{"doi":"10.1159/000520278","title":"First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials","abstract":"INTRODUCTION: Atezolizumab (ATEZO) plus bevacizumab (BEVA) represents the new standard of care for the treatment of advanced hepatocellular carcinoma (HCC). However, the choice of the second-line treatment after the failure of immunotherapy-based first-line remains elusive. Taking into account the weaknesses of the available evidence, we developed a simulation model based on available phase III randomized clinical trials (RCTs) to identify optimal risk/benefit sequential strategies. METHODS: A Markov model was built to estimate the overall survival (OS) of sequential first- and second-line systemic treatments. Sequences starting with first-line ATEZO plus BEVA followed by 5 second-line treatments (sorafenib [SORA], lenvatinib [LENVA], regorafenib, cabozantinib, and ramucirumab) were compared. The probability of transition between states (initial treatment, cancer progression, and death) was derived from RCTs. Life-year gained (LYG) was the main outcome. Rates of severe adverse events (SAEs) (≥ grade 3) were calculated. The incremental safety-effectiveness ratio (ISER) was calculated as the difference in probability of SAEs divided by LYG between the 2 most effective sequences. RESULTS: ATEZO plus BEVA followed by LENVA (median OS, 24 months) or SORA (median OS, 23 months) was the most effective sequence, producing a LYG of 0.50 and 0.42 year, respectively. ATEZO plus BEVA followed by SORA was the safest sequence (SAEs 63%). At a willingness-to-risk threshold of 10% of SAEs for LYG, ATEZO plus BEVA followed by second-line SORA was favored in 72% of cases, while at a threshold of 30% of SAEs for LYG, ATEZO plus BEVA followed by second-line LENVA was favored in 69% of cases. CONCLUSION: Our simulation model provides a strong rationale to support ongoing trials evaluating second-line tyrosine-kinase inhibitors after first-line ATEZO plus BEVA. Future evidence from ongoing RCTs and prospective real-world studies are needed to prove the net health benefit of sequential treatment options for advanced HCC.","journal":"Liver Cancer","year":2021,"id":157554,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":50,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":614172,"name":"María Reig","orcid":"0000-0002-5711-9534","position":1,"is_corresponding":false},{"id":664716,"name":"Ciro Celsa","orcid":"0000-0002-5662-2162","position":2,"is_corresponding":false},{"id":664717,"name":"Ferràn Torres","orcid":"0000-0002-7355-7913","position":3,"is_corresponding":false},{"id":664718,"name":"Salvatore Battaglia","orcid":"0000-0002-2867-917X","position":4,"is_corresponding":false},{"id":664719,"name":"Marco Enea","orcid":"0000-0002-9281-5746","position":5,"is_corresponding":false},{"id":664720,"name":"Giacomo Emanuele Maria Rizzo","orcid":"0000-0001-9335-6740","position":6,"is_corresponding":false},{"id":664721,"name":"Salvatore Petta","orcid":"0000-0002-0822-9673","position":7,"is_corresponding":false},{"id":625133,"name":"Vincenza Calvaruso","orcid":"0000-0002-0287-1059","position":8,"is_corresponding":false},{"id":664722,"name":"V. Di Marco","orcid":"0000-0001-6397-4206","position":9,"is_corresponding":false},{"id":40956,"name":"Antonio Craxı̀","orcid":"0000-0002-4480-9544","position":10,"is_corresponding":false},{"id":106840,"name":"Amit G. Singal","orcid":"0000-0002-1172-3971","position":11,"is_corresponding":false},{"id":85713,"name":"Jordi Bruix","orcid":"0000-0002-9826-0753","position":12,"is_corresponding":false},{"id":664723,"name":"Calogero Cammà","orcid":"0000-0002-9224-1914","position":13,"is_corresponding":false},{"id":664715,"name":"Giuseppe Cabibbo","orcid":"0000-0002-0946-3859","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:44:21.786014Z","pmid":"35222509","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}