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Ipilimumab and Nivolumab/Pembrolizumab In Open access Original research J Immunother Cancer: first published as 10.1136/jitc-2020-001945 on 9 February 2021. Downloaded from Ipilimumab and nivolumab/ pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors 1 1 1 Jeffrey Sum Lung Wong , Gerry Gin Wai Kwok, Vikki Tang, Bryan Cho Wing Li,1 Roland Leung,1 Joanne Chiu,1 Ka Wing Ma,2 Wong Hoi She,2 Josephine Tsang,1 Chung Mau Lo,2 Tan To Cheung,2 Thomas Yau1 To cite: Wong JSL, Kwok GGW, ABSTRACT overexpression of immune checkpoints Tang V, et al. Ipilimumab and Background Programmed cell death protein 1 (PD-1) including the programmed cell death nivolumab/pembrolizumab pathway blockade with immune checkpoint inhibitors protein 1 (PD-1) pathway and programmed in advanced hepatocellular (ICIs) is a standard therapy in advanced hepatocellular carcinoma refractory to prior death ligand 1 (PDL-1), and the cytotoxic carcinoma (HCC) nowadays. No strategies to overcome immune checkpoint inhibitors. T- lymphocyte- associated protein 4 (CTLA-4) ICI resistance have been described. We aimed to evaluate Journal for ImmunoTherapy pathway. This results in reduction of prolif- the use of ipilimumab and anti-PD-1 ICIs (nivolumab or of Cancer 2021;9:e001945. eration, inhibition of activation and func- doi:10.1136/jitc-2020-001945 pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs. tional exhaustion of T cells leading to tumor immune escape. Targeting these character- ► Additional material is Methods Patients with advanced HCC with documented published online only. To view tumor progression on prior ICIs and subsequently received istics, immune checkpoint inhibitors (ICIs) please visit the journal online ipilimumab with nivolumab/pembrolizumab were analyzed. have significantly advanced the systemic (http:// dx. doi. org/ 10. 1136/ jitc- Objective response rate (ORR), median duration of treatment of inoperable, advanced HCC. 2020- 001945). response (DOR), time-to- progression (TTP), overall survival Nivolumab, an anti- PD-1 antibody, demon- (OS), and treatment-rela ted adverse events (TRAEs) were strated good efficacy and safety as second- The American Society of Clinical assessed. Oncology 2021 Gastrointestinal line treatment for advanced HCC in the Results Twenty-five patients were included. The median 2 Cancer Symposium. age was 62 (range: 51–83). About 68% were of Child-Pugh CheckMate-040 trial. Nivolumab as first- line (CP) Grade A and 48% had primary resistance to prior ICI. treatment for advanced HCC also demon- Accepted 26 December 2020 At median follow- up of 37.7 months, the ORR was 16% strated clinical benefits when compared http://jitc.bmj.com/ with a median DOR of 11.5 months (range: 2.76–30.3). with sorafenib in the CheckMate-459 trial, Three patients achieved complete response. The median although statistical significance was not TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS obtained.3 In addition, pembrolizumab was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, received accelerated regulatory approval 2 year and 3 year survival rates were 42.4%, 32.3% for second-line treatment of advanced HCC and 21.6%, respectively. The ORR was 16.7% in primary based on the Keynote-224 trial.4 Nevertheless, on September 24, 2021 by guest. Protected copyright. resistance group and 15.4% in acquired resistance group in the subsequent Keynote-240 trial, both the (p=1.00). All responders were of CP A and Albumin- Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were median progression- free survival (PFS) and significantly associated with OS (p=0.006 and p<0.001, overall survival (OS) of pembrolizumab did respectively). Overall, 52% of patients experienced TRAEs not reach statistical significance per specified and 12% experienced Grade 3 or above TRAEs. criteria.5 Recently, atezolizumab (an anti- PD- © Author(s) (or their employer(s)) 2021. Re- use Conclusions Ipilimumab and nivolumab/pembrolizumab L1- antibody) in combination with bevaci- permitted under CC BY-NC. No can achieve durable antitumor activity and encouraging zumab was approved for first-line treatment commercial re- use. See rights survival outcomes with acceptable toxicity in patients with of advanced HCC based on results from the and permissions. Published by advanced HCC who had prior treatment with ICIs. IMbrave150 trial, which demonstrated an BMJ. impressive objective response rate (ORR) of 1Department of Medicine, Queen Mary Hospital, The University of BACKGROUND 27.3%, median PFS of 6.8 months and OS Hong Kong, Hong Kong, China Liver cancer is the fourth leading cause of at 12 months of 67.2%, all superior to the 2Department of Surgery, Queen cancer death worldwide, with the majority sorafenib arm.6 Based on these emerging Mary Hospital, The University of (75%–85%) being hepatocellular carcinoma data, ICIs will be increasingly used in both Hong Kong, Hong Kong, China (HCC).1 HCC often arises from a microen- first- line and second- line settings for the Correspondence to vironment characterized by chronic inflam- treatment of patients with advanced HCC. Dr Thomas Yau; tyaucc@ hku. hk mation, intrinsic immunosuppression and Importantly, the majority of patients treated Wong JSL, et al. J Immunother Cancer 2021;9:e001945. doi:10.1136/jitc-2020-001945 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001945 on 9 February 2021. Downloaded from Table 1 Baseline characteristics Table 1 Continued Patient characteristics Patient characteristics Median age (range), years 62 (51–83) TACE 15 (60%) Male, n (%) 22 (88%) Prior systemic treatment 10 (40%) HCC etiology, n (%) Sorafenib 7 (28%) Hepatitis B (HBV) 19 (76%) Lenvatinib 1 (4%) Hepatitis C (HCV) 2 (8%) Enzalutamide 1 (4%) Alcoholic 1 (4%) PEG- BCT-100, oxaliplatin, capecitabine 1 (4%) NASH 2 (8%) FGF401 1 (4%) Cryptogenic 1 (4%) AFP, alpha- fetoprotein; ALBI, Albumin- Bilirubin; BCLC, Barcelona BCLC stage, n (%) clinic liver cancer; CP, Child- Pugh; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; NASH, non- alcoholic B 4 (16%) steatohepatitis; PD-1, programmed cell death protein 1; TACE, C 19 (76%) Transarterial chemoembolization. D 2 (8%) Extrahepatic metastases, n (%) 20 (80%) Vascular invasion, n (%) 3 (12%) with ICIs will either never respond (primary resistance) or eventually develop resistance (acquired resistance). AFP ≥400 μg/L, n(%) 11 (44%) Hence, there is an unmet need to investigate the appro- CP Grade priate treatment for the rapidly expanding group of A 17 (68%) patients with advanced HCC who had tumor progression B 6 (24%) on prior anti- PD-1/L1 therapies. C 2 (8%) To improve the therapeutic efficacy of ICIs, anti-CTLA-4 and anti- PD-1/L-1 are increasingly used simultaneously, ALBI Grade with the combination of ipilimumab (an anti- CTLA-4 1 9 (36%) antibody) and nivolumab having received Food and 2 11 (44%) Drug Administration approval in various cancer types. 3 5 (20%) In patients with advanced HCC previously treated with Baseline performance status sorafenib, ipilimumab–nivolumab has also received regu- latory approval based on the promising results of the 0–1 23 (92%) CheckMate-040 cohort 4 trial which reported an ORR 2 2 (8%) of up to 32% and a median OS of up to 23 months.7 http://jitc.bmj.com/ Prior ICI Recently, durvalumab (an anti- PDL-1 antibody) in combi- Nivolumab 19 (76%) nation with tremelimumab (an anti-CTLA-4 antibody) Pembrolizumab 5 (20%) reported an ORR of up to 22.7% and a median OS of up to 18.7 months in population with advanced HCC.8 Atezolizumab with bevacizumab 1 (4%) Interestingly, in advanced melanoma, non-small- cell lung Agents in combination with prior ICI cancer and metastatic renal cell carcinoma, salvage ipilim- on September 24, 2021 by guest. Protected copyright. None 21 (84%) umab and nivolumab have lately demonstrated promising Bevacizumab 2 (8%) anti- tumor activities in patients with prior PD-1 pathway 9–12 Capecitabine, oxaliplatin, irinotecan 1 (4%) blockade. To evaluate the efficacy and safety of combined CTLA-4 Cabozantinib 1 (4%) and PD-1 blockade in patients with advanced HCC who Primary resistance to prior ICI 12 (48%) failed PD-1 pathway blockade, we conducted an analysis Lines of systemic therapies prior to of patients who received a combination of ipilimumab ipilimumab + anti-PD-1, n (%) and nivolumab/pembrolizumab after tumor progression 1 15 (60%) on prior anti- PD-1/L-1. 2 7 (28%) 3 3 (12%) METHODS Therapies prior to any ICI, n (%) This was a single-center retrospective analysis approved by Prior local treatment 19 (76%) The University of Hong Kong/Hospital Authority Hong Curative surgical resection 16 (64%) Kong West Cluster Institutional Review Board. Patients were identified from a prospectively maintained HCC Radiotherapy 5 (20%) database at Queen Mary Hospital, Hong Kong. Between Continued June 2016 and February 2020, consecutive patients with 2 Wong JSL, et al. J Immunother Cancer 2021;9:e001945. doi:10.1136/jitc-2020-001945 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-001945 on 9 February 2021. Downloaded from HCC who were ineligible for surgical or locoregional or last clinic follow- up. Time- to- progression (TTP) was therapies and had documented tumor progression on calculated from the date of first dose to radiological anti- PD-1/L-1 were included for analysis. All included progression, or censored at date of death or last follow- up patients received at least one dose of a combination of while on treatment for patients without progression. OS ipilimumab and nivolumab/pembrolizumab. Patients was calculated from the date of first dose to death of any who received any other concomitant anticancer therapy cause or censored at last follow- up for patients who were were excluded. still alive at study cut-off.
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