PMID- 35950298 OWN - NLM STAT- MEDLINE DCOM- 20230522 LR - 20231213 IS - 1743-7563 (Electronic) IS - 1743-7555 (Linking) VI - 19 IP - 3 DP - 2023 Jun TI - Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter? PG - 312-319 LID - 10.1111/ajco.13837 [doi] AB - INTRODUCTION: Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. METHODS: Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). RESULTS: Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p = .28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p = .49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p = .66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p = .37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p = .097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p = .32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p = .20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p = .118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). CONCLUSION: Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option. CI - (c) 2022 John Wiley & Sons Australia, Ltd. FAU - Ng, Kennedy Yao Yi AU - Ng KYY AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. FAU - Wong, Lawrence Wen Jun AU - Wong LWJ AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. FAU - Ang, Andrea Jing Shi AU - Ang AJS AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. FAU - Lee, Ailica Wan Xin AU - Lee AWX AD - Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Tay, Desiree Shu Hui AU - Tay DSH AD - Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Tan, Jack Jie En AU - Tan JJE AD - Yong Loo Lin School of Medicine, National University of Singapore, Singapore. FAU - Tan, Sze Huey AU - Tan SH AD - Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, Singapore. AD - Oncology Academic Programme, Duke-NUS Medical School, Singapore. FAU - Choo, Su Pin AU - Choo SP AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. AD - Curie Oncology, Singapore. FAU - Tai, David Wai-Meng AU - Tai DW AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. AD - Oncology Academic Programme, Duke-NUS Medical School, Singapore. FAU - Lee, Joycelyn Jie Xin AU - Lee JJX AUID- ORCID: 0000-0002-1070-6125 AD - Division of Medical Oncology, National Cancer Centre Singapore, Singapore. AD - Oncology Academic Programme, Duke-NUS Medical School, Singapore. LA - eng GR - Bayer/ PT - Journal Article DEP - 20220810 PL - Australia TA - Asia Pac J Clin Oncol JT - Asia-Pacific journal of clinical oncology JID - 101241430 RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Tyrosine Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Humans MH - *Carcinoma, Hepatocellular/drug therapy MH - Immune Checkpoint Inhibitors/adverse effects MH - Tyrosine Kinase Inhibitors MH - Protein Kinase Inhibitors/adverse effects MH - Retrospective Studies MH - *Liver Neoplasms/drug therapy OTO - NOTNLM OT - hepatocellular carcinoma OT - immune checkpoint inhibitors OT - sequencing OT - tyrosine kinase inhibitors EDAT- 2022/08/12 06:00 MHDA- 2023/05/22 06:41 CRDT- 2022/08/11 03:03 PHST- 2021/04/01 00:00 [received] PHST- 2022/07/21 00:00 [accepted] PHST- 2023/05/22 06:41 [medline] PHST- 2022/08/12 06:00 [pubmed] PHST- 2022/08/11 03:03 [entrez] AID - 10.1111/ajco.13837 [doi] PST - ppublish SO - Asia Pac J Clin Oncol. 2023 Jun;19(3):312-319. doi: 10.1111/ajco.13837. Epub 2022 Aug 10.