Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (APOLLO): a randomised, controlled, phase 3 trial.

Anlotinib plus penpulimab has demonstrated encouraging activity and safety in a phase 2 study.

在一项2期研究中，阿洛替尼联合penpulimab显示出令人鼓舞的疗效和安全性。

In this phase 3 trial, we aimed to assess whether the combination of anlotinib plus penpulimab improved survival versus sorafenib in patients with unresectable HCC.

在这项III期试验中，我们旨在评估安罗替尼联合penpulimab是否能改善不可切除性肝细胞癌患者的生存期，与索拉非尼相比。

Methods

APOLLO was a multicentre, open-label, parallel-controlled, randomised, phase 3 trial conducted at 79 centres in China.

APOLLO是一项在中国79个中心进行的多中心、开放标签、平行对照、随机化的III期试验。

Patients aged 18-75 years with unresectable HCC, no previous systemic therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned (2:1) to anlotinib (10 mg orally once daily on days 1-14) plus penpulimab (200 mg intravenously on day 1), or sorafenib (400 mg orally twice daily) every 3 weeks.

年龄在18-75岁之间、无法切除的肝细胞癌（HCC）患者，之前未接受过系统治疗，且东部肿瘤协作组（ECOG）表现状态为0或1的患者，按2:1的比例随机分配至阿诺替尼（每日口服10毫克，第1-14天）加penpulimab（第1天静脉注射200毫克），或每3周口服索拉非尼（每日两次，每次400毫克）治疗。

Randomisation was done centrally using block randomisation with a fixed block size of 3 and stratified by the presence of macrovascular invasion or extrahepatic metastasis, α-fetoprotein concentration, and ECOG performance status.

随机分组是通过中心使用固定块大小为3的分层区组随机化方法进行的，根据是否存在大血管侵犯或肝外转移、α-胎儿蛋白浓度以及ECOG表现状态进行分层。

Sex (male or female) and ethnicity (Chinese or other) were self-reported.

性别（男性或女性）和种族（中国或其他）是自我报告的。

The co-primary endpoints were progression-free survivalassessed by masked independent review committee and overall survivalin the intention-to-treatpopulation.

共同主要终点是通过蒙面独立审查委员会评估的无进展生存期和意向治疗人群的总生存期。

Safety was assessed in all participants who received at least one dose of the study drug and had at least one recorded safety assessment.

对所有至少接受一次研究药物并至少有一次记录的安全性评估的参与者进行了安全性评估。

Final progression-free survivaland second interim overall survivalanalyses are presented.

呈现了最终无进展生存期和第二次中期总生存期的分析结果。

This trial is registered at ClinicalTrials.gov, NCT04344158, and follow-up is ongoing.

该试验已在ClinicalTrials.gov注册，编号为NCT04344158，随访正在进行中。

Results

From Aug 11, 2020, to June 20, 2023, 940 patients were screened for inclusion in the trial, 291 were excluded, and 649 were randomly assigned to an intervention (433 were assigned to the anlotinib plus penpulimab group and 216 were assigned to the sorafenib group. 551 (85%) of the 649 patients were male and 98 (15%) were female.

从2020年8月11日至2023年6月20日，共有940名患者被筛查以纳入试验，其中291名被排除，649名被随机分配到干预组（433名被分配到阿乐替尼加penpulimab组，216名被分配到索拉非尼组。649名患者中有551名（85%）为男性，98名（15%）为女性。

All patients were Chinese with a median age of 57 years (IQR 50-65).

所有患者均为中国人，中位年龄为57岁（四分位数间距50-65岁）。

For the final analysis of progression-free survival(June 5, 2023), 636 patients (424 patients in the anlotinib plus penpulimab group vs 212 patients in the sorafenib group) comprised the intention-to-treatpopulation.

在2023年6月5日的无进展生存期（progression-free survival，PFS）最终分析中，共有636名患者（阿乐替尼联合派姆单抗组424名患者对比索拉非尼组212名患者）构成了意向治疗人群。

For the second interim analysis of overall survival(Jan 29, 2024), 649 patients (433 vs 216) comprised the intention-to-treatpopulation.

在2024年1月29日进行的总生存期的第二次中期分析中，649名患者（433比216）构成了意向治疗人群。

Median follow-up was 6·2 months (IQR 5·5-7·5) for the anlotinib plus penpulimab group and 4·2 months (2·9-7·1) for the sorafenib group for final progression-free survivalanalysis, and 15·3 months (14·3-17·3) for the anlotinib plus penpulimab group and 14·5 months (11·5-17·0) for the sorafenib group for the second interim overall survivalanalysis.

在最终无进展生存期分析中，阿乐替尼联合penpulimab组的中位随访时间为6.2个月（四分位数间距5.5-7.5），而索拉非尼组为4.2个月（2.9-7.1）。在第二次中期总生存期分析中，阿乐替尼联合penpulimab组的中位随访时间为15.3个月（14.3-17.3），索拉非尼组为14.5个月（11.5-17.0）。

Median progression-free survivalwas significantly extended with anlotinib plus penpulimab versus sorafenib (6·9 months [95% CI 5·8-8·0] vs 2·8 months [2·7-4·1]; hazard ratio[HR] 0·52 [95% CI 0·41-0·66]; p<0·0001).

与索拉非尼相比，阿诺替尼联合penpulimab显著延长了中位无进展生存期（6.9个月 [95% 置信区间 5.8-8.0] 对比 2.8个月 [2.7-4.1]；风险比 [HR] 0.52 [95% 置信区间 0.41-0.66]；p<0.0001）。

Median overall survivalwas significantly prolonged with anlotinib plus penpulimab compared with sorafenib (16·5 months [95% CI 14·7-19·0] vs 13·2 months [9·7-16·9]; HR 0·69 [95% CI 0·55-0·87]; p=0·0014).

与索拉非尼相比，阿诺替尼联合penpulimab显著延长了中位总生存期（16.5个月 [95% 置信区间 14.7-19.0] 对比 13.2个月 [9.7-16.9]；风险比 [HR] 0.69 [95% 置信区间 0.55-0.87]；p=0.0014）。

The most common grade 3 or worse treatment-related adverse events were hypertension (75 [17%] patients in the anlotinib plus penpulimab group vs 22 [10%] in the sorafenib group) and decrease in platelet count (39 [9%] vs 13 [6%]).

最常见的3级或更严重的治疗相关不良事件是高血压（安罗替尼联合penpulimab组有75名[17%]患者，索拉非尼组有22名[10%]患者）和血小板计数减少（分别有39名[9%]和13名[6%]患者）。

Treatment-related serious adverse events occurred in 90 (21%) and 19 (9%) patients in the respective groups; treatment-related deaths occurred in one (<1%) patient in the anlotinib plus penpulimab group (upper gastrointestinal haemorrhage) and two (1%) patients in the sorafenib group (hepatic failure and death of unknown cause).

治疗相关严重不良事件分别发生在90名（21%）和19名（9%）患者中；治疗相关死亡发生在安罗替尼联合penpulimab组的1名（<1%）患者（上消化道出血）和索拉非尼组的2名（1%）患者（肝功能衰竭和不明原因死亡）。

interpretation

Anlotinib plus penpulimab significantly improved progression-free survivaland overall survivalversus sorafenib in unresectable HCC and might be a new first-line option.

阿诺替尼联合penpulimab显著改善了不可切除HCC患者的无进展生存期和总生存期，与索拉非尼相比，可能成为新的首选一线治疗方案。

These findings require verification in other regions of the world.

这些发现需要在世界其他地区进行验证。

funding

Chia Tai Tianqing Pharmaceutical Group.

正大天晴药业集团。