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Journal Article•DOI•

Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

Masatoshi Kudo1, Richard S. Finn2, Shukui Qin, Kwang Hyub Han3, Kenji Ikeda, Fabio Piscaglia4, Ari David Baron5, Joong-Won Park, Guohong Han6, Jacek Jassem7, Jean-Frédéric Blanc8, Arndt Vogel9, Dmitry Komov, T.R. Jeffry Evans10, Carlos Lopez, Corina E. Dutcus11, Matthew Guo11, Kenichi Saito11, Silvija Kraljevic11, Toshiyuki Tamai11, Min Ren11, Ann-Lii Cheng12 •
Kindai University1, University of California, Los Angeles2, Yonsei University3, University of Bologna4, California Pacific Medical Center5, Fourth Military Medical University6, Gdańsk Medical University7, University of Bordeaux8, Hannover Medical School9, Beatson West of Scotland Cancer Centre10, Eisai11, National Taiwan University12
24 Mar 2018-The Lancet (Elsevier)-Vol. 391, Iss: 10126, pp 1163-1173
TL;DR: Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma and the safety and tolerability profiles of lenvatinIB were consistent with those previously observed.
About: This article is published in The Lancet.The article was published on 2018-03-24 and is currently open access. It has received 3046 citations till now. The article focuses on the topics: Lenvatinib & Sorafenib.

Summary (1 min read)

Jump to: [Introduction] and [In a phase 2 trial, lenvatinib, an inhibitor of vascular endothelial growth factor receptor 1‒3, fibroblast 43]

Introduction

  • Kudo, M. et al. (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
  • There may be differences between this version and the published version.
  • †These 3 authors contributed equally to this study 20 (details are shown in the Contributors section).

In a phase 2 trial, lenvatinib, an inhibitor of vascular endothelial growth factor receptor 1‒3, fibroblast 43

  • Growth factor receptor 1‒4, platelet-derived growth factor receptor alpha, RET, and KIT, showed activity 44 in hepatocellular carcinoma (HCC).
  • The noninferiority margin was set at 1·08.
  • 63 Lenvatinib was noninferior to sorafenib in overall survival in untreated advanced HCC.

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Journal Article•DOI•
Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

[...]

Jorge A. Marrero1, Laura Kulik, Claude B. Sirlin2, Andrew X. Zhu3, Richard S. Finn4, Michael Abecassis, Lewis R. Roberts5, Julie K. Heimbach5 •
University of Texas Southwestern Medical Center1, University of California, San Diego2, Harvard University3, University of California, Los Angeles4, Mayo Clinic5
01 Aug 2018-Hepatology
TL;DR: This paper aims to demonstrate the efforts towards in-situ applicability of EMMARM, as to provide real-time information about concrete mechanical properties such as E-modulus and compressive strength.

2,416 citations

Cites background from "Lenvatinib versus sorafenib in firs..."

  • ...Recently, data from an open-label, randomized phase 3 trial of the multikinase inhibitor, lenvatinib, versus sorafenib was reported(168) (Table 3)....

    [...]

Journal Article•DOI•
A global view of hepatocellular carcinoma: trends, risk, prevention and management.

[...]

Ju Dong Yang1, Pierre Hainaut2, Gregory J. Gores1, Amina Amadou2, Amelie Plymoth3, Lewis R. Roberts1 •
Mayo Clinic1, University of Grenoble2, Karolinska Institutet3
22 Aug 2019-Nature Reviews Gastroenterology & Hepatology
TL;DR: Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
Abstract: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.

2,122 citations

Journal Article•DOI•
Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.

[...]

Andrew X. Zhu1, Richard S. Finn2, Julien Edeline, Stéphane Cattan, Sadahisa Ogasawara3, Daniel H. Palmer4, Chris Verslype5, Vittorina Zagonel, Laetitia Fartoux, Arndt Vogel6, Debashis Sarker7, Gontran Verset, Stephen L. Chan8, Jennifer J. Knox9, Bruno Daniele, Andrea L. Webber10, Scot Ebbinghaus10, Junshui Ma10, Abby B. Siegel10, Ann-Lii Cheng11, Masatoshi Kudo12, Angela Tatiana Alistar, Jamil Asselah, Jean-Frédéric Blanc, Ivan Borbath, Timothy Cannon, Ki Chung, Allen Lee Cohn, David Cosgrove, Nevena Damjanov, Mukul Gupta, Yoshivasu Karino, Mark Karwal, Andreas Kaubisch, Robin Kate Kelley, Jena-Luc Van Laethem, Timothy Larson, James Lee, Daneng Li, Atisha Manhas, Gulam Abbas Manji, Kazushi Numata, Benjamin M. Parsons, Andrew Scott Paulson, Carmine Pinto, Robert A. Ramirez, Suresh Ratnam, Magnus Rizell, Olivier Rosmorduc, Yvonne Sada, Yutaka Sasaki, Per I Stal, Simone I. Strasser, Joerg Trojan, Gina M. Vaccaro, Hans Van Vlierberghe, Alan Weiss, Karl-Heinz Weiss, Tatsuya Yamashita •
Harvard University1, University of California, Los Angeles2, Chiba University3, University of Liverpool4, Katholieke Universiteit Leuven5, Hochschule Hannover6, University of Cambridge7, The Chinese University of Hong Kong8, Princess Margaret Cancer Centre9, Merck & Co.10, National Taiwan University11, Kindai University12
01 Jul 2018-Lancet Oncology
TL;DR: Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib and is undergoing further assessment in two phase 3, randomised trials as a second-line treatment.
Abstract: Summary Background Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. Methods KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. Findings Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Interpretation Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Funding Merck & Co, Inc.

1,630 citations

Journal Article•DOI•
Molecular therapies and precision medicine for hepatocellular carcinoma

[...]

Josep M. Llovet1, Josep M. Llovet2, Robert Montal1, Daniela Sia2, Richard S. Finn3 •
University of Barcelona1, Icahn School of Medicine at Mount Sinai2, University of California, Los Angeles3
30 Jul 2018-Nature Reviews Clinical Oncology
TL;DR: Treatment advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.
Abstract: The global burden of hepatocellular carcinoma (HCC) is increasing and might soon surpass an annual incidence of 1 million cases Genomic studies have established the landscape of molecular alterations in HCC; however, the most common mutations are not actionable, and only ~25% of tumours harbour potentially targetable drivers Despite the fact that surveillance programmes lead to early diagnosis in 40–50% of patients, at a point when potentially curative treatments are applicable, almost half of all patients with HCC ultimately receive systemic therapies Sorafenib was the first systemic therapy approved for patients with advanced-stage HCC, after a landmark study revealed an improvement in median overall survival from 8 to 11 months New drugs — lenvatinib in the frontline and regorafenib, cabozantinib, and ramucirumab in the second line — have also been demonstrated to improve clinical outcomes, although the median overall survival remains ~1 year; thus, therapeutic breakthroughs are still needed Immune-checkpoint inhibitors are now being incorporated into the HCC treatment armamentarium and combinations of molecularly targeted therapies with immunotherapies are emerging as tools to boost the immune response Research on biomarkers of a response or primary resistance to immunotherapies is also advancing Herein, we summarize the molecular targets and therapies for the management of HCC and discuss the advancements expected in the near future, including biomarker-driven treatments and immunotherapies

1,122 citations

Journal Article•DOI•
Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.

[...]

Andrew X. Zhu1, Yoon-Koo Kang2, Chia Jui Yen3, Richard S. Finn4, Peter R. Galle, Josep M. Llovet5, Josep M. Llovet6, Eric Assenat, Giovanni Brandi, Marc Pracht, Ho Yeong Lim7, Kun-Ming Rau8, Kenta Motomura, Izumi Ohno, Philippe Merle, Bruno Daniele, Dong Bok Shin9, Guido Gerken, Christophe Borg, Jean-Baptiste Hiriart, Takuji Okusaka, Manabu Morimoto, Yanzhi Hsu10, Paolo Abada10, Masatoshi Kudo11 •
Harvard University1, Asan Medical Center2, National Cheng Kung University3, University of California, Los Angeles4, University of Barcelona5, Icahn School of Medicine at Mount Sinai6, Samsung Medical Center7, Memorial Hospital of South Bend8, Gachon University9, Eli Lilly and Company10, Kindai University11
01 Feb 2019-Lancet Oncology
TL;DR: Overall survival, progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, and time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) were significantly improved in the ramucirumab group compared with the placebo group.
Abstract: Summary Background Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. Methods REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. Findings Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0–12·5), median overall survival (8·5 months [95% CI 7·0–10·6] vs 7·3 months [5·4–9·1]; hazard ratio [HR] 0·710 [95% CI 0·531–0·949]; p=0·0199) and progression-free survival (2·8 months [2·8–4·1] vs 1·6 months [1·5–2·7]; 0·452 [0·339–0·603]; p Interpretation REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma. Funding Eli Lilly.

1,057 citations

References
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Journal Article•DOI•
Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.

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Jacques Ferlay1, Isabelle Soerjomataram1, Rajesh Dikshit2, Sultan Eser3, Colin Mathers, Marise Souto Rebelo, Donald Maxwell Parkin4, David Forman1, Freddie Bray1 •
International Agency for Research on Cancer1, Tata Memorial Hospital2, Hacettepe University3, Clinical Trial Service Unit4
01 Mar 2015-International Journal of Cancer
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).

24,414 citations

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New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)

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Elizabeth Eisenhauer1, P. Therasse2, Jan Bogaerts3, Lawrence H. Schwartz4, Daniel J. Sargent5, Robert Ford6, Janet Dancey, S. Arbuck7, S. Gwyther8, Margaret M. Mooney, Larry Rubinstein, Lalitha K. Shankar, Lori E. Dodd, Robert M. Kaplan, Denis Lacombe3, Jaap Verweij9 •
Queen's University1, GlaxoSmithKline2, European Organisation for Research and Treatment of Cancer3, Memorial Sloan Kettering Cancer Center4, Mayo Clinic5, Princeton University6, Schering-Plough7, East Surrey Hospital8, Erasmus University Medical Center9
01 Jan 2009-European Journal of Cancer
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.

20,760 citations

Journal Article•DOI•
Sorafenib in Advanced Hepatocellular Carcinoma

[...]

Josep M. Llovet1, Sergio Ricci2, Vincenzo Mazzaferro, Philip Hilgard3, Edward Gane4, Jean-Frédéric Blanc, André Cosme de Oliveira5, Armando Santoro, Jean-Luc Raoul6, Alejandro Forner, Myron Schwartz7, Camillo Porta, Stefan Zeuzem8, Luigi Bolondi9, Tim F. Greten10, Peter R. Galle11, Jean Francois Seitz12, Ivan Borbath13, Dieter Häussinger14, Tom Giannaris15, Minghua Shan16, M. Moscovici15, D. Voliotis15, Jordi Bruix1 •
University of Barcelona1, University of Pisa2, University of Duisburg-Essen3, Auckland City Hospital4, University of São Paulo5, European University6, Icahn School of Medicine at Mount Sinai7, Goethe University Frankfurt8, University of Bologna9, Hannover Medical School10, University of Mainz11, Aix-Marseille University12, Université catholique de Louvain13, University of Düsseldorf14, Bayer15, Bayer Corporation16
24 Jul 2008-The New England Journal of Medicine
TL;DR: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.
Abstract: Background No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. Methods In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. Results At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. Conclusions In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo.

10,074 citations

Journal Article•DOI•
Management of hepatocellular carcinoma: An update

[...]

Jordi Bruix1, Morris Sherman2•
University of Barcelona1, University Health Network2
01 Mar 2011-Hepatology
TL;DR: The American Association for the Study of Liver Diseases (AASLD) practice guidelines on the management of hepatocellular carcinoma (HCC) were updated in 2010 as discussed by the authors.

6,964 citations

AASLD PRACTICE GUIDELINE Management of Hepatocellular Carcinoma: An Update

[...]

Jordi Bruix, Morris Sherman
01 Jan 2010
TL;DR: Since the publication of the American Association for the Study of Liver Diseases (AASLD) practice guidelines on the management of hepatocellular carcinoma (HCC) in 2005, new information has emerged that requires that the guidelines be updated.
Abstract: Since the publication of the American Association for the Study of Liver Diseases (AASLD) practice guidelines on the management of hepatocellular carcinoma (HCC) in 2005, new information has emerged that requires that the guidelines be updated. The full version of the new guidelines is available on the AASLD Web site at http://www.aasld.org/practiceguidelines/ Documents/Bookmarked%20Practice%20Guidelines/ HCCUpdate2010.pdf. Here, we briefly describe only new or changed recommendations.

6,642 citations

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Sorafenib in Advanced Hepatocellular Carcinoma

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24 Jul 2008-The New England Journal of Medicine
Josep M. Llovet, Sergio Ricci, Vincenzo Mazzaferro, Philip Hilgard, Edward Gane, Jean-Frédéric Blanc, André Cosme de Oliveira, Armando Santoro, Jean-Luc Raoul, Alejandro Forner, Myron Schwartz, Camillo Porta, Stefan Zeuzem, Luigi Bolondi, Tim F. Greten, Peter R. Galle, Jean Francois Seitz, Ivan Borbath, Dieter Häussinger, Tom Giannaris, Minghua Shan, M. Moscovici, D. Voliotis, Jordi Bruix 
Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial

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Frequently Asked Questions (13)
Q1. What are the contributions in this paper?

In this paper, Lenvatinib was used in advanced hepatocellular carcinoma ( HCC ) trial. 

The final 350 pharmacokinetic model for lenvatinib included body weight effect as an allometric constant on both 351 clearance and volume parameters, whereby both parameters increased with increasing body weight. 

The most common treatment-emergent adverse events among patients who received lenvatinib were 271hypertension (201; 42·2%), diarrhoea (184; 38·7%), decreased appetite (162; 34·0%), and decreased 272 weight (147; 30·9%). 

18 Based on dose adjustments depending on body weights 114 as well as pharmacokinetic modelling data,19 a starting dose of lenvatinib based on body weight was 115 adopted (12 mg and 8 mg once daily for patients with body weights ≥60 kg and <60 kg, respectively) for 116 further clinical development in HCC. 

Efficacy and safety of sorafenib in patients in the Asia-Pacific 459 region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-460 controlled trial. 

Allocation was performed with an interactive voice/web-response system 159 with region (Asia-Pacific or Western) macroscopic portal vein invasion or extrahepatic spread or both 160 (yes or no), Eastern Cooperative Oncology Group performance status (0 or 1), and body weight (<60 kg 161 or ≥60 kg) as stratification factors. 

due to the current paucity of systemic treatment options for 105 patients with advanced HCC, a critical need exists to develop new agents for the effective management 106 of this disease. 

Of these, 21 publications described the use of targeted agents for the treatment of 73 hepatocellular carcinoma, 11 of which were studies of single-agent sorafenib and 3 of which were 74 studies of sorafenib in combination with another agent. 

182A population pharmacokinetic analysis for lenvatinib was conducted to derive individual 183 pharmacokinetic parameters and lenvatinib exposures for this study. 

The significant improvement in 326 progression-free survival, time to progression, and objective response rate with lenvatinib in this study 327 may indicate, as in some other tumours, the emergence of a broader paradigm in drug assessment and 328 treatment in advanced HCC. 

mRECIST to predict survival in advanced hepatocellular 535 carcinoma: Analysis of two randomised phase II trials comparing nintedanib vs sorafenib. 

A total of 954 patients from 20 216 countries were randomly assigned to receive lenvatinib (478 patients) or sorafenib (476 patients) (Figure 217 S1 in the Supplementary Appendix). 

In the lenvatinib arm, 11 260 (7·0%) patients in the Western region had any anticancer procedure during follow-up compared with 18 261 (11·5%) patients in the sorafenib arm in this region (Table S3 in the Supplementary Appendix).