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Laura Kulik,1 Leonardo G da Fonseca,2 Aiwu Ruth He,3 Jordi Rimola,4 Andrea Wilson Woods,5 York F Zöllner,6 Peter R Galle7 1Northwestern University, Chicago, IL, USA; 2Clinical Oncology, Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil; 3Georgetown University, Washington, DC, USA; 4Radiology Department, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain; 5Blue Faery: The Adrienne Wilson Liver Cancer Association, Birmingham, AL, USA; 6Hamburg University of Applied Sciences, Competence Center Health, Hamburg, Germany; 7University Medical Centre Mainz, Mainz, GermanyCorrespondence: Peter R GalleUniversity Medical Centre Mainz, Mainz, GermanyTel +49 6131 177275Email Peter.Galle@unimedizin-mainz.deAbstract: A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.Keywords: hepatocellular carcinoma, immuno-oncologics, biomarkers, patient-reported outcomes

Abstract Preliminary work has shown that portal hypertension plays a key role for the prognosis in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Specifically, the presence of ascites appears to be a strong negative predictor for these patients. However, it remains unclear whether different ascites volumes influence prognosis. Therefore, the aim of this work was to investigate the influence of different ascites volumes on survival for patients with HCC undergoing TACE. A total of 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020 were included. In patients with ascites, the fluid was segmented, and the volume quantified by slice-wise addition using contrast-enhanced CT imaging. Median overall survival (OS) was calculated and univariate and multivariate Cox regression analysis has been performed. Ascites was present in 102 (31.9%) patients. Ascites volume as continuous variable was significantly associated with an increased hazard ratio in univariate analysis (p

Abstract Background Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC). Methods OCT1 (SLC22A1) and OCT3 (SLC22A3) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs. Results Real time PCR showed a downregulation of SLC22A1 and SLC22A3 in HCC compared to TST (p ≤ 0.001). A low SLC22A1 expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, SLC22A1 was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low SLC22A1 expression (< median) showed a higher SLC22A3 expression compared to HCC with high SLC22A1 expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the SLC22A3 expression. In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC. Conclusion The downregulation of OCT1 is associated with tumor progression and a worse patient survival.

The multikinase inhibitor sorafenib was the only approved systemic therapy in advanced hepatocellular carcinoma (hcc) for about a decade. In recent years, the number of approved agents has increased significantly as a result of a number of positive phase iii clinical trials. Lenvatinib as a first-line treatment, and regorafenib, cabozantinib, and ramucirumab in the second-line setting are now approved by the U.S. Food and Drug Administration (fda) and the European Medicines Agency. In phase ii studies, immunotherapy with nivolumab and monotherapy using pembrolizumab yielded impressive results for overall survival in therapy-naïve and pretreated patients, leading to the accelerated approval by the fda of nivolumab and pembrolizumab for second-line treatment. However, phase iii trials of nivolumab in the first line and pembrolizumab in the second line as single agents failed to reach statistical significance, although clinical benefit for a subset of patients with long durations of response could be demonstrated. Despite that setback, immunotherapy for hcc is a promising therapeutic approach, and the combination of immunotherapy with other treatment modalities such as monoclonal antibodies, tyrosine kinase inhibitors, or local therapies has the potential to increase the overall response rate and survival. Recently, the results of a phase iii trial of combination atezolizumab-bevacizumab compared with sorafenib showed a highly significant survival benefit and median overall survival that was not reached in the immunotherapy arm, making the combination the preferred standard of care in first-line therapy. Despite the impressive results and generally good toxicity profile of immunotherapy, patients who respond to therapy constitute only a subset of the overall population, and response rates are still limited. This review focuses on the currently reported results and ongoing clinical trials of checkpoint inhibitor-based immunotherapy in hcc. [ABSTRACT FROM AUTHOR]

Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II–related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. Interferon signaling and major histocompatibility complex–related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response. [ABSTRACT FROM AUTHOR]

SUMMARY We previously demonstrated that high levels of IL-6/sIL-6R complexes are present in sera of patients with systemic juvenile idiopathic arthritis (s-JIA) and that the amount of IL-6 estimated in the IL-6/sIL-6R complexes is markedly higher than that measured by the B9 assay. Here, we show that two additional bioassays, employing human myeloma XG-1 cells and human hepatoma Hep3B cells, detected serum IL-6 levels similar to those measured by the B9 assay and approximately 10-fold lower than the IL-6 levels estimated to be present in the IL-6/sIL-6R complex. Using an assay for the measurement of the amount of circulating IL-6 complexed with the sIL-6R and available for binding to gp130 (gp130 binding activity), we show that the IL-6/gp130 binding activity is similar to that detected by the bioassays and again significantly lower than that estimated to be present in the IL-6/sIL-6R complex. Addition of recombinant human IL-6 (rhIL-6) to sera of patients or controls results in a markedly lower increase in the gp130 binding activity in patients than in controls. Moreover, sera from s-JIA patients inhibited in a dose dependent manner the gp130 binding activity assay. These results show that sera from patients with s-JIA contain a factor, or factors, that inhibit(s) the binding of the IL-6/sIL-6R complex to gp130. This inhibitory activity does not appear to be due to soluble gp130, C-reactive protein or autoantibodies to IL-6. [ABSTRACT FROM AUTHOR]

Abstract Background Clinically significant portal hypertension (CSPH) has been identified as an important prognostic factor in patients with hepatocellular carcinoma (HCC) undergoing curative treatment. This study aimed to assess PH estimates as prognostic factors in patients with HCC treated with immunotherapy. Methods All patients with HCC treated with an immunotherapeutic agent in first or subsequent lines at our tertiary care center between 2016 and 2021 were included (n = 50). CSPH was diagnosed using the established PH score for non-invasive PH estimation in pre-treatment CT data (cut-off ≥ 4). Influence of PH on overall survival (OS) and progression-free survival (PFS) was assessed in uni- and multivariable analyses. Results Based on the PH score, 26 patients (52.0%) were considered to have CSPH. After treatment initiation, patients with CSPH had a significantly impaired median OS (4.1 vs 33.3 months, p

Abstract: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide. Due to late diagnosis and advanced underlying liver cirrhosis, only limited treatment options with marginal clinical benefits have been available in up to 70% of patients. However, major progress has been achieved with regard to surveillance, early diagnosis, and multimodal treatment approaches during the last years leading to an improvement in prognosis. Particularly, the increasing knowledge of molecular hepatocarcinogenesis today provides the opportunity for targeted therapy. The multikinase inhibitor sorafenib has broadened the therapeutic horizon for patients with advanced disease and is currently under investigation for patients in early and intermediate stages as adjuvant therapy after resection/local ablation or in combination with transcatheter arterial chemoembolization. Future research will continue to unravel the key signaling cascades in different subclasses of HCC patients according to their genomic and proteomic profiling. These approaches bear the potential to individualize anticancer therapy, in the end allowing treatment of those benefiting most and excluding those who do not. This article shortly reviews the current knowledge in the management of HCC and provides insights into future perspectives with a special focus on recent progress in multidisciplinary treatment modalities. [Copyright &y& Elsevier]

Primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a significant contributor to cancer-related mortality worldwide. Oxidative stress and lipid peroxidation play a key role in chronic liver diseases and have been shown to be pivotal for tumor initiation and progression. 4-hydroxy-nonenal (4-HNE), one of the major mediators of oxidative stress and a well-established biomarker for lipid peroxidation, can act as a signal transducer, inducing inflammation and exerting carcinogenic effects. However, the role of 4-HNE in primary liver cancer remains poorly explored. In this study, we investigated 4-HNE levels in 797 liver carcinomas, including 561 HCC and 236 iCCA, by immunohistochemistry. We then correlated 4-HNE levels with comprehensive clinical data and survival outcomes. In HCC, lower expression levels of 4-HNE were associated with vascular invasion, a high tumor grade, a macrotrabecular-massive HCC subtype, and poor overall survival. Concerning iCCA, large duct iCCA showed significantly higher 4-HNE levels when compared to small duct iCCA. Yet, in iCCA, 4-HNE levels did not correlate with known prognostic parameters or survival outcomes. To conclude, in HCC but not in iCCA, low amounts of 4-HNE predict unfavorable survival outcomes and are associated with aggressive tumor behavior. These findings provide insights into the role of 4-HNE in liver cancer progression and may enable novel therapeutic strategies.

Abstract Background The PAGE-B score (Platelet Age GEnder–HBV) selects chronic hepatitis B (cHB) patients showing no relevant 5-year risk for hepatocellular carcinoma (HCC). We, therefore, explored potential cost reduction following the introduction of a PAGE-B tailored ultrasound screening in a single center cohort of cHB patients receiving stable antiviral therapy. Methods cHB patients attending throughout the year 2018 were documented. Patients eligible for PAGE-B score were classified into high (≥18 points), intermediate (10–17 points) and low (≤9 points) HCC risk groups. Patients of the low HCC risk group could postpone HCC screening to reduce HCC screening expenses. Full costs for hepatic ultrasound were assessed. Results Throughout the year cHB patients (n = 607) attended our clinic, which included PAGE-B eligible patients (n = 227, 37.4%) of whom n = 94 (15.8%) were allocated to the low HCC risk group. Sonographic HCC screening during a median exam time of 12.4 min (IQR 9.2–17.2) resulted in total costs of 22.82 Euro/exam. Additional opportunistic expenses caused by patient’s lost earnings or productivity were 15.6–17.5 €/exam and 26.7 €/exam, respectively. Following a PAGE-B tailored HCC screening at our institution annual full costs for cHB patients could be reduced by 15.51%, which equals a cost reduction by 1.91% for our total sonography unit. In comparison, 1.35% up to 7.65% of HBV-infected patients of Caucasian descent could postpone HCC screening according to population-based estimates from Germany. Conclusions PAGE-B risk score adapted screening for HCC is an efficient and cost neutral tool to reduce costs for sonography in Caucasian patients with chronic hepatitis B receiving antiviral treatment.

Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. Lay summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes.

ObjectivesThe Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are immunonutritive scoring systems with proven predictive ability in various cancer entities, including hepatocellular carcinoma (HCC). We performed the first evaluation of the CONUT score for patients undergoing transarterial chemoembolization (TACE) and compared CONUT and PNI in the ability to predict median overall survival (OS).MethodsBetween 2010 and 2020, we retrospectively identified 237 treatment-naïve patients with HCC who underwent initial TACE at our institution. Both scores include the albumin level and total lymphocyte count. The CONUT additionally includes the cholesterol level. Both scores were compared in univariate and multivariate regression analyses taking into account established risk factors. In a second step, a subgroup analysis was performed on BCLC stage B patients, for whom TACE is the recommended first-line treatment.ResultsA high CONUT score and low PNI were associated with impaired median OS (8.7 vs. 22.3 months, p

Abstract Background In hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality worldwide, the Child-Turcotte-Pugh score (CTP) is one of the most established tools to assess hepatic reserve and determine survival. Serum levels of insulin-like growth factor-1 (IGF-1) are decreased in patients with chronic liver disease or HCC. A modified score combining circulating IGF-1 with the CTP score (IGF-CTP) was recently proposed. Methods IGF-CTP scoring was evaluated in 216 patients diagnosed with HCC between 2007 and 2017 to assess the predictive value of serum IGF-1 levels for patient risk stratification and overall survival (OS). Results Liver cirrhosis was identified in 80.1% of the study cohort, and alcohol-induced liver disease was the most frequent underlying cause of HCC (44.4%). Serum IGF-1 levels were significantly lower in patients with HCC in cirrhosis compared with non-cirrhotic HCC (p

Abstract Background Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. Methods A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell’s C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. Results The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell’s C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P

Background Ph 1b data has shown promising efficacy and safety for atezo + bev in unresectable HCC pts who have not received prior systemic therapy. Here, we report the primary analysis data from the Ph 3 IMbrave150 trial comparing atezo + bev vs sor in this pt population. Methods IMbrave150 enrolled systemic treatment (tx)-naïve pts with unresectable HCC. Pts were randomised 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg BID until unacceptable toxicity or loss of clinical benefit per investigator. Coprimary endpoints were OS and PFS by independent review facility (IRF)-assessed RECIST 1.1. The key secondary endpoints IRF-ORR per RECIST 1.1 and IRF-ORR per HCC mRECIST were also part of the study statistical testing hierarchy. Results The ITT population included 336 pts randomised to atezo + bev and 165 randomised to sor. Baseline demographics were well balanced between arms. With a median follow up of 8.6 mo, OS HR was 0.58 (95% CI, 0.42, 0.79; P = 0.0006) and PFS HR was 0.59 (95% CI, 0.47, 0.76; P < 0.0001; see table) for atezo + bev vs sor. ORR was 27% vs 12% (P < 0.0001) per IRF RECIST 1.1 and 33% vs 13% (P < 0.0001) per IRF HCC mRECIST for atezo + bev vs sor, respectively. Results were generally consistent across clinical subgroups. Atezo + bev delayed deterioration of quality of life vs sor. Median tx duration was 7.4 mo for atezo, 6.9 for bev and 2.8 for sor. Grade 3-4 AEs occurred in 57% of pts receiving atezo + bev and 55% of pts receiving sor. Grade 5 AEs were seen in 5% and 6% of pts, respectively. Conclusions IMbrave150 demonstrated statistically significant and clinically meaningful improvement in both OS and PFS for atezo + bev vs sor in pts with unresectable HCC who have not received prior systemic therapy. The safety of atezo + bev is consistent with the known safety profile of each agent, and no new safety signals were identified. Atezo + bev has the potential to be a practice changing tx in HCC. Clinical trial identification NCT03434379. Editorial acknowledgement Medical writing assistance for this abstract was provided by Jessica Bessler, PhD, of Health Interactions, Ltd. and funded by F. Hoffmann-La Roche, Ltd. Legal entity responsible for the study F. Hoffmann-La Roche, Ltd. Funding F. Hoffmann-La Roche, Ltd. Table: LBA3 Coprimary endpoints  Atezo + bev n = 336  Sor n = 165  OS  Median, mo 95% CI  NE  13.2 (10.4, NE)  HR a 95% CI  0.58 (0.42, 0.79)  P value a,b   0.0006  PFS  Median, mo 95% CI  6.8 (5.7, 8.3)  4.3 (4.0, 5.6)  HR a 95% CI  0.59 (0.47, 0.76)  P value a,b   <0.0001  Coprimary endpoints  Atezo + bev n = 336  Sor n = 165  OS  Median, mo 95% CI  NE  13.2 (10.4, NE)  HR a 95% CI  0.58 (0.42, 0.79)  P value a,b   0.0006  PFS  Median, mo 95% CI  6.8 (5.7, 8.3)  4.3 (4.0, 5.6)  HR a 95% CI  0.59 (0.47, 0.76)  P value a,b   <0.0001  NE, non-estimable. a Stratified analysis. b Log rank. Table: LBA3 Coprimary endpoints  Atezo + bev n = 336  Sor n = 165  OS  Median, mo 95% CI  NE  13.2 (10.4, NE)  HR a 95% CI  0.58 (0.42, 0.79)  P value a,b   0.0006  PFS  Median, mo 95% CI  6.8 (5.7, 8.3)  4.3 (4.0, 5.6)  HR a 95% CI  0.59 (0.47, 0.76)  P value a,b   <0.0001  Coprimary endpoints  Atezo + bev n = 336  Sor n = 165  OS  Median, mo 95% CI  NE  13.2 (10.4, NE)  HR a 95% CI  0.58 (0.42, 0.79)  P value a,b   0.0006  PFS  Median, mo 95% CI  6.8 (5.7, 8.3)  4.3 (4.0, 5.6)  HR a 95% CI  0.59 (0.47, 0.76)  P value a,b   <0.0001  NE, non-estimable. a Stratified analysis. b Log rank. Disclosure A-L. Cheng: Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd.; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan; Honoraria (self): Bayer; Honoraria (self): Merck Sharp Dohme; Honoraria (self): Merck Serono. M. Ikeda: Honoraria (self): Abbott Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly Japan; Honoraria (self): Nippon Kayaku; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): NanoCarrier; Research grant / Funding (self): ASLAN Pharmaceuticals; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Baxter; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kowa; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Ono Pharmaceutical, Yakult, Zeria Pharmaceutical. P.R. Galle: Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): SIRTEX; Honoraria (self): Merck; Honoraria (self): Lilly; Honoraria (self): Blueprint; Honoraria (self): AdaptImmune; Honoraria (self): Eisai; Honoraria (self): Roche; Honoraria (self): Ipsen. M.P. Ducreux: Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Servier; Advisory / Consultancy: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony: Merck KGaA; Research grant / Funding (self): Pfizer; Spouse / Financial dependant: Sandoz. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche/Genentech. M. Kudo: Honoraria (self), Research grant / Funding (institution): AbbVie; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Gilead Sciences; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Otsuka. V. Breder: Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy: BioCad; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: MSD Oncology; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Takeda. P. Merle: Research grant / Funding (self): ONXEO; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Bristol-Myers Squibb. A. Kaseb: Shareholder / Stockholder / Stock options: Gilead Sciences; Honoraria (self), Advisory / Consultancy: Bayer Health; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Exelixis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer/Onyx. D. Li: Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Exelixis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Honoraria (institution), Speaker Bureau / Expert testimony: Lexicon; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony: Advanced Accelerator Applications. W. Verret: Full / Part-time employment: Genentech. Z.D. Xu: Full / Part-time employment: Roche. S. Hernandez: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. J. Liu: Full / Part-time employment: Roche. C. Huang: Full / Part-time employment: Roche. S. Mulla: Full / Part-time employment: Roche. R. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: BristolMyersSquibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche/Genentech; Speaker Bureau / Expert testimony: Novartis. [ABSTRACT FROM AUTHOR]