Rossari Federico, Tada Toshifumi, Suda Goki, Shimose Shigeo, Kudo Masatoshi, Yoo Changhoon, Cheon Jaekyung, Finkelmeier Fabian, Lim Ho Yeong, Presa José, Masi Gianluca, Bergamo Francesca, Amadeo Elisabeth, Vitiello Francesco, Kumada Takashi, Sakamoto Naoya, Iwamoto Hideki, Aoki Tomoko, Chon Hong Jae, Himmelsbach Vera, Iavarone Massimo, Cabibbo Giuseppe, Montes Margarida, Foschi Francesco Giuseppe, Vivaldi Caterina, Soldà Caterina, Sho Takuya, Niizeki Takashi, Nishida Naoshi, Steup Christoph, Hirooka Masashi, Kariyama Kazuya, Tani Joji, Atsukawa Masanori, Takaguchi Koichi, Itobayashi Ei, Fukunishi Shinya, Tsuji Kunihiko, Ishikawa Toru, Tajiri Kazuto, Ochi Hironori, Yasuda Satoshi, Toyoda Hidenori, Ogawa Chikara, Nishimura Takashi, Hatanaka Takeshi, Kakizaki Satoru, Shimada Noritomo, Kawata Kazuhito, Hiraoka Atsushi, Tada Fujimasa, Ohama Hideko, Nouso Kazuhiro, Morishita Asahiro, Tsutsui Akemi, Nagano Takuya, Itokawa Norio, Okubo Tomomi, Imai Michitaka, Kosaka Hisashi, Naganuma Atsushi, Koizumi Yohei, Nakamura Shinichiro, Kaibori Masaki, Iijima Hiroko, Hiasa Yoichi, Persano Mara, Foti Silvia, Camera Silvia, Stefanini Bernardo, Scartozzi Mario, Cascinu Stefano, Casadei-Gardini Andrea, Rimini Margherita
Department of Oncology, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.
Liver Cancer. 2024 Apr 10;13(5):522-536. doi: 10.1159/000537915. eCollection 2024 Oct.
The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab (A + B) is equally effective in viral and nonviral patients.
We retrospectively analyzed 885 HCC patients treated with the first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% nonviral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multivariate models to explore potential differences on overall survival (OS), time-to-progression (TTP), disease control rates (DCRs) based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to the second-line treatments and outcomes were also reported and compared between etiologies.
Overall, no statistically significant differences were found in median OS (mOS: viral 15.9 months; nonviral 16.3 months), TTP (mTTP: viral 8.3 months; nonviral 7.2 months), and DCRs (viral 78.1%; nonviral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and nonviral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e., NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of the second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups.
Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and nonviral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.
晚期肝细胞癌（HCC）病因对免疫治疗反应的影响存在争议，IMbrave - 150试验早期和近期的事后分析以及PD - 1/PD - L1阻滞剂临床试验的荟萃分析结果相互矛盾。因此，尚不清楚一线全身治疗阿替利珠单抗联合贝伐单抗（A + B）在病毒感染和非病毒感染患者中是否同样有效。
我们回顾性分析了来自东西方多个中心接受一线A + B治疗的885例HCC患者，其中53.9%为病毒感染病因，46.1%为非病毒感染病因。采用单因素和多因素模型分析基线临床和实验室特征，以探讨基于病因的总生存期（OS）、疾病进展时间（TTP）、疾病控制率（DCR）的潜在差异，并确定病因亚组中的假定预后因素。还报告并比较了不同病因的治疗毒性、二线治疗的使用情况及结果。
总体而言，基于病因的中位OS（mOS：病毒感染患者15.9个月；非病毒感染患者16.3个月）、TTP（mTTP：病毒感染患者8.3个月；非病毒感染患者7.2个月）和DCR（病毒感染患者78.1%；非病毒感染患者80.8%）均未发现统计学上的显著差异。生存和进展的预后因素在病毒感染和非病毒感染病因中主要相同，包括甲胎蛋白、天冬氨酸转氨酶、中性粒细胞与淋巴细胞比值（NLR）和ALBI评分。探索性分析强调，免疫因素（即NLR和嗜酸性粒细胞计数）与病毒感染患者的治疗结果可能存在更强的关联。两个病因亚组的毒性特征、二线治疗的使用情况和类型及其OS结果几乎重叠。
在多中心、真实世界人群中，阿替利珠单抗联合贝伐单抗的疗效不会因HCC的潜在病因不同而有所差异，这与IMbrave - 150试验近期的事后分析结果一致。初步分析表明，病毒感染和非病毒感染患者之间的一些预后因素存在差异，这可能是由于生物学和免疫学差异所致。有必要进行按病因分层的前瞻性和对比试验，以验证这些发现并指导临床实践。
