دورية أكاديمية
أعرض في EDS

Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling.

التفاصيل البيبلوغرافية
العنوان: Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling.
المؤلفون: Kelley RK; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Joseph NM; Department of Pathology, University of California, San Francisco (UCSF), San Francisco, California, USA., Nimeiri HS; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA., Hwang J; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Kulik LM; Division of Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, USA., Ngo Z; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Behr SC; Department of Radiology, University of California, San Francisco (UCSF), San Francisco, California, USA., Onodera C; Clinical Cancer Genomics Lab, UCSF Health, San Francisco, California, USA., Zhang K; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Bocobo AG; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Benson AB; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA., Venook AP; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA., Gordan JD; Helen Diller Family Comprehensive Cancer Center (HDFCCC), University of California, San Francisco (UCSF), San Francisco, California, USA.
المصدر: Liver cancer [Liver Cancer] 2021 Sep 06; Vol. 10 (6), pp. 561-571. Date of Electronic Publication: 2021 Sep 06 (Print Publication: 2021).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: S. Karger Country of Publication: Switzerland NLM ID: 101597993 Publication Model: eCollection Cited Medium: Print ISSN: 2235-1795 (Print) Linking ISSN: 16645553 NLM ISO Abbreviation: Liver Cancer Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: Basel : S. Karger
مستخلص: Background: The mammalian target of rapamycin ( mTOR ) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose.
Methods: We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d . The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint.
Results: Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP.
Conclusions: The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
Competing Interests: R.K.K. reports the following conflicts of interest: research funding to institution from Agios, Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Merck, Novartis, Partner Therapeutics, QED, Taiho; consulting/advisory fees to self from Exact Sciences, Genentech/Roche, and Gilead; travel support for satellite symposium from Ipsen. H.S.N. reports the conflicts of interest: employment by Foundation Medicine, Inc. L.M.K. reports the following conflicts of interest: Advisory board consultant for Bayer, Eisai, Exelixis, Genentech; consultant for Merck; speaker for Eisai, Gilead, Target HCC, and Peerview CME. Z.N. reports the conflicts of interest: employment by Nektar Therapeutics. S.C.B. reports the conflicts of interest: consulting/advisory fees to self from AAA Novartis and Progenics. A.B.B. reports the following conflicts of interest: research funding to institution from Celgene, Infinity Pharmaceuticals, Merck Sharp and Dohme, Taiho Pharmaceutical, Rafael Pharmaceuticals, Medimmune/AstraZeneca, Xencor, ST Pharm, Elevar Therapeutics, Lexicon Pharmaceuticals/TerSera; advisor or consultant for Bristol-Myers Squibb, Therabionic, Guardant, Merck (advisory), Lexicon, Amgen (DMC/advisor), Artemida Pharma, Array/Pfizer (advisory), AbbVie, Apexigen, Tyme, SynCore, Samsung, HalioDx, Janssen, Natera; Research Data Monitoring Committee member for Bristol-Myers Squibb, Astellas, Amgen, Syncore, Tyme. A.P.V. reports the following conflicts of interest: research funding to institution from Amgen Novartis; consulting/advisory fees from Array, QED and Glaxo Smith Kline. J.D.G. reports the conflicts of interest: consulting/advisory fees to self from Genentech/Roche. N.M.J., J.H., C.O., K.Z., and A.G.B. report no conflict of interest to declare.
(Copyright © 2021 by S. Karger AG, Basel.)
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فهرسة مساهمة: Keywords: Hepatocellular carcinoma; Mammalian target of rapamycin; Next-generation sequencing; Sorafenib; Temsirolimus
تواريخ الأحداث: Date Created: 20211224 Latest Revision: 20220429
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8647100
DOI: 10.1159/000518297
PMID: 34950179
قاعدة البيانات: MEDLINE
الوصف
تدمد:2235-1795
DOI:10.1159/000518297