肝脏疾病的早期发现提高了治愈肝癌的机会

StephenW

突破

15 年前，还没有能够延长总体生存期的肝癌治疗方法。

“我们对患有晚期疾病的患者进行了化疗，除了我们想为他们做点什么之外，真的没有任何其他原因，”大学大卫格芬医学院血液学/肿瘤学系医学教授理查德·S·芬恩 (Richard S. Finn) 说加利福尼亚州、洛杉矶和 Jonsson 综合癌症中心的研究人员告诉 Healio Gastroenerology。

所需的突破性临床医生于 2007 年抵达，当时，肝癌项目创始人兼主任、西奈山医学院医学教授 Josep M. Llovet 医学博士在 ASCO 年会上介绍了 SHARP 试验的结果。

在包括 602 名晚期疾病患者的第 3 期双盲随机试验中，与分配给安慰剂的患者相比，接受索拉非尼治疗的患者的 OS 增加了 44%（中位 OS，10.7 个月与 7.9 个月；HR = 0.69； 95% 置信区间，0.55-0.87）。


“这是我们第一次对 HCC 进行全身治疗，”Llovet 告诉 Healio Gastroenterology。 “人们站起来鼓掌。非常非常好。”

Finn 表示，这些数据开启了肝癌研究的临床发展阶段。

“[SHARP 试验] 表明，索拉非尼将生存期的中位数提高了大约 3 个月，”他说。 “肿瘤不一定会缩小，但它可以提高生存率，这最终是最重要的事情。它为进步奠定了基础。结果表明，你可以开发一种治疗肝癌的药物，你可以在精心设计的研究中取得成功。”

尽管如此，随后的进展起初进展缓慢。

“我们对其他药物进行了 10 年的测试，所有试验都呈阴性。我们很震惊，”Llovet 说。 “有些是阴性的，因为这种药物很强大但有毒，比如舒尼替尼 [Sutent, Pfizer]，而另一些则不够强大。”

下一次突破发生在 2017 年 4 月。

Stivarga（瑞戈非尼，拜耳）——一种激酶抑制剂，通过阻断几种促进癌症生长的酶起作用——成为自索拉非尼以来第一个获得 FDA 批准的晚期肝癌治疗方法。 16 个月后，基于 3 期 REFLECT 试验的数据，Lenvima（乐伐替尼，卫材）获得 FDA 批准，成为十年来第一个获批用于不可切除 HCC 的一线疗法。一年之内，FDA 又批准了另外两种多激酶抑制剂 Cabometyx（cabozantinib，Exelixis）和 Cyramza（ramucirumab，礼来）。

另外三种疗法获得了加速批准——抗 PD-1 抗体 Opdivo（nivolumab，百时美施贵宝）和 Keytruda（pembrolizumab，默克），以及 nivolumab 加上抗 CTLA-4 抗体 Yervoy（ipilimumab，百时美施贵宝）——尽管这些批准一直是 FDA 审查的主题。

在经历了长达十年的干旱之后，2017 年至 2020 年批准用于 HCC 的药物浪潮为推进研究和改善结果的无数机会打开了窗口。

“我们从那些关于试验设计和肝癌自然史的负面研究中学到了一些东西，”芬恩说。 “开发这些更具活性的药物需要时间和反复试验。”

Finn 领导了 IMbrave150 3 期试验，该试验在不可切除的 HCC 患者中比较了 PD-L1 抑制剂 Tecentriq（atezolizumab，基因泰克/罗氏）加 VEGF 抑制剂阿瓦斯汀（贝伐单抗，基因泰克/罗氏）与索拉非尼。该试验的结果于 5 月发表在《新英格兰医学杂志》上，被认为是研究的下一个里程碑，并导致 FDA 批准该患者群体的组合。

中位随访 15.6 个月后，1 月份发布的更新分析显示，联合用药可将死亡风险降低 34%（中位 OS，19.2 个月与 13.4 个月；HR = 0.66；95% CI，0.52-0.85）。

“这是组合新时代的曙光，真正的突破，”Llovet 说。 “[来自 IMbrave150] 报告的第一个 HR 为 0.58，这是非常出色的。随着随访时间的延长，HR 出现了一些回落，降至 0.66，这仍然很突出。大约 30% 的客观响应率非常非常好。”
Gānzàng jíbìng de zǎoqí fāxiàn tígā

StephenW

Early discovery of liver disease improves chances to cure liver cancer

Breakthroughs

Fifteen years ago, there was no treatment for liver cancer that prolonged overall survival.

“We gave chemotherapy to patients with advanced disease, really for no reason other than we wanted to do something for them,” Richard S. Finn, MD, professor of medicine in the division of hematology/oncology at David Geffen School of Medicine at University of California, Los Angeles, and Jonsson Comprehensive Cancer Center, told Healio Gastroenerology.

The breakthrough clinicians needed arrived in 2007, when Josep M. Llovet, MD, founder and director of the liver cancer program and professor of medicine at Mount Sinai School of Medicine, presented results of the SHARP trial at the ASCO Annual Meeting.

In the phase 3, double-blind, randomized trial that included 602 patients with advanced disease, those who received sorafenib had a 44% increase in OS compared with those assigned placebo (median OS, 10.7 months vs. 7.9 months; HR = 0.69; 95% CI, 0.55-0.87).


“It was the first time we had a systemic therapy for HCC,” Llovet told Healio Gastroenterology. “People were standing up and clapping. It was very, very nice.”

These data ushered in a period of intense clinical development in liver cancer research, according to Finn.

“[The SHARP trial] showed that sorafenib improved survival by a median of about 3 months,” he said. “Tumors didn’t necessarily shrink, but it improved survival, which is ultimately the most important thing. It set the stage for progress. The results showed you can develop a drug for liver cancer, that you can be successful in a well-designed study.”

Still, the progress that followed moved slowly at first.

“We had 10 years of additional drugs being tested and all trials were negative. We were shocked,” Llovet said. “Some were negative because the drug was powerful but toxic, like sunitinib [Sutent, Pfizer], and others were not powerful enough.”

The next breakthrough occurred in April 2017.

Stivarga (regorafenib, Bayer) — a kinase inhibitor that works by blocking several enzymes that promote cancer growth — became the first FDA-approved treatment for advanced liver cancer since sorafenib. Sixteen months later, based on data from the phase 3 REFLECT trial, Lenvima (lenvatinib, Eisai) received FDA approval, becoming the first front-line therapy approved for unresectable HCC in a decade. Within a year, FDA approved two more multi-kinase inhibitors, Cabometyx (cabozantinib, Exelixis) and Cyramza (ramucirumab, Eli Lilly).

Three additional treatments received accelerated approval — the anti-PD-1 antibodies Opdivo (nivolumab, Bristol Myers Squibb) and Keytruda (pembrolizumab, Merck), and nivolumab plus the anti-CTLA-4 antibody Yervoy (ipilimumab, Bristol Myers Squibb) — although these approvals have been the subject of an FDA review.

After a decade-long drought, the tidal wave of drugs approved for HCC from 2017 to 2020 opened the window to a myriad of opportunities for advancing research and improving outcomes.

“We’ve learned some things from what we did during those negative studies in regard to trial design and the natural history of liver cancer,” Finn said. “It took time and trial and error to develop these more active drugs.”

Finn led the phase 3 IMbrave150 trial, which compared the PD-L1 inhibitor Tecentriq (atezolizumab, Genentech/Roche) plus the VEGF inhibitor Avastin (bevacizumab, Genentech/Roche) with sorafenib among patients with unresectable HCC. Results of the trial, published in May in The New England Journal of Medicine, are considered the next milepost in research and led to FDA approval of the combination for this patient population.

An updated analysis presented in January after median follow-up of 15.6 months showed the combination reduced the risk for death by 34% (median OS, 19.2 months vs. 13.4 months; HR = 0.66; 95% CI, 0.52-0.85).

“It’s the dawn of a new era of combinations, a true breakthrough,” Llovet said. “The first HR reported [from IMbrave150] was 0.58, which is outstanding. With longer follow-up there was some regression to the HR, to 0.66, which is still outstanding. The objective response rate of approximately 30% is very, very good.”

StephenW

https://www.healio.com/news/gast ... ;M_BT=2282221051954