD, MBA

Medical Oncologist

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted OncologyTM: What data support the use of lenvatinib (Lenvima) for patients with HCC?

GHASSAN K. ABOU-ALFA, MD, MBA: The REFLECT study [NCT01761266] looked into sorafenib [Nexavar] versus lenvatinib. [The design] was standard, with nothing particular about this study. Patients with Child-Pugh score A were treated in the first line, [and had] appropriate eligibility for systemic therapy. Patients were randomly assigned to lenvatinib or sorafenib. The primary end point was overall survival [OS]. Interestingly, the patients were stratified by region, by the extent of vascular involvement or extent of the disease, performance status, and body weight.

This was a study looking for noninferiority. [The goal was] to see the 2 Kaplan-Meier curves hugging each other, and that's exactly what we had, with 13.6 months median OS for lenvatinib versus 12.3 months median OS for sorafenib. [Almost] no difference at all with the hazard ratio of 0.92 [95% CI, 0.79-1.06], which is close to 1, exactly what you want it to be.1

Interestingly, the progression-free survival [PFS] in this study was 3 times higher for lenvatinib compared with sorafenib. On top of that, the benefit addressed all patients, independent of what they had for disease in regard to the different demographics. But more importantly, even through locally advanced disease, it might sometimes benefit patients. Patients with Barcelona Clinic Liver Cancer [BCLC]-B stage disease do very well. And this is a very important message, because not all patients with stage BCLC-B are going to get embolization.

What did patients in this study receive as therapy in the second line following progression?

In the lenvatinib arm, post-study, about one-third got sorafenib [or another therapy] and the others did not get any therapy. But for sorafenib, this was early in the story of all of those therapies, so 12% remained on sorafenib [since] there were no other choices. When we didn't have anything else, we slowed down the disease by keeping the sorafenib on. We are not doing it anymore, because we have choices. Patients may have gotten tired of sorafenib after lenvatinib, but there was no immunotherapy at that time.

What were the results of the phase 3 LEAP-002 trial (NCT03713593) of patients with HCC?

This is a very straightforward study; it was first line. We established lenvatinib as a standard of care [in the REFLECT trial]. This trial investigated lenvatinib plus pembrolizumab [Keytruda], the combination of a TKI plus immune checkpoint inhibitor, compared with lenvatinib plus placebo. It was a randomized, blinded study…and the primary end point was OS. There were the same standard requirements for the study.

This was presented at the 2022 European Society for Medical Oncology Congress in Paris [in September 2022].2 The patient population had a median age of approximately 66 years, close to 50% of patients had hepatitis B, about 20% had hepatitis C, and about 78%, which is similar to what we see in every study, were BCLC-C—in other words, with metastatic disease, and the rest are BCLC-B, which is locally advanced disease.

The results show that the median OS for the lenvatinib plus pembrolizumab was 21.2 months and single-agent lenvatinib was 19.0 months.2 The hazard ratio was 0.84, [indicating] no [significant] difference between the 2 results [95% CI, 0.708-0.997; P = .0227]. All the excitement and anticipation about the use of the lenvatinib/pembrolizumab combination did not pan out. But more intriguingly, single-agent lenvatinib had an [unexpectedly high] median OS of 19.0 months. Even though there was a [slight] improvement favoring the lenvatinib/pembrolizumab arm, at the end of the day, lenvatinib was as good.

The ORR [by RECIST 1.1] for lenvatinib/pembrolizumab was 26% and 17% with lenvatinib alone. There was quite a high rate of stable disease [in both arms]. By modified RECIST criteria, where you are looking into [treatment-induced tumor] necrosis, ORR was 40% for lenvatinib/pembrolizumab versus 34% with lenvatinib. There was [some improvement] with pembrolizumab added to lenvatinib, but not that much difference compared with single-agent lenvatinib.

What treatments did these patients receive after disease progression?

On the lenvatinib/pembrolizumab arm, about 14% got immunotherapy, and then in the lenvatinib/placebo arm, 22% received immunotherapy. It wasn’t a huge number of patients. You might have argued that the median OS for lenvatinib alone was 19.0 months because everybody received pembrolizumab or [other immunotherapy] afterwards. But only about 20% got that.