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Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1...

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Published in:Journal for immunotherapy of cancer 2021-02, Vol.9 (2), p.e001945
Main Authors: Wong, Jeffrey Sum Lung, Kwok, Gerry Gin Wai, Tang, Vikki, Li, Bryan Cho Wing, Leung, Roland, Chiu, Joanne, Ma, Ka Wing, She, Wong Hoi, Tsang, Josephine, Lo, Chung Mau, Cheung, Tan To, Yau, Thomas
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container_issue 2
container_start_page e001945
container_title Journal for immunotherapy of cancer
container_volume 9
creator Wong, Jeffrey Sum Lung
Kwok, Gerry Gin Wai
Tang, Vikki
Li, Bryan Cho Wing
Leung, Roland
Chiu, Joanne
Ma, Ka Wing
She, Wong Hoi
Tsang, Josephine
Lo, Chung Mau
Cheung, Tan To
Yau, Thomas
description BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p
doi_str_mv 10.1136/jitc-2020-001945
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No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p&lt;0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.</description><identifier>ISSN: 2051-1426</identifier><identifier>EISSN: 2051-1426</identifier><identifier>DOI: 10.1136/jitc-2020-001945</identifier><identifier>PMID: 33563773</identifier><language>eng</language><publisher>England: BMJ Publishing Group LTD</publisher><subject>Aged ; Aged, 80 and over ; Antibodies ; Antibodies, Monoclonal, Humanized - adverse effects ; Antibodies, Monoclonal, Humanized - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Apoptosis ; Cancer ; Cancer therapies ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - immunology ; Carcinoma, Hepatocellular - mortality ; Carcinoma, Hepatocellular - pathology ; Cell death ; Clinical/Translational Cancer Immunotherapy ; Disease Progression ; Drug Resistance, Neoplasm ; FDA approval ; Female ; Hepatitis ; Humans ; Immune Checkpoint Inhibitors - adverse effects ; Immune Checkpoint Inhibitors - therapeutic use ; Immunotherapy ; Investigations ; Ipilimumab - adverse effects ; Ipilimumab - therapeutic use ; Liver cancer ; Liver Neoplasms - drug therapy ; Liver Neoplasms - immunology ; Liver Neoplasms - mortality ; Liver Neoplasms - pathology ; Male ; Middle Aged ; Monoclonal antibodies ; Nivolumab - adverse effects ; Nivolumab - therapeutic use ; Proteins ; Regulatory approval ; Retrospective Studies ; Salvage Therapy ; Targeted cancer therapy ; Time Factors ; Treatment Outcome ; Tumor Microenvironment ; Tumors</subject><ispartof>Journal for immunotherapy of cancer, 2021-02, Vol.9 (2), p.e001945</ispartof><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2021 Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b526t-bfb6d7a05939d215478a32ed16927b6afa4ae10c8c56cf35e5d49b8dc0e88a893</citedby><cites>FETCH-LOGICAL-b526t-bfb6d7a05939d215478a32ed16927b6afa4ae10c8c56cf35e5d49b8dc0e88a893</cites><orcidid>0000-0002-2356-0831</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2552988492/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2552988492?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27549,27550,27924,27925,37012,37013,44590,53791,53793,75126,77601,77632</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33563773$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wong, Jeffrey Sum Lung</creatorcontrib><creatorcontrib>Kwok, Gerry Gin Wai</creatorcontrib><creatorcontrib>Tang, Vikki</creatorcontrib><creatorcontrib>Li, Bryan Cho Wing</creatorcontrib><creatorcontrib>Leung, Roland</creatorcontrib><creatorcontrib>Chiu, Joanne</creatorcontrib><creatorcontrib>Ma, Ka Wing</creatorcontrib><creatorcontrib>She, Wong Hoi</creatorcontrib><creatorcontrib>Tsang, Josephine</creatorcontrib><creatorcontrib>Lo, Chung Mau</creatorcontrib><creatorcontrib>Cheung, Tan To</creatorcontrib><creatorcontrib>Yau, Thomas</creatorcontrib><title>Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors</title><title>Journal for immunotherapy of cancer</title><addtitle>J Immunother Cancer</addtitle><description>BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p&lt;0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antibodies</subject><subject>Antibodies, Monoclonal, Humanized - adverse effects</subject><subject>Antibodies, Monoclonal, Humanized - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - immunology</subject><subject>Carcinoma, Hepatocellular - mortality</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell death</subject><subject>Clinical/Translational Cancer Immunotherapy</subject><subject>Disease Progression</subject><subject>Drug Resistance, Neoplasm</subject><subject>FDA approval</subject><subject>Female</subject><subject>Hepatitis</subject><subject>Humans</subject><subject>Immune Checkpoint Inhibitors - adverse effects</subject><subject>Immune Checkpoint Inhibitors - therapeutic use</subject><subject>Immunotherapy</subject><subject>Investigations</subject><subject>Ipilimumab - adverse effects</subject><subject>Ipilimumab - therapeutic use</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - immunology</subject><subject>Liver Neoplasms - mortality</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Nivolumab - adverse effects</subject><subject>Nivolumab - therapeutic use</subject><subject>Proteins</subject><subject>Regulatory approval</subject><subject>Retrospective Studies</subject><subject>Salvage Therapy</subject><subject>Targeted cancer therapy</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><issn>2051-1426</issn><issn>2051-1426</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>9YT</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqFkstr1UAUh4Motly7dyUBN4LEzjMz2QhStL1QcKPr4cwjvROTmThJLlT84500tbRuXM3rm48zZ35F8RqjDxjT-rzzs6kIIqhCCDeMPytOCeK4wozUzx_NT4qzaepQhhClUsqXxQmlvKZC0NPi9370vR-WAXQJwZbBH2O_rs5HN-gUe__r7syHEuwRgnG2PLgR5mhc3y89pNJAMj7EAcrk2gRmjum2nGM5Jh9T6YdhCa40B2d-jNGHOasOXvtMTa-KFy30kzu7H3fF9y-fv11cVddfL_cXn64rzUk9V7rVtRWAeEMbSzBnQgIlzuK6IULX0AIDh5GRhtempdxxyxotrUFOSpAN3RX7zWsjdCrXNUC6VRG8utuI6UZBmr3pneKtFFZrRgnNLSVUcuyYpkzXDactg-z6uLnGRQ_OGhfmBP0T6dOT4A_qJh6VkIKTLNkV7-4FKf5c3DSrwU9rMyG4uEyKMCmxFFiQjL79B-3ikkJulSI8y6RkzUqhjTIpTlP-g4diMFJrUtSaFLUmRW1JyVfePH7Ew4W_ucjA-w3QQ_d_3R_P08qX</recordid><startdate>202102</startdate><enddate>202102</enddate><creator>Wong, Jeffrey Sum Lung</creator><creator>Kwok, Gerry Gin Wai</creator><creator>Tang, Vikki</creator><creator>Li, Bryan Cho Wing</creator><creator>Leung, Roland</creator><creator>Chiu, Joanne</creator><creator>Ma, Ka Wing</creator><creator>She, Wong Hoi</creator><creator>Tsang, Josephine</creator><creator>Lo, Chung Mau</creator><creator>Cheung, Tan To</creator><creator>Yau, Thomas</creator><general>BMJ Publishing Group LTD</general><general>BMJ Publishing Group</general><scope>9YT</scope><scope>ACMMV</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-2356-0831</orcidid></search><sort><creationdate>202102</creationdate><title>Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors</title><author>Wong, Jeffrey Sum Lung ; Kwok, Gerry Gin Wai ; Tang, Vikki ; Li, Bryan Cho Wing ; Leung, Roland ; Chiu, Joanne ; Ma, Ka Wing ; She, Wong Hoi ; Tsang, Josephine ; Lo, Chung Mau ; Cheung, Tan To ; Yau, Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b526t-bfb6d7a05939d215478a32ed16927b6afa4ae10c8c56cf35e5d49b8dc0e88a893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antibodies</topic><topic>Antibodies, Monoclonal, Humanized - adverse effects</topic><topic>Antibodies, Monoclonal, Humanized - therapeutic use</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - immunology</topic><topic>Carcinoma, Hepatocellular - mortality</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell death</topic><topic>Clinical/Translational Cancer Immunotherapy</topic><topic>Disease Progression</topic><topic>Drug Resistance, Neoplasm</topic><topic>FDA approval</topic><topic>Female</topic><topic>Hepatitis</topic><topic>Humans</topic><topic>Immune Checkpoint Inhibitors - adverse effects</topic><topic>Immune Checkpoint Inhibitors - therapeutic use</topic><topic>Immunotherapy</topic><topic>Investigations</topic><topic>Ipilimumab - adverse effects</topic><topic>Ipilimumab - therapeutic use</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - immunology</topic><topic>Liver Neoplasms - mortality</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Nivolumab - adverse effects</topic><topic>Nivolumab - therapeutic use</topic><topic>Proteins</topic><topic>Regulatory approval</topic><topic>Retrospective Studies</topic><topic>Salvage Therapy</topic><topic>Targeted cancer therapy</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>Tumor Microenvironment</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wong, Jeffrey Sum Lung</creatorcontrib><creatorcontrib>Kwok, Gerry Gin Wai</creatorcontrib><creatorcontrib>Tang, Vikki</creatorcontrib><creatorcontrib>Li, Bryan Cho Wing</creatorcontrib><creatorcontrib>Leung, Roland</creatorcontrib><creatorcontrib>Chiu, Joanne</creatorcontrib><creatorcontrib>Ma, Ka Wing</creatorcontrib><creatorcontrib>She, Wong Hoi</creatorcontrib><creatorcontrib>Tsang, Josephine</creatorcontrib><creatorcontrib>Lo, Chung Mau</creatorcontrib><creatorcontrib>Cheung, Tan To</creatorcontrib><creatorcontrib>Yau, Thomas</creatorcontrib><collection>BMJ Open Access Journals</collection><collection>BMJ Journals:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; 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No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p&lt;0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.</abstract><cop>England</cop><pub>BMJ Publishing Group LTD</pub><pmid>33563773</pmid><doi>10.1136/jitc-2020-001945</doi><orcidid>https://orcid.org/0000-0002-2356-0831</orcidid><oa>free_for_read</oa></addata></record>
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subjects Aged
Aged, 80 and over
Antibodies
Antibodies, Monoclonal, Humanized - adverse effects
Antibodies, Monoclonal, Humanized - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Apoptosis
Cancer
Cancer therapies
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - immunology
Carcinoma, Hepatocellular - mortality
Carcinoma, Hepatocellular - pathology
Cell death
Clinical/Translational Cancer Immunotherapy
Disease Progression
Drug Resistance, Neoplasm
FDA approval
Female
Hepatitis
Humans
Immune Checkpoint Inhibitors - adverse effects
Immune Checkpoint Inhibitors - therapeutic use
Immunotherapy
Investigations
Ipilimumab - adverse effects
Ipilimumab - therapeutic use
Liver cancer
Liver Neoplasms - drug therapy
Liver Neoplasms - immunology
Liver Neoplasms - mortality
Liver Neoplasms - pathology
Male
Middle Aged
Monoclonal antibodies
Nivolumab - adverse effects
Nivolumab - therapeutic use
Proteins
Regulatory approval
Retrospective Studies
Salvage Therapy
Targeted cancer therapy
Time Factors
Treatment Outcome
Tumor Microenvironment
Tumors
title Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors
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