肿瘤瞭望消化时讯

ESMO IO 2023｜肝癌免疫治疗最新研究进展

肿瘤瞭望消化时讯

编者按：2023年ESMO IO大会（ESMO Immuno-Oncology Congress 2023）已于12月6—8日在瑞士日内瓦召开，会议汇集了全球范围内肿瘤学专家，共同交流探讨肿瘤免疫治疗的前沿内容。现整理了入选的5项肝癌研究，以飨读者！


LBA4 - Low-dose stereotactic body radiotherapy prior to pre-operative cemiplimab for patients with resectable hepatocellular carcinoma可切除肝细胞癌患者术前低剂量立体定向放疗序贯cemiplimab

研究背景

免疫检查点抑制剂（ICIs）是晚期肝细胞癌（HCC）的标准治疗方案。在HCC和其他肿瘤中进行的小型试验评估了立体定向体放疗（SBRT）对诱导免疫原性细胞死亡和增强ICI活性的作用。早期HCC通常手术切除，但70%的患者会复发。我们之前发表了第一项使用cemiplimab（PD-1抑制剂，西米普利单抗）治疗可切除HCC的围手术期研究，结果显示，在2剂西米普利单抗治疗后，35%的患者出现≥50%的坏死。在这里，我们提出了第一个研究早期HCC患者在ICIs前低剂量SBRT的试验。

研究方法

在这项单臂、开放标签的2期试验（NCT03916627）中，可切除的HCC的成年患者接受SBRT （8Gy x 3次），然后在手术切除前接受2个周期350 mg的新辅助西米普利单抗（每3周1周期）和8个周期的辅助西米普利单抗。主要终点是显著的肿瘤坏死（STN；切除的肿瘤中有>70%坏死）。次要终点包括总反应率、不良事件发生率（ae）和淋巴细胞浸润的变化。在治疗期间，患者接受治疗前活检和连续采血进行探索性分析，包括多重免疫组织化学和单细胞蛋白质组学和转录组学分析。数据截止日期为2023年9月15日；包括1例患者在数据截止后获得的手术结果。

研究结果

从2021年12月到2023年8月，20名患者入组：中位年龄为65岁，80%为男性，50%为亚洲人，85%有病毒性肝炎病史。16例接受手术切除的患者中，3例（19%）实现STN, 2例（13%）肿瘤完全坏死；6例（38%）肿瘤坏死≥50%。最常见的不良反应是贫血（35%）、转氨酶升高（30%）和高血糖（30%）。新辅助治疗期间未发生≥3级治疗相关不良事件。

研究结论

这是首个报告SBRT + ICIs治疗可切除HCC患者疗效的临床试验。病理反应率与单独使用西米普利单抗观察到的相似。计划的深部组织和血液分析将用于确定该组合与单用西米普利单抗相比的免疫动力学效应。临床试验信息：NCT03916627。


89P - Hepatic arterial infusion chemotherapy sequential transarterial embolization combined with lenvatinib and tislelizumab in patients with high-risk unresectable hepatocellular carcinoma: a single arm phase 2 trial肝动脉灌注化疗序贯经动脉栓塞联合仑伐替尼和替雷利珠单抗治疗高危不可切除肝细胞癌：单臂2期试验

研究背景

肝动脉灌注化疗（HAIC）、经肝动脉栓塞（TAE）和仑伐替尼是不可切除肝细胞癌（HCC）的主要治疗方法。本研究旨在评估HAIC序贯TAE联合仑伐替尼和替雷利珠单抗（PD-1抑制剂）一线治疗高危不可切除HCC患者的安全性和有效性。

研究方法

这是一项单臂、开放标签、2期试验（NCT05532319），正在进行中。符合条件的高危不可切除HCC （CNLC Ib，II和III期），ECOG PS为0或1分且肝功能足够的患者接受至少一个周期的HAIC序贯TAE（每4周）联合仑伐替尼和替雷利珠单抗（每3周静脉注射200mg）。主要终点是6个月时的无进展生存（PFS）率。次要终点包括客观缓解率（ORR）、接受根治性治疗的患者比例、显著肿瘤坏死、PFS、OS和安全性。

研究结果

在2022年11月1日至2023年8月12日期间，纳入了35例高危不可切除HCC患者。14例（40%）患者的肿瘤负荷超过肝脏体积的50%。6个月的PFS率为83.6%。HAIC序贯TAE一个周期后的ORR为31.9%（15/47，RECIST 1.1）和63.8%（30/47，mRECIST）。两个周期HAIC序贯TAE后的ORR分别为35.1%（26/40，RECIST 1.1）和80.0%（32/40，mRECIST）。部分缓解后接受根治性治疗19例（54.3%），其中根治性肝切除10例（28.6%），放疗6例（17.1%），射频消融2例（5.7%），肝移植1例（2.9%）。术后组织病理学显示，接受完全肝切除术的患者100%的肿瘤出现明显的肿瘤坏死。中位PFS和OS均未达到。大多数不良事件为1级或2级。最常见的是血小板减少症（22.9%）、谷丙转氨酶升高（20%）和血清白蛋白降低（17.1%）。

研究结论

HAIC序贯TAE联合仑伐替尼和替雷利珠单抗是治疗高危不可切除HCC的一种安全有效的方式。


90P - HAIC plus sintilimab and bevacizumab biosimilar as treatment for patients with advanced hepatocellular carcinoma (HCC): a phase II trialHAIC联合信迪利单抗和贝伐单抗生物类似药治疗晚期肝细胞癌（HCC）：一项II期试验

研究背景

在ORIENT-32研究中，信迪利单抗（PD-1抑制剂）和贝伐珠单抗生物类似物（bev）联合治疗显示出出色的疗效和安全性，HAIC在研究中表现出令人印象深刻的肿瘤应答。我们评估了联合治疗作为初始不可切除HCC一线治疗的有效性和安全性。

研究方法

该研究是一项正在进行的开放标签、单臂、II期试验。BCLC B期或C期初始不可切除HCC患者（pts）纳入了这项II期试验。符合条件的患者每3周接受信迪利单抗（200mg, IV, D1）和bev（15 mg/kg,IV,D1）治疗，以及每3-6周接受FOLFOX-HAIC治疗。符合切除条件的患者在bev停药至少4周后进行肝切除术。信迪利单抗和bev一直使用到疾病进展或不可接受的毒性或长达24个月，FOLFOX-HAIC使用3-6次。主要终点是RECIST v1.1标准的无进展生存期（PFS），关键次要终点包括客观缓解率（ORR）、疾病控制率（DCR）、手术转化率、病理反应、总生存期（OS）和安全性。

研究结果

截至2023年7月25日数据截止，共有43名患者入组，其中41名患者至少接受了一个疗程的治疗，38名患者接受了至少一次肿瘤评估。中位随访时间为6.34个月（0.2~14.62个月）。没有达到mPFS和mOS。根据RECIST v1.1, ORR和DCR分别为68.42%和100% (26 PR和12 SD)。基于mRECIST的ORR和DCR分别为86.84%和100% (8 CR, 25 PR和5 SD)。10例患者符合肝切除术标准，6例患者行肝切除术。在这6名患者中，入组前5名患者处于IIIA期，1名患者处于IIIB期。无术后死亡率。大多数治疗相关不良事件（TRAE）为1-2级，3级TRAE发生率为14.63%。3级TRAEs包括血小板计数下降、高血压、ALT升高、白细胞计数下降、皮疹、脑出血和上消化道出血。

研究结论

采用HAIC联合信迪利单抗和贝伐珠单抗类似物一线治疗初始不可切除HCC的全身治疗耐受性良好且有效。更长的随访正在进行中。临床试验信息：ChiCTR2000034758。


91P - A real-world study of tislelizumab (Anti-PD-1) plus tyrosine kinase inhibitors for intermediate or advanced hepatocellular carcinoma替雷利珠单抗（PD-1抑制剂）联合酪氨酸激酶抑制剂治疗中晚期肝细胞癌的真实世界研究

研究背景

目前缺乏阐明替雷利珠单抗联合酪氨酸激酶抑制剂（TKIs）治疗肝细胞癌（HCC）的有效性和安全性的数据。在此，我们探索了真实世界中替雷利珠单抗加TKIs治疗中晚期HCC患者（pts）的方案。

研究方法

在这项研究中，在2021年7月至2023年7月期间纳入了73名患者。患者被分配替雷利珠单抗+ TKIs (n=33)，或替雷利珠单抗+TKIs+TACE (n=40)，其中TKIs包括仑伐替尼(49.3%)，瑞戈非尼(23.3%)，多纳非尼(21.9%)，阿帕替尼(2.7%)和安罗替尼(2.7%)。主要终点是客观缓解率（ORR, mRECIST标准）和无进展生存期（PFS）。次要终点包括6个月和12个月的PFS率、疾病控制率（DCR）和安全性。

研究结果

73例患者中，男性占80.8%，BCLC B期占53.4%，Child-Pugh A期占75.3%，一线治疗占69.9%，平均年龄62.8岁。所有患者的平均随访时间为13.3个月（95% CI: 11.9-14.8），平均TACE治疗次数为0.8次（范围0-3）。ORR和DCR分别为42.5%和79.5%，中位PFS为12.6个月（95%CI: 8.71-16.49），6个月和12个月PFS分别为69.6%和50.4%。与替雷利珠单抗+TKIs组相比，替雷利珠单抗+TKIs+TACE组获得了更长的中位PFS(12.7个月(95%CI：9.17-16.23) vs. 8.4个月(95%CI：4.83-11.97)，P=0.132)，更高的ORR (55.0% vs. 27.3%， P=0.017)和DCR(87.5% vs. 69.7%，P=0.061)。59例（80.8%）患者报告了任何级别的治疗相关不良事件（TRAE），16例（21.9%）患者出现3级TRAE。最常见的TRAE（≥10%）包括手足综合征（24.7%）、转氨酶升高（15.1%）、高胆红素血症（13.7%）、腹泻（13.7%）和发烧（11.0%）。发生率超过5%的3级TRAEs包括手足综合征（8.2%），转氨酶升高（6.8%）。未发现4/5级TRAE和新的安全信号。

研究结论

替雷利珠单抗联合TKIs和TACE似乎为中晚期HCC患者提供令人鼓舞的疗效和可接受的安全性。进一步的患者招募和更长时间的随访是必要的。


92P - TAE-HAIC plus lenvatinib and PD-1 inhibitors versus TAE-HAIC plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: A propensity score matching studyTAE-HAIC联合仑伐替尼和PD-1抑制剂与TAE-HAIC联合阿替利珠单抗和贝伐珠单抗治疗不可切除的肝细胞癌：一项倾向评分匹配研究

研究背景

全身治疗联合经动脉为基础的治疗对不可切除的HCC有很好的效果。阿替利珠单抗+ 贝伐珠单抗（“T+A”）是晚期HCC的标准一线治疗方案，而仑伐替尼联合程序性死亡-1（PD-1）抑制剂也具有协同抗肿瘤作用。本研究旨在比较TAE-HAIC联合仑伐替尼和PD-1抑制剂与TAE-HAIC联合“T+A”治疗不可切除HCC的疗效和安全性。

研究方法

在这项回顾性研究中，初始不可切除的HCC患者接受了TAE-HAIC加仑伐替尼和PD-1抑制剂（THLP组）或TAE-HAIC加“T+A”（THTA组）的治疗。主要终点是总生存期（OS）。次要结局包括无进展生存期（PFS）和肿瘤反应（mRECIST），以及不良事件（AE）。我们采用倾向性评分匹配（PSM）方法来减少两组之间的偏差。

研究结果

从2020年6月到2023年6月，共有339例患者入组，其中THLP组233例，THTA组106例。按3:1的比例PSM后，分别将153例和51例患者分配到THLP组和THAT组。THLP组的中位OS更长(21.3个月 vs. 18.2个月；P=0.486)，而THTA组的中位PFS更长(6.8个月 vs. 6.3个月；P=0.552)，两者无统计学差异。两组的客观反应率(ORR)无统计学差异(73.3% vs. 68.3%；P=0.635)和疾病控制率(DCR)(91.7% vs. 89.3%；P=0.716)。两组3/4级AE发生率无显著差异，并且AE均可控制。两组均未发生与治疗相关的5级AE。

研究结论

TAE-HAIC联合仑伐替尼和PD-1抑制剂与TAE-HAIC联合“T+A”治疗不可切除HCC的结果相似，并且表现出可接受的毒性反应，这需要更大规模的随机临床试验来验证。

摘要原文

LBA4 - Low-dose stereotactic body radiotherapy prior to pre-operative cemiplimab for patients with resectable hepatocellular carcinoma

Background

Immune checkpoint inhibitors (ICIs) are the standard of care for advanced hepatocellular carcinoma (HCC). Small trials in HCC and other tumours have evaluated the addition of stereotactic body radiotherapy (SBRT) to induce immunogenic cell death and augment ICI activity. Early-stage HCC is often surgically resected but recurrence occurs in ∼70% of patients. We previously presented the first study of perioperative ICI using cemiplimab in resectable HCC and showed ≥50% necrosis in 35% of patients after 2 doses of cemiplimab. Here we present the first trial to investigate low-dose SBRT prior to ICIs in patients with early-stage HCC.

Methods

In this single-arm, open-label phase 2 trial (NCT03916627), adults with resectable HCC tumours received SBRT (8Gy x3 fractions), then 2 cycles of neoadjuvant cemiplimab 350 mg every 3 weeks before surgical resection and 8 cycles of adjuvant cemiplimab. The primary endpoint was significant tumour necrosis (STN; >70% necrosis of the resected tumour). Secondary endpoints included overall response rate, incidence of adverse events (AEs) and change in lymphocyte infiltration. Patients had pre-treatment biopsies and serial blood collection during treatment for exploratory analyses, including multiplex immunohistochemistry and single-cell proteomic and transcriptomic analysis. Data cutoff was 15 Sep 2023; surgical results obtained from 1 patient after the data cutoff are included.

Results

20 patients were enrolled from Dec 2021 to Aug 2023: median age was 65 years, 80% were male, 50% were Asian, and 85% had a history of viral hepatitis. Of 16 patients who underwent surgical resection 3 (19%) achieved STN, 2 (13%) of which had complete tumour necrosis; in total, 6 (38%) had ≥50% tumour necrosis. Most common AEs were anaemia (35%), elevated transaminases (30%) and hyperglycemia (30%). No Grade ≥3 treatment-related AEs occurred during neoadjuvant therapy.

Conclusions

This is the first clinical trial to report efficacy of SBRT + ICIs in patients with resectable HCC. Pathologic response rates were similar to those observed with cemiplimab alone. Planned deep tissue and blood analyses will be used to define the immunodynamic effects of this combination compared to cemiplimab alone.

Clinical trial identification

NCT03916627.


89P - Hepatic arterial infusion chemotherapy sequential transarterial embolization combined with lenvatinib and tislelizumab in patients with high-risk unresectable hepatocellular carcinoma: a single arm phase 2 trial

Background

Hepatic arterial infusion chemotherapy (HAIC), transarterial embolization (TAE), and lenvatinib are main treatments in unresectable hepatocellular carcinoma (HCC). This study aims to evaluate the safety and efficacy of HAIC sequential TAE combined with lenvatinib and tislelizumab (an anti-PD-1) as a first-line treatment in patients with high-risk unresectable HCC.

Methods

This is a single-arm, open-label, phase 2 trial (NCT05532319), which is ongoing. Eligible patients with high-risk unresectable HCC (CNLC stage Ib, II and III), ECOG performance status of 0 or 1 and adequate liver function received at least one cycle of HAIC sequential TAE (every 4 weeks) combined with lenvatinib and tislelizumab (200 mg intravenously every 3 weeks). The primary endpoint was the progression-free survival (PFS) rate at six months. Secondary endpoints included objective response rate (ORR), the proportion of patients who underwent curative treatments, significant tumour necrosis, PFS, OS and safety.

Results

Between Nov 1, 2022 and Aug 12, 2023, 35 patients with high-risk unresectable HCC were enrolled. The tumour load of 14 (40%) patients exceeds 50% of the liver volume. The PFS rate at six months was 83.6%. The ORR after one cycle of HAIC sequential TAE was 31.9% (15/47, RECIST 1.1) and 63.8% (30/47, mRECIST). The ORR after two cycle of HAIC sequential TAE was 35.1% (26/40, RECIST 1.1) and 80.0% (32/40, mRECIST). 19 patients (54.3%) received curative treatment after reaching partial response, including 10 (28.6%) curative hepatic resection, 6 (17.1%) radiotherapy, 2 (5.7%) radiofrequency ablation and 1 (2.9%) liver transplantation. Significant tumour necrosis was observed in 100% tumours based on postoperative histopathology in patients who received completed hepatectomy. Median PFS and OS were not reached. Most adverse events were grade 1 or 2. The most common were thrombocytopenia (22.9%), alanine aminotransferase elevating (20%) and serum albumin decreasing (17.1%).

Conclusions

HAIC sequential TAE combined with lenvatinib and tislelizumab is a safe and effective treatment modality in patient with high-risk unresectable HCC.


90P - HAIC plus sintilimab and bevacizumab biosimilar as treatment for patients with advanced hepatocellular carcinoma (HCC): a phase II trial

Background

The combination treatment using sintilimab (a PD-1 antibody) and bevacizumab (bev) biosimilar demonstrated excellent efficacy and safety in ORIENT-32 study and HAIC performed impressive tumor response in researches. We assessed the efficacy and safety of the combination therapy as first-line treatment for initial unresectable HCC.

Methods

The study was an ongoing open-label, single-arm, phase II trial. Treatment-naïve HCC patients (pts) with initial unresectable and BCLC stage B or C were enrolled in this phase II trial. Eligible pts received sintilimab (200 mg, IV, D1) and bev (15 mg/kg, IV, D1) per 3 weeks, as well as FOLFOX-HAIC per 3-6 weeks. Pts eligible for resection were referred for hepatectomy after bev weaned over at least a 4-week period. Sintilimab and bev were given until disease progression or unacceptable toxicity or up to 24 months, and FOLFOX-HAIC were given 3-6 times. Primary endpoints were progression-free survival (PFS) per RECIST v1.1 and key secondary endpoints included objective response rate (ORR), disease control rate (DCR), surgical conversion rate, pathologic response, overall survival (OS) and safety.

Results

At data cutoff on July 25, 2023, 43 pts were enrolled, 41 of them underwent at least one course of treatment and 38 enrollees received at least one tumor assessment. The median follow-up time was 6.34 months (range 0.2–14.62). mPFS and mOS were not reached. According to RECIST v1.1, ORR and DCR were 68.42% and 100% (26 PR and 12 SD). Moreover, ORR and DCR were 86.84% and 100% (8 CR, 25 PR and 5 SD) based on mRECIST, respectively. 10 pts met the criteria for hepatectomy and 6 pts received liver resection. Among this 6 pts, 5 pts was in stage IIIA and 1 in IIIB before enrollment. No postoperative mortality was observed. Most treatment-related AEs (TRAE) were grade 1-2, and the incidence of grade 3 TRAEs was 14.63%. Grade 3 TRAEs includes decreased platelet count, hypertension, increased ALT, decreased white blood cell count, rash, hematencephalon and upper gastrointestinal hemorrhage.

Conclusions

Systemic therapy using HAIC plus Sintilimab and bev as first-line therapy for initial unresectable HCC was well tolerated and effective. Longer follow up is ongoing.

Clinical trial identification

ChiCTR2000034758.

91P - A real-world study of tislelizumab (Anti-PD-1) plus tyrosine kinase inhibitors for intermediate or advanced hepatocellular carcinoma

Background

Data on elucidating the efficacy and safety of tislelizumab combined with tyrosine kinase inhibitors (TKIs) in hepatocellular carcinoma (HCC) are lacking. Herein, we explored the regimen of tislelizumab plus TKIs for intermediate or advanced HCC patients (pts) in a real-world setting.

Methods

In this study, 73 pts were included between Jul. 2021 and Jul. 2023. Pts were assigned either with tislelizumab plus TKIs (n=33), or tislelizumab plus TKIs plus TACE (n=40), where TKIs included lenvatinib (49.3%), regorafenib (23.3%), donafenib (21.9%), apatinib (2.7%) and anlotinib (2.7%). The primary endpoints were objective response rate (ORR, mRECIST criteria) and progression-free survival (PFS). The secondary endpoints included 6-month and 12-month PFS rates, disease control rate (DCR) and safety.

Results

Among the 73 pts, 80.8% were male, 53.4% had BCLC stage B, 75.3% were Child-Pugh A, 69.9% were first-line recipients and the average age was 62.8 years. The mean follow-up period was 13.3 (95% CI: 11.9-14.8) months and the mean number of TACE sessions were 0.8 (range 0-3) for all patients. The ORR and DCR were 42.5% and 79.5% with a median PFS of 12.6 months (95% CI: 8.71-16.49) and the 6-month, 12-month PFS rates were 69.6% and 50.4%. Compared to the tislelizumab plus TKIs group, the tislelizumab plus TKIs plus TACE group achieved longer median PFS (12.7 months (95% CI 9.17-16.23) vs. 8.4 months (95% CI 4.83-11.97), P=0.132), higher ORR (55.0% vs 27.3%, P = 0.017) and DCR (87.5% vs 69.7%, P = 0.061). Any-grade TRAEs were reported in 59 (80.8%) pts, and grade 3 TRAEs were reported in 16 (21.9%) pts. Most frequent TEAEs (≥10%) included hand-foot syndrome (24.7%), increased transaminase (15.1%), hyperbilirubinemia (13.7%), diarrhea (13.7%) and fever (11.0%). G3 TRAEs occurred in more 5% pts included hand-foot syndrome (8.2%), increased transaminase (6.8%). No grade 4/5 TRAE and new safety signal were identified.

Conclusions

Tislelizumab plus TKIs with TACE appeared to deliver encouraging efficacy and acceptable safety for pts with intermediate or advanced HCC. Further patient recruitment and longer follow up are warranted.


92P - TAE-HAIC plus lenvatinib and PD-1 inhibitors versus TAE-HAIC plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: A propensity score matching study

Background

Systemic therapy combined with transarterial-based therapy has demonstrated promising results for unresectable HCC. Atezolizumab plus bevacizumab (“T+A”) is the standard first-line therapeutic regimen for advanced HCC, while lenvatinb combined programmed death-1 (PD-1) inhibitors shows synergistic anti-tumor effect as well. This study aims to compare the efficacy and safety of TAE-HAIC plus lenvatinib and PD-1 inhibitors versus TAE-HAIC plus “T+A” for unresectable HCC.

Methods

In this retrospective study, treatment-naïve unresectable HCC patients who were treated with TAE-HAIC plus lenvatinib and PD-1 inhibitors (THLP group) or TAE-HAIC plus “T+A” (THTA group) were included. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS) and tumor response according to modified RECIST, and adverse events (AEs). We performed propensity score matching (PSM) approaches to reduce bias between two groups.

Results

From June 2020 to June 2023, 339 patients were enrolled in this study: 233 in the THLP group and 106 in the THTA group. After PSM with a ratio of 3:1, 153 and 51 patients were assigned to the THLP and THAT group, respectively. The THLP group showed a longer median OS (21.3 versus 18.2 months; P = 0.486), while median PFS was longer in the THTA group (6.8 versus 6.3 months; P = 0.552), both without statistical differences. There were no statistical differences in objective response rate (ORR) (73.3% versus 68.3%; P =0.635) and disease control rate (DCR) (91.7% versus 89.3%; P =0.716) neither. No significant difference in the rate of the grade 3/4 AEs was observed between the two groups, and all AEs were controllable. No treatment-related grade 5 AE took place in the two groups.

Conclusions

TAE-HAIC plus lenvatinib and PD-1 inhibitors or TAE-HAIC plus “T+A” demonstrated similar outcomes for unresectable HCC with acceptable toxic effects, which needs to be validated with larger-scale randomized clinical trials.

相关推荐