Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial
Abstract Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS...
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| Veröffentlicht in: | Liver cancer (Basel ) 2023-09, Vol.12 (4), p.309-320 |
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| creator | Merle, Philippe Kudo, Masatoshi Edeline, Julien Bouattour, Mohamed Cheng, Ann-Lii Chan, Stephen Lam Yau, Thomas Garrido, Marcelo Knox, Jennifer Daniele, Bruno Breder, Valeriy Lim, Ho Yeong Ogasawara, Sadahisa Cattan, Stéphane Chao, Yee Siegel, Abby B. Martinez-Forero, Iván Wei, Ziwen Liu, Chih-Chin Finn, Richard S. |
| description | Abstract
Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC. |
| doi_str_mv | 10.1159/000529636 |
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Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.</description><identifier>ISSN: 2235-1795</identifier><identifier>EISSN: 1664-5553</identifier><identifier>DOI: 10.1159/000529636</identifier><identifier>PMID: 37901200</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Cancer ; FDA approval ; Hepatitis B ; Hepatitis C ; Immunotherapy ; Infections ; Life Sciences ; Liver cancer ; Monoclonal antibodies ; Mortality ; Patients ; Population ; Regulatory approval ; Research Article ; Review boards ; Statistical analysis ; Targeted cancer therapy</subject><ispartof>Liver cancer (Basel ), 2023-09, Vol.12 (4), p.309-320</ispartof><rights>2023 The Author(s). Published by S. Karger AG, Basel</rights><rights>2023 The Author(s). Published by S. Karger AG, Basel.</rights><rights>2023 The Author(s). Published by S. Karger AG, Basel. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the associated terms available at: https://uk.sagepub.com/en-gb/eur/reusing-open-access-and-sage-choice-content</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2023 The Author(s). Published by S. Karger AG, Basel 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-99d7d2468fcda8550ec3707c96835bbff0c870186ae35631133954b5d16cd5803</citedby><cites>FETCH-LOGICAL-c553t-99d7d2468fcda8550ec3707c96835bbff0c870186ae35631133954b5d16cd5803</cites><orcidid>0000-0002-8230-394X ; 0000-0002-6244-4294 ; 0000-0002-8289-7741 ; 0000-0002-2638-3156 ; 0000-0002-6540-9064 ; 0000-0003-3029-7207 ; 0000-0002-4102-3474 ; 0000-0001-8905-8986 ; 0000-0002-3919-4135 ; 0000-0001-5578-340X ; 0000-0003-3474-6647 ; 0000-0001-8998-5480 ; 0000-0002-5221-9755 ; 0000-0002-9152-6512 ; 0000-0001-9325-2300 ; 0000-0003-2494-2126</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601873/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10601873/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,27635,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37901200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04265920$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Merle, Philippe</creatorcontrib><creatorcontrib>Kudo, Masatoshi</creatorcontrib><creatorcontrib>Edeline, Julien</creatorcontrib><creatorcontrib>Bouattour, Mohamed</creatorcontrib><creatorcontrib>Cheng, Ann-Lii</creatorcontrib><creatorcontrib>Chan, Stephen Lam</creatorcontrib><creatorcontrib>Yau, Thomas</creatorcontrib><creatorcontrib>Garrido, Marcelo</creatorcontrib><creatorcontrib>Knox, Jennifer</creatorcontrib><creatorcontrib>Daniele, Bruno</creatorcontrib><creatorcontrib>Breder, Valeriy</creatorcontrib><creatorcontrib>Lim, Ho Yeong</creatorcontrib><creatorcontrib>Ogasawara, Sadahisa</creatorcontrib><creatorcontrib>Cattan, Stéphane</creatorcontrib><creatorcontrib>Chao, Yee</creatorcontrib><creatorcontrib>Siegel, Abby B.</creatorcontrib><creatorcontrib>Martinez-Forero, Iván</creatorcontrib><creatorcontrib>Wei, Ziwen</creatorcontrib><creatorcontrib>Liu, Chih-Chin</creatorcontrib><creatorcontrib>Finn, Richard S.</creatorcontrib><title>Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial</title><title>Liver cancer (Basel )</title><addtitle>Liver Cancer</addtitle><description>Abstract
Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.</description><subject>Cancer</subject><subject>FDA approval</subject><subject>Hepatitis B</subject><subject>Hepatitis C</subject><subject>Immunotherapy</subject><subject>Infections</subject><subject>Life Sciences</subject><subject>Liver cancer</subject><subject>Monoclonal antibodies</subject><subject>Mortality</subject><subject>Patients</subject><subject>Population</subject><subject>Regulatory approval</subject><subject>Research Article</subject><subject>Review boards</subject><subject>Statistical analysis</subject><subject>Targeted cancer therapy</subject><issn>2235-1795</issn><issn>1664-5553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNptks9v0zAUxyMEYtXYgTtClnaBQ-A5jn-EC6qqbq2I2CS6AyfLsZ02JYmDkxSN8_5wXDoKmzhZeu_zvu-Hv1H0EsM7jGn2HgBokjHCnkQTzFgaU0rJ02iSJITGmGf0JDrr-23AQADwjD-PTgjPACcAk-ju2jaFd3X1c2xUgVSPvljtWhPnVWvRamO96m5R6Tyamp1qtTVoYTs1OG3reqyVRzPlddW6Rn1AuWvX1qOV9Q26cHXtfsQ3HSq9a9Cwseh6o3qLCPo0__r5ajWPkxTQyleqfhE9K1Xd27P79zS6uZivZos4v7pczqZ5rMNKQ5xlhpskZaLURglKwWrCgeuMCUKLoixBCw5YMGUJZQRjQjKaFtRgpg0VQE6j5UHXOLWVna8a5W-lU5X8HXB-LZUfKl1bqQ1nogDDBVEppWVRgGAcmNGhlRAsaH08aHVj0VijbTt4VT8QfZhpq41cu53EwMKMnASFtweFzaO6xTSX-xikCaNZAjsc2Df33bz7Ptp-kE3V779AtdaNvUyESLGghCYBPX-Ebt3o23BXmWQAZG-J9G9z7V3fe1seJ8Ag976SR18F9vW_qx7JPy4KwKsD8E35YIAjcKw__286X84OhOxMSX4B02HZLw</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Merle, Philippe</creator><creator>Kudo, Masatoshi</creator><creator>Edeline, Julien</creator><creator>Bouattour, Mohamed</creator><creator>Cheng, Ann-Lii</creator><creator>Chan, Stephen Lam</creator><creator>Yau, Thomas</creator><creator>Garrido, Marcelo</creator><creator>Knox, Jennifer</creator><creator>Daniele, Bruno</creator><creator>Breder, Valeriy</creator><creator>Lim, Ho Yeong</creator><creator>Ogasawara, Sadahisa</creator><creator>Cattan, Stéphane</creator><creator>Chao, Yee</creator><creator>Siegel, Abby B.</creator><creator>Martinez-Forero, Iván</creator><creator>Wei, Ziwen</creator><creator>Liu, Chih-Chin</creator><creator>Finn, Richard S.</creator><general>S. 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Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>Liver cancer (Basel )</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Merle, Philippe</au><au>Kudo, Masatoshi</au><au>Edeline, Julien</au><au>Bouattour, Mohamed</au><au>Cheng, Ann-Lii</au><au>Chan, Stephen Lam</au><au>Yau, Thomas</au><au>Garrido, Marcelo</au><au>Knox, Jennifer</au><au>Daniele, Bruno</au><au>Breder, Valeriy</au><au>Lim, Ho Yeong</au><au>Ogasawara, Sadahisa</au><au>Cattan, Stéphane</au><au>Chao, Yee</au><au>Siegel, Abby B.</au><au>Martinez-Forero, Iván</au><au>Wei, Ziwen</au><au>Liu, Chih-Chin</au><au>Finn, Richard S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial</atitle><jtitle>Liver cancer (Basel )</jtitle><addtitle>Liver Cancer</addtitle><date>2023-09-01</date><risdate>2023</risdate><volume>12</volume><issue>4</issue><spage>309</spage><epage>320</epage><pages>309-320</pages><issn>2235-1795</issn><eissn>1664-5553</eissn><abstract>Abstract
Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>37901200</pmid><doi>10.1159/000529636</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-8230-394X</orcidid><orcidid>https://orcid.org/0000-0002-6244-4294</orcidid><orcidid>https://orcid.org/0000-0002-8289-7741</orcidid><orcidid>https://orcid.org/0000-0002-2638-3156</orcidid><orcidid>https://orcid.org/0000-0002-6540-9064</orcidid><orcidid>https://orcid.org/0000-0003-3029-7207</orcidid><orcidid>https://orcid.org/0000-0002-4102-3474</orcidid><orcidid>https://orcid.org/0000-0001-8905-8986</orcidid><orcidid>https://orcid.org/0000-0002-3919-4135</orcidid><orcidid>https://orcid.org/0000-0001-5578-340X</orcidid><orcidid>https://orcid.org/0000-0003-3474-6647</orcidid><orcidid>https://orcid.org/0000-0001-8998-5480</orcidid><orcidid>https://orcid.org/0000-0002-5221-9755</orcidid><orcidid>https://orcid.org/0000-0002-9152-6512</orcidid><orcidid>https://orcid.org/0000-0001-9325-2300</orcidid><orcidid>https://orcid.org/0000-0003-2494-2126</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2235-1795 |
| ispartof | Liver cancer (Basel ), 2023-09, Vol.12 (4), p.309-320 |
| issn | 2235-1795 1664-5553 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2884185352 |
| source | PubMed Central; Directory of Open Access Journals; EZB Electronic Journals Library; Karger Open Access Journals |
| subjects | Cancer FDA approval Hepatitis B Hepatitis C Immunotherapy Infections Life Sciences Liver cancer Monoclonal antibodies Mortality Patients Population Regulatory approval Research Article Review boards Statistical analysis Targeted cancer therapy |
| title | Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial |
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