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Galle PR, Dufour JF, Peck-Radosavljevic M, Trojan J, Vogel A. Systemic therapy of advanced hepatocellular carcinoma. Future Oncol 2020; 17:1237-1251. [PMID: 33307782 DOI: 10.2217/fon-2020-0758] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
For a decade, sorafenib remained the only approved first-line treatment and standard of care for advanced hepatocellular carcinoma. The treatment landscape has been evolving rapidly over the past 2 years with the approval of additional first-and second-line systemic treatments, most of which are targeted therapies. The expected approval of immunotherapies constitutes a paradigm shift: for the first time in years, a checkpoint inhibitor in combination with a VEGF antibody recently outperformed sorafenib with regards to efficacy. The wider availability of systemic therapies increases the chance for longer overall survival but raises new questions concerning the role of local options, treatment choice and sequential treatment. Following an expert discussion at the German Cancer Congress 2020 in Berlin, this article aims to summarize the current evidence on and experience of treatment choice and sequence in first- and second-line therapy.
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Affiliation(s)
- Peter R Galle
- Department of Internal Medicine, University Medical Center Mainz, 55131, Mainz, Rheinland-Pfalz, Germany
| | | | - Markus Peck-Radosavljevic
- Klagenfurt am Wörthersee Hospital, 3 Internal Medicine & Gastroenterology, Hepatology, Endocrinology, Rheumatology & Nephrology, Klagenfurt, Austria
| | - Jörg Trojan
- Hospital of the Goethe University Frankfurt Center of Internal Medicine, Frankfurt am Main, Hessen, Germany
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Abstract
Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be diagnosed with dynamic imaging with very high accuracy, and tissue diagnosis is not needed for cancer therapy. There is a unique role of established as well as developing biomarkers in diagnosis, prognosis, and management of HCC. Sequencing HCC tumors has yielded substantial insights into HCC tumor biology and has raised the possibility of precision oncology in which therapy decisions are guided by cancer genetics. However, it is not ready for prime time yet.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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Cervello M, Emma MR, Augello G, Cusimano A, Giannitrapani L, Soresi M, Akula SM, Abrams SL, Steelman LS, Gulino A, Belmonte B, Montalto G, McCubrey JA. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY) 2020; 12:3053-3094. [PMID: 32018226 PMCID: PMC7041742 DOI: 10.18632/aging.102777] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/12/2020] [Indexed: 04/12/2023]
Abstract
Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in recent years. Personalized genomics and various other omics approaches may identify actionable biochemical targets, which are activated in individual patients, which may enhance therapeutic outcomes. Further studies are needed to identify predictive biomarkers and aberrantly activated signaling pathways capable of guiding the clinician in choosing the most appropriate therapy for the individual patient.
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Affiliation(s)
- Melchiorre Cervello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Maria R. Emma
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Giuseppa Augello
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
| | - Lydia Giannitrapani
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maurizio Soresi
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Shaw M. Akula
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Stephen L. Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Linda S. Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Alessandro Gulino
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Beatrice Belmonte
- Tumour Immunology Unit, Human Pathology Section, Department of Health Science, University of Palermo, Palermo, Italy
| | - Giuseppe Montalto
- Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy
- Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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Rimassa L, Pressiani T, Merle P. Systemic Treatment Options in Hepatocellular Carcinoma. Liver Cancer 2019; 8:427-446. [PMID: 31799201 PMCID: PMC6883446 DOI: 10.1159/000499765] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 03/21/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma (HCC) typically have poor survival outcomes. Until recently, sorafenib was the only systemic therapy option available and no agents were approved after sorafenib failure. However, rapid changes are beginning to emerge in the treatment landscape of advanced HCC, with approvals of regorafenib, nivolu-mab, lenvatinib, pembrolizumab, and cabozantinib and positive phase II/III clinical trial results with other agents. SUMMARY Here, we provide a comprehensive overview of the clinical trial data of systemic agents that are currently approved for advanced HCC (sorafenib, regorafenib, and nivolumab), including agents recently approved in 2018 (lenvatinib, pembrolizumab, and cabozantinib) and those with recent positive phase II/III results (ramucirumab). Key features of the clinical trial design, including patient selection criteria, the use of biomarkers in HCC, and criteria for efficacy assessment, and their implications in real-world practice are discussed. Important ongoing and planned trials in advanced HCC are summarized to provide a glimpse into the future of advanced HCC treatment. From a physician's viewpoint, the treatment algorithms for advanced HCC are undergoing significant changes, as additional and imminent approvals impact the choices of first- and second-line treatment and decisions regarding the timing of therapy initiation. With these additional choices at hand, treatment sequencing remains a complex task and should take patient selection and tolerance profiles into account. KEY MESSAGES The treatment of advanced HCC remains challenging and complex. The rapid developments in systemic therapy for advanced HCC should be considered when determining the best choice and sequence of treatment for patients with advanced HCC.
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Affiliation(s)
- Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center – IRCCS, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center – IRCCS, Milan, Italy
| | - Philippe Merle
- Hepatology Unit, Croix-Rousse Hospital, Groupement Hospitalier Lyon Nord, Lyon, France
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Personeni N, Pressiani T, Bozzarelli S, Rimassa L. Targeted agents for second-line treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2019; 11:788-803. [PMID: 31662820 PMCID: PMC6815920 DOI: 10.4251/wjgo.v11.i10.788] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/25/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023] Open
Abstract
Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.
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Affiliation(s)
- Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
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Abstract
Regorafenib (Stivarga®), a small molecule inhibitor of multiple kinases, is the first drug to be approved for the treatment of hepatocellular carcinoma (HCC) in patients who have progressed during or after sorafenib therapy. Its approval was based on the results of the randomized, double-blind, placebo-controlled, multinational, phase III RESORCE trial in patients with HCC who had progressed during sorafenib therapy. In RESORCE, regorafenib significantly prolonged overall survival (OS; primary endpoint), progression-free survival (PFS) and time to progression (TTP) compared with placebo, with the OS benefit appearing to be largely due to disease stabilization. Regorafenib had an acceptable tolerability profile. The most common treatment-related adverse events in the regorafenib group included hand-foot skin reaction, fatigue, diarrhoea and hypertension. No fatal hepatic failure was reported with regorafenib in patients with HCC in RESORCE. In conclusion, current evidence suggests that regorafenib is an important new targeted therapy option for the treatment of HCC patients who have progressed on sorafenib therapy.
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Affiliation(s)
- Young-A Heo
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
| | - Yahiya Y Syed
- Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand
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Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, Rota Caremoli E, Porta C, Daniele B, Bolondi L, Mazzaferro V, Harris W, Damjanov N, Pastorelli D, Reig M, Knox J, Negri F, Trojan J, López López C, Personeni N, Decaens T, Dupuy M, Sieghart W, Abbadessa G, Schwartz B, Lamar M, Goldberg T, Shuster D, Santoro A, Bruix J. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol 2018; 19:682-693. [PMID: 29625879 DOI: 10.1016/s1470-2045(18)30146-3] [Citation(s) in RCA: 302] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score ≥2 in ≥50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and α-fetoprotein concentrations (≤200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18·1 months (IQR 14·1-23·1), median overall survival was 8·4 months (95% CI 6·8-10·0) in the tivantinib group and 9·1 months (7·3-10·4) in the placebo group (hazard ratio 0·97; 95% CI 0·75-1·25; p=0·81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV-HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group).
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Affiliation(s)
- Lorenza Rimassa
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Eric Assenat
- Service d'Oncologie Médicale, CHRU Saint Eloi, Montpellier, France
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine III, Section of Gastroenterology/Hepatology, Medizinische Universitaet Wien, Wien, Austria; Department of Internal Medicine and Gastroenterology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Marc Pracht
- Centre Eugène Marquis et CH Saint Malo, Rennes, France
| | - Vittorina Zagonel
- Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology-IRCCS, Padua, Italy
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Hôpital Claude Huriez, Lille Cedex, France
| | | | - Camillo Porta
- IRCCS San Matteo University Hospital Foundation, Pavia, Italy
| | - Bruno Daniele
- Department of Oncology and Medical Oncology Unit, AO G Rummo Hospital, Benevento, Italy
| | - Luigi Bolondi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research, Sant'Orsola-Malpighi Hospital, Bologna, Italy
| | - Vincenzo Mazzaferro
- Department of Gastro-Intestinal Surgery and Liver Transplantation, University of Milan, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - William Harris
- University of Washington School of Medicine, Seattle, WA, USA
| | - Nevena Damjanov
- Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA
| | - Davide Pastorelli
- Department of Oncology, Santa Maria del Prato Hospital, Feltre, Italy
| | - María Reig
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Jennifer Knox
- Solid Tumor Medical Oncology, McCain Centre for Pancreatic Cancer, University Health Network, Princess Margaret Cancer Center at the OPG, Toronto, ON, Canada
| | - Francesca Negri
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Jörg Trojan
- Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt, Germany
| | - Carlos López López
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Nicola Personeni
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Thomas Decaens
- Institute for Advanced Biosciences-INSERM U1209, CNRS UMR 5309 and Department of Hepatogastroenterology Université Grenoble-Alpes, Grenoble, France; Clinique Universitaire d'Hépato-gastroentérologie, Pôle Digidune, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France
| | - Marie Dupuy
- Service d'Oncologie Médicale, CHRU Saint Eloi, Montpellier, France
| | - Wolfgang Sieghart
- Department of Internal Medicine III, Section of Gastroenterology/Hepatology, Medizinische Universitaet Wien, Wien, Austria
| | | | | | | | | | | | - Armando Santoro
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Jordi Bruix
- Barcelona Clinic Liver Cancer Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
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Gong J, Pan K, Fakih M, Pal S, Salgia R. Value-based genomics. Oncotarget 2018; 9:15792-15815. [PMID: 29644010 PMCID: PMC5884665 DOI: 10.18632/oncotarget.24353] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 01/19/2018] [Indexed: 12/18/2022] Open
Abstract
Advancements in next-generation sequencing have greatly enhanced the development of biomarker-driven cancer therapies. The affordability and availability of next-generation sequencers have allowed for the commercialization of next-generation sequencing platforms that have found widespread use for clinical-decision making and research purposes. Despite the greater availability of tumor molecular profiling by next-generation sequencing at our doorsteps, the achievement of value-based care, or improving patient outcomes while reducing overall costs or risks, in the era of precision oncology remains a looming challenge. In this review, we highlight available data through a pre-established and conceptualized framework for evaluating value-based medicine to assess the cost (efficiency), clinical benefit (effectiveness), and toxicity (safety) of genomic profiling in cancer care. We also provide perspectives on future directions of next-generation sequencing from targeted panels to whole-exome or whole-genome sequencing and describe potential strategies needed to attain value-based genomics.
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Affiliation(s)
- Jun Gong
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Kathy Pan
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Sumanta Pal
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA
| | - Ravi Salgia
- Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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