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Treatment for hepatocellular carcinoma (HCC) has experienced major advancements since the last update of the official Barcelona Clinic Liver Cancer (BCLC) prognosis and treatment strategy published in 2018. Advancements in the field have emerged in all areas, but in this manuscript, we present those that have primed a change in the strategy and comment why some encouraging data in select interventions are still considered immature and in need of further research to gain their incorporation into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that is needed to take clinical decisions in individual patients so that the recommendation takes into account all the needed parameters to allow a personalised approach.

BACKGROUND Biliary tract cancers (BTCs) typically present at an advanced stage, and systemic chemotherapy is often of limited benefit. METHODS Hybrid capture–based comprehensive genomic profiling (CGP) was performed for 412 intrahepatic cholangiocarcinomas (IHCCAs), 57 extrahepatic cholangiocarcinomas (EHCCAs), and 85 gallbladder carcinomas (GBCAs). The mutational profile was correlated with the clinical outcome of standard and experimental therapies for 321 patients. Clinical variables, detected mutations, and administered therapies were correlated with overall survival (OS) in a Cox regression model. RESULTS The most frequent genetic aberrations (GAs) observed were tumor protein 53 (TP53; 27%), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B; 27%), KRAS (22%), AT-rich interactive domain-containing protein 1A (ARID1A; 18%), and isocitrate dehydrogenase 1 (IDH1; 16%) in IHCCA; KRAS (42%), TP53 (40%), CDKN2A/B (17%), and SMAD4 (21%) in EHCCA; and TP53 (59%), CDKN2A/B (19%), ARID1A (13%), and ERBB2 (16%) in GBCA. Fibroblast growth factor receptor (FGFR; 11%) and IDH mutations (20%) were mostly limited to IHCCA but appeared to be mutually exclusive. In the IHCCA group, TP53 and KRAS mutations were associated significantly with poor OS, whereas FGFR2 mutations were associated with improved OS (P = .001), a younger age at onset, and female sex. IDH1/2 mutations were not prognostic. In a multivariate model, the effects of TP53 and FGFR GAs remained significant (P

Background SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to prolong survival and improve tolerability. This phase III study compared clinical efficacy and safety of NIVO with SOR as 1L therapy in pts with aHCC. Methods Systemic therapy–naive pts aged ≥18 years with aHCC were randomized 1:1 to NIVO (240mg IV Q2W) or SOR (400mg oral BID). Primary endpoint was overall survival (OS). Additional endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review per RECIST v1.1, efficacy by tumor programmed death ligand 1 (PD-L1) expression, and safety. Results 743 pts with aHCC were randomized to NIVO (n=371) or SOR (n=372) with minimum follow-up of 22.8 months at data cutoff. OS did not meet the predefined threshold of statistical significance (HR 0.84, P=0.0419). Median OS (mOS) was 16.4mo for NIVO and 14.7mo for SOR (HR 0.85 [95% CI: 0.72–1.02]; P=0.0752). Clinical benefit was observed across predefined subgroups, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and region (Asia vs non-Asia). ORR was 15% for NIVO (14 pts with complete response [CR]) and 7% for SOR (5 pts with CR; Table). Grade 3/4 treatment-related adverse events were reported in 81 pts (22%) in the NIVO arm and 179 pts (49%) in the SOR arm and led to discontinuation in 16 (4%) and 29 (8%) pts, respectively. No new safety signals were observed with NIVO. 140 pts (38%) in the NIVO arm and 170 pts (46%) in the SOR arm received subsequent therapy. Additional OS analyses and patient-reported outcomes will be presented to support the benefit of NIVO.Table: LBA38_PREfficacy resultsTable: LBA38_PRNIVOSORn=371n=372Median OS (95% CI), mo16.4 (13.9–18.4)14.7 (11.9–17.2)12-mo OS rate, % (95% CI)59.7 (54.4–64.6)55.1 (49.8–60.1)24-mo OS rate, % (95% CI)36.8 (31.8–41.8)33.1 (28.3–38.0)Median PFS, mo (95% CI)3.7 (3.1–3.9)3.8 (3.7–4.5)ORR, n (%)57 (15)26 (7)BOR, n (%)Complete response14 (4)5 (1)Partial response43 (12)21 (6)ORR by baseline tumor PD-L1 expression, n/n (%)PD-L1 ≥1%20/71 (28)6/64 (9)PD-L1 Conclusions Though the primary endpoint of OS did not achieve statistical significance vs SOR, NIVO showed clinically meaningful improvements in OS, ORR, and CR rate as 1L treatment for aHCC. NIVO demonstrated a favorable safety profile consistent with previous reports. Clinical trial identification NCT02576509. Editorial acknowledgement Writing and editorial assistance was provided by Andrea L. Hammons of Parexel International (Waltham, MA, USA) and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure T. Yau: Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb. R.S. Finn: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Roche/ Genentech. A. Cheng: 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; Advisory / Consultancy: Merck Sharp Dohme; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin; Speaker Bureau / Expert testimony: Amgen Taiwan; Advisory / Consultancy: Ispen; 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 (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis. P. Mathurin: Honoraria (self), Speaker Bureau / Expert testimony: Ipsen; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: Bayer Healthcare ; Honoraria (self), Speaker Bureau / Expert testimony: AbbVie; Honoraria (self), Speaker Bureau / Expert testimony: Gilead; Honoraria (self), Speaker Bureau / Expert testimony: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Sanofi. J. Edeline: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony: IPSEN; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Travel / Accommodation / Expenses: Amgen. M. Kudo: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: Ono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medico's Hirata; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): EA Pharma; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Gilead. J.J. Harding: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony: Elly Lilly ; Honoraria (self), Speaker Bureau / Expert testimony: CytomX; Honoraria (self), Speaker Bureau / Expert testimony: QED. P. Merle: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: AstraZeneca. O. Rosmorduc: Honoraria (self): Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Sirtex; Honoraria (self): Eisai. L. Wyrwicz: Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Beigene; Research grant / Funding (self): Eisai. E. Schott: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bayer. S.P. Choo: Honoraria (self), Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Sirtex; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen. R.K. Kelley: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Honoraria (self), Speaker Bureau / Expert testimony, IDMC membership: Genentech/Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): AstraZeneca. D. Begic: Full / Part-time employment: Bristol-Myers Squibb. J. Neely: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Sangro: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: BTG; Advisory / Consultancy: H3 Biomedicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Onxeo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sirtex Medical; Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Terumo. All other authors have declared no conflicts of interest.

Background C improved overall survival (OS) and progression-free survival (PFS) vs P in the phase 3 CELESTIAL trial (NCT01908426). Median OS was 10.2mo with C vs 8.0mo with P (HR 0.76, 95% CI 0.63–0.92; p=0.005), and median PFS was 5.2mo vs 1.9mo (HR 0.44, 95% CI 0.36–0.52; p Methods 707 patients (pts) were randomized 2:1 to receive C (60mg qd) or P. Pts were Child-Pugh grade A and ECOG PS≤1 and must have received prior sorafenib and could have received up to 2 prior lines of systemic therapy for HCC. UV and MV analyses of OS were done using the Cox proportional hazard regression model to compare subgroups defined by baseline variables within each treatment group (Bruix, J Hepatol 2017). MV analyses used backward selection with cutoffs of p≤0.1 for inclusion and p≤0.05 for retention of prognostic factors in the final model. Variables with p≤0.05 for treatment-subgroup interaction were considered possible predictive factors for treatment benefit. Results Age, sex, race, region, and etiology were not significant covariates in stepwise UV and MV analyses of OS. Nine baseline variables related to disease status, laboratory values, or prior therapy were identified as possible prognostic factors for OS in one or both treatment groups (Table). No covariates were found to be predictive of an OS benefit with C. Conclusions Exploratory UV and MV analyses identified high baseline values of AFP, alkaline phosphatase, ALBI grade, neutrophil to lymphocyte ratio, and number of disease sites as possible prognostic factors for shorter OS in previously treated aHCC. Disease etiology and demographic factors such as race and region were not found to be prognostic for OS.Table749PTableMV analysis of OSCabozantinibPlacebop-valueHRp-valueHRECOG PS [≥1 vs 0]0.00201.430.961.01Macrovascular invasion (MVI) [yes vs no]0.00231.470.161.28Number of sites [2 vs 1]0.0471.330.00241.84Number of sites [3 vs 1] Clinical trial identification NCT01908426. Editorial acknowledgement David Markby, Exelixis Inc. Legal entity responsible for the study Exelixis Inc. Funding Exelixis Inc. Disclosure T. Meyer: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): BTG; Research grant / Funding (institution): Ipsen. R.K. Kelley: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution), Inst.: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Inst.: Agios; Advisory / Consultancy, Research grant / Funding (institution), Inst.: BMS; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Taiho. M. Mangeshkar: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis Inc. A. Cheng: Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self), 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 Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan. A.B. El-Khoueiry: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: CytomX Therapeutics; Research grant / Funding (self): Astex Pharmaceuticals. G.K. Abou-Alfa: Advisory / Consultancy: 3DMedcare; Advisory / Consultancy, Research grant / Funding (institution): Agios; Research grant / Funding (institution): ActaBiologica; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Amgen; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Advisory / Consultancy: Aslan; Research grant / Funding (institution): Array; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy: BMS; Advisory / Consultancy: Boston Scientific; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy: Cipla; Advisory / Consultancy: CytomX; Advisory / Consultancy: Daiichi; Advisory / Consultancy: Debio; Advisory / Consultancy: Delcath; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Genoscience; Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Halozyme; Advisory / Consultancy: Hengrui; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Advisory / Consultancy: Inovio; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Jazz; Advisory / Consultancy: Jansen; Advisory / Consultancy: Kyowa Kirin; Advisory / Consultancy: LAM; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Loxo; Research grant / Funding (institution): Mabvax; Advisory / Consultancy: Merck; Advisory / Consultancy: Mina; Research grant / Funding (institution): Novartis; Advisory / Consultancy: Novella; Research grant / Funding (institution): OncoQuest; Advisory / Consultancy: Onxeo; Advisory / Consultancy: PCI Biotech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Pieris; Research grant / Funding (institution): Polaris Puma; Advisory / Consultancy, Research grant / Funding (institution): QED; Advisory / Consultancy: Redhill; Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Servier; Advisory / Consultancy: Silenseed; Advisory / Consultancy: Sillajen; Advisory / Consultancy: Sobi; Advisory / Consultancy: Targovax; Advisory / Consultancy: Tekmira; Advisory / Consultancy: Twoxa; Advisory / Consultancy: Vicus; Advisory / Consultancy: Yakult; Advisory / Consultancy: Yiviva.

Background C inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). C is approved in the United States and Europe for treatment of aHCC after prior S based on improved overall survival (OS) vs placebo in the phase 3 CELESTIAL trial (Abou-Alfa NEJM 2018). C may promote an immune-permissive tumor environment, which could enhance response to immune checkpoint inhibitors. C is being evaluated in combination with the anti-PD-L1 antibody A in multiple tumor types including HCC in a phase 1 study; recommended dose, preliminary clinical activity, and safety of the combination have been established in aRCC (Agarwal Ann Oncol 2018). A in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian Ann Oncol 2018). Here, we present the study design of a phase 3 trial of C + A vs S in pts with aHCC who have not received prior systemic therapy. Trial design This global, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of C + A vs S as first-line treatment for aHCC. C vs S will also be evaluated as a secondary endpoint. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS ≤ 1, and measurable disease per RECIST 1.1. Pts are randomized 2:1:1 to an experimental arm of C (40 mg qd) + A (1200 mg infusion q3w), a control arm of S (400 mg bid), and a C monotherapy arm (60 mg qd). 740 pts are planned to be enrolled at ∼250 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). OS and progression-free survival (PFS) for C+A vs S are primary endpoints, and PFS for C vs S is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. The first patient was enrolled in December 2018, and enrollment is ongoing. Clinical trial identification NCT03755791 (Other Study ID Numbers: XL184-312). Legal entity responsible for the study Exelixis. Funding Exelixis. Disclosure T. Yau: Advisory / Consultancy: Exelixis; Honoraria (self): Ipsen, Exelixis. L. Rimassa: Advisory / Consultancy: Lilly, Bayer, Baxter, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Eisai, Hengrui, MSD; Honoraria (self): AstraZeneca, AbbVie, Gilead, Roche; Travel / Accommodation / Expenses: ArQule, Ipsen. A-L. Cheng: Advisory / Consultancy, Advisory Board: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Advisory / Consultancy, Consultancy: Bayer Schering Pharma, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche/Genentech, and IQVIA; Honoraria (self): Bayer, Eisai, and Merck Sharp Dohme, Merck Serono, Novartis, Ono Pharmaceutical, Roche/Genentech, and IQVIA. J-W. Park: Advisory / Consultancy, Advisory board: Astra-Zeneca, Ono, BMS, Bayer, Midatech; Research grant / Funding (self): Ono-BMS, AstraZeneca, Blueprint, Roche, Eisai, Exelixis, Kowa; Advisory / Consultancy, Consultancy: Ono, Genetech, Roche, BMS, Bayer, Ipsen; Honoraria (self): Bayer, Ono, Eisai. F. Braiteh: Shareholder / Stockholder / Stock options: Agios; Bristol-Myers Squibb; Clovis Oncology; Insys Therapeutics; Tesaro; Honoraria (self): Abbott Nutrition; Amgen; ARIAD; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; HERON; Incyte; Insys Therapeutics; Insys Therapeutics; Ipsen; Lexicon; Lilly; Taiho Pharmaceutical; Advisory / Consultancy: Ambry Genetics; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Clovis Oncology; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Ipsen; Lexicon; Lilly; Merck; Merrimack; Pfizer; Regeneron; Sanofi; Speaker Bureau / Expert testimony: Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Lilly; Merck; Merck; Merrimack; Pfizer; Taiho Pharmaceutical; Travel / Accommodation / Expenses: - Amgen; AstraZeneca/MedImmune; Bayer; Bayer/Onyx; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Clovis Oncology; Exelixis; HERON; Incyte; Insys Therapeutics; Ipsen; Lexicon; Merrimack; Novartis; Pfizer; Regeneron; Roche/Genentech; Sanofi; Taiho Ph. F. Benzaghou: Full / Part-time employment: IPSEN; Shareholder / Stockholder / Stock options: IPSEN. P. Thuluvath: Honoraria (self): AbbVie; Gilead Sciences; Advisory / Consultancy: AbbVie; Eisai; Gilead Sciences; Speaker Bureau / Expert testimony: AbbVie; Gilead Sciences; Research grant / Funding (institution): AbbVie (Inst); Allergan (Inst); Conatus (Inst); Cymabay Therapeutics (Inst); Eisai (Inst); Sillajen (Inst); Target Pharmasolutions (Inst); Tobira Therapeutics (Inst); Zydus Pharmaceuticals (Inst). S. Hazra: Full / Part-time employment: Exelixis; Shareholder / Stockholder / Stock options: Exelixis. S. Milwee: Full / Part-time employment: Exelixis; Shareholder / Stockholder / Stock options: Exelixis. B. Tan: Research grant / Funding (institution): Exelixis. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Bayer; Bristol-Myers Squibb; eisai; Exelixis; Lilly; Merck; Novartis; Sanofi; Research grant / Funding (institution): Bayer (Inst); Bristol-Myers Squibb (Inst); Lilly (Inst); Merck (Inst); Novartis (Inst). R.K. Kelley: Advisory / Consultancy, funding to institution: Agios, AstraZeneca, Bayer, BMS; Advisory / Consultancy, funding to self: IDMC: Genentech/Roche; Research grant / Funding (institution): Agios, AstraZeneca, Bayer, BMS, Eli Lilly, Exelixis, EMD Serono, Medimmune, Merck, Novartis, QED, Taiho. All other authors have declared no conflicts of interest.

Background CELESTIAL (NCT01908426), a phase 3 study in patients with aHCC who progressed on sorafenib (≤2 previous systemic treatments allowed), demonstrated improved survival and progression-free survival with cabozantinib over placebo. CELESTIAL was stopped early for benefit at the second interim analysis (hazard ratio for death in overall population, 0.76 [95% confidence interval 0.63–0.92; p = 0.005] resulting in short follow-up for some patients). This retrospective analysis compared patient experience of three discrete health states in patients receiving second-line cabozantinib vs placebo in CELESTIAL: time with grade 3/4 toxicity before progression (TOX); time without grade 3/4 toxicity before progression (TWiST); and survival time after progression or relapse (REL). Methods Overall, 495 patients in CELESTIAL had sorafenib as the only prior therapy (cabozantinib, 331; placebo, 164). For each patient, times spent in TOX, TWiST and REL were calculated. Toxicities were based on reported adverse events. Patients censored prior to progression or death (32%) accrued time in each health state up to that date. Results Second-line cabozantinib was associated with significantly longer mean TOX (49.8 vs 9.8 days, p Conclusions Patients with aHCC receiving second-line cabozantinib after sorafenib spent significantly more time without disease symptoms and toxicity than those receiving placebo, despite an increase in days with grade 3/4 toxicity before progression. Table . 754P Health state Cabozantinib (N = 331) Mean days (95% CI) Placebo (N = 164) Mean days (95% CI) Difference cabozantinib - placebo Mean days (95% CI; t test) TOX 49.8 (39.2–60.3) 9.8 (2.6–17.0) 40.0 (27.3–52.7; p TWiST 110.9 (96.7–125.2) 78.1 (64.7–91.5) 32.8 (13.3–52.3; p = 0.001) REL 174.5 (152.5–196.5) 178.6 (144.1–213.0) -4.1 (-43.5–35.4; p = 0.85) CI, confidence interval; REL, survival time after progression/relapse; TOX, time with a grade 3/4 toxicity before progression; TWiST, time without disease symptoms and grade 3/4 toxicity Clinical trial identification NCT01908426. Editorial acknowledgement Oxford PharmaGenesis, Oxford, UK for providing editorial support, which was sponsored by Ipsen, Abingdon, UK in accordance with Good Publication Practice guidelines. Legal entity responsible for the study Ipsen. Funding Ipsen. Disclosure N. Freemantle: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Biogen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Yesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Allergan; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PTC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca. G.K. Abou-Alfa: Advisory / Consultancy: 3DMedcare; Advisory / Consultancy, Research grant / Funding (institution): Agions; Advisory / Consultancy: Alignmed; Advisory / Consultancy: Antengene; Advisory / Consultancy: Aptus; Advisory / Consultancy: Aslan; Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Beigene; Advisory / Consultancy: Bioline; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Boston Scientific; Advisory / Consultancy: Bridgebio; Advisory / Consultancy: Carsgen; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Casi; Advisory / Consultancy: Cipla; Advisory / Consultancy: Cytom X; Advisory / Consultancy: Daiichi. A. Cheng: Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): Merck Sharp Dohme; Honoraria (self), 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; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix Ltd.; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd; Speaker Bureau / Expert testimony: Amgen Taiwan. R.K. Kelley: Advisory / Consultancy: Genentech/ Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Agios; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): QED; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Taiho. V. Valcheva: Full / Part-time employment: Ipsen. F. Benzaghou: Full / Part-time employment: Ipsen. P. Mollon: Full / Part-time employment: Ipsen.

Background ALBI grade is an objective measure of liver function for patients with HCC; higher ALBI grade is associated with worse prognosis. In the phase 3 CELESTIAL trial (NCT01908426), cabozantinib, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) vs placebo in patients with previously treated HCC and is now approved for patients with HCC who received prior sorafenib. Here, we evaluate outcomes based on ALBI grade in the CELESTIAL trial. Methods 707 patients were randomized 2:1 to cabozantinib (60 mg daily) or placebo. Eligible patients had HCC, Child-Pugh score A, and ECOG PS ≤ 1. Patients received prior sorafenib and ≤2 lines of prior systemic therapy for HCC. Baseline ALBI score was calculated from serum albumin and total bilirubin measured centrally, and was used to determine ALBI grade (Johnson, J Clin Oncol. 2015;33:550-8). Results At baseline, 186 patients (40%) were ALBI grade 1 and 282 (60%) were ALBI grade 2 in the cabozantinib arm; 182 patients (43%) were ALBI grade 1 and 133 (56%) were ALBI grade 2 in the placebo arm. Two patients in each arm were ALBI grade 3. Patients with ALBI grade 1 had better ECOG PS (61% ECOG 0 & 39% ECOG 1) vs those with ALBI grade 2 (48% ECOG 0 & 52% ECOG 1). In patients with ALBI grade 1, median OS was 17.5 months with cabozantinib vs 11.4 months with placebo (HR 0.63, 95% CI 0.46-0.86). In patients with ALBI grade 2, median OS was 8.0 months with cabozantinib vs 6.4 months with placebo (HR 0.84, 95% CI 0.66-1.06). In patients with ALBI grade 1, median PFS was 6.5 months with cabozantinib vs 1.9 months with placebo (HR 0.42, 95% CI 0.32-0.56) and in patients with ALBI grade 2, median PFS was 3.7 months with cabozantinib vs 1.9 months with placebo (HR 0.46, 95% CI 0.37-0.58). Common grade 3/4 adverse events in both groups were consistent with the overall population. Treatment related discontinuations in the cabozantinib arm were 12% and 19% for patients with ALBI grade 1 and 2. Conclusions Patients treated with cabozantinib had longer PFS and OS vs patients receiving placebo, regardless of ALBI grade. Outcomes were generally better in patients with ALBI grade 1 vs 2. Clinical trial identification NCT01908426 (Other Study ID Numbers: XL184-309). Editorial acknowledgement Suvajit Sen (Exelixis). Legal entity responsible for the study Exelixis. Funding Exelixis. Disclosure S.L. Chan: Advisory / Consultancy: Amgen. R. Miksad: Full / Part-time employment: Flatiron Health; Shareholder / Stockholder / Stock options: Flatiron Health; Research grant / Funding (institution): Exelixis, Bayer. I. Cicin: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Sharp & Dohme Corp; Advisory / Consultancy: F. Hoffmann-La Roche; Advisory / Consultancy: Pfizer. H.J. Klumpen: Advisory / Consultancy: IPSEN; Research grant / Funding (institution), Local PI for clinical trial from the following organizations: IPSEN Exelexis, ITM, SIRTEX, Taiho, BAYER, DAICHII, Novartis, BTG. S. Kim: Research grant / Funding (institution): Genentech, Roche, Pfizer; Advisory / Consultancy: Amgen, Bayer, Boehringer Ingelheim, MSD, Novartis, Roche, Sanofi, Servier. J. Youkstetter: Shareholder / Stockholder / Stock options, Full / Part-time employment: Exelixis. S. Sen: Full / Part-time employment, Self and spouse: Exelixis; Shareholder / Stockholder / Stock options, Self and spouse: Exelixis. A-L. Cheng: Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutica; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Nucleix; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: IQVIA; Honoraria (self): Merck Sharp Dohme. A.B. El-Khoueiry: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Astex; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy: Agenus; Advisory / Consultancy: Merck; Advisory / Consultancy: EISAI; Advisory / Consultancy: Pieris; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Apeiron. T. Meyer: Advisory / Consultancy: BMS, BAYER, EISAI, BTG, AZ, BEIGENE, TARVEDA, MSD; Research grant / Funding (institution): BTG BAYER. R.K. Kelley: Advisory / Consultancy: Agios, AstraZeneca, Bayer, BMS (funding to institution) IDMC: Genentech/Roche (funding to self); Research grant / Funding (institution): Agios, AstraZeneca, Bayer, BMS, Eli Lilly, Exelixis, EMD Serono, Medimmune, Merck, Novartis, QED, Taiho. G.K. Abou-Alfa: Research grant / Funding (self): ActaBiologica,; Advisory / Consultancy, Research grant / Funding (self): Agios,; Research grant / Funding (self): Array,; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer,; Advisory / Consultancy, Research grant / Funding (self): Beigene,; Advisory / Consultancy, Research grant / Funding (self): BMS,; Research grant / Funding (self): Casi,; Research grant / Funding (self): Celgene,; Research grant / Funding (self): Exelixis,; Research grant / Funding (self): Genentech,; Research grant / Funding (self): Halozyme,; Research grant / Funding (self): Incyte,; Research grant / Funding (self): Lilly,; Research grant / Funding (self): Mabvax,; Research grant / Funding (self): Novartis,; Research grant / Funding (self): OncoQuest,; Research grant / Funding (institution): Polaris Puma; Research grant / Funding (self): QED,; Research grant / Funding (self): Roche; Advisory / Consultancy: 3DMedcare,Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas, AstraZeneca, Bayer, Beigene, Bioline, BMS, Boston Scientifc, Bridgebio, Carsgen, Celgene, Casi, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Flatiron, Genoscience, Halozyme. All other authors have declared no conflicts of interest.

INTRODUCTION: Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

2606 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in > 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (> 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.

4118 Background: TGF-ß signaling is associated with HCC progression in moderate to poorly differentiated tumors overexpressing alpha-fetoprotein (AFP) levels. We report here the safety and antitumor activity of LY in HCC patients with elevated AFP in this ongoing study. Methods: Patients with advanced HCC who progressed on sorafenib (SF) or are ineligible to receive SF, advanced Child-Pugh A/B7 HCC, AFP ≥1.5x ULN, ECOG PS ≤1, measurable disease (RECIST 1.1), and ≤1 prior systemic regimen were eligible. LY was administered as intermittent dosing of 14 days on/14 days off (28 days =1 cycle). Patients were randomized to either 160 mg/day (Arm A) or 300 mg/day (Arm B) LY. Primary endpoints were time-to-progression (TTP) and biomarker changes (serum AFP, TGF-ß and E-cadherin) for each dose. Secondary endpoints included toxicity (CTCAE, V 4.0) and pharmacokinetics (PK). Results: 106 patients were enrolled (Arm A=37; B=69), including 92% non-Asians. Baseline characteristics were (Arm A/B): median age 61/66 years; PS=0 60/51%; Child-Pugh A 97/86%; etiology: hepatitis C 30/33%, hepatitis B 24/25%, alcohol 22/22%. Overall, 78/83% of patients had received prior SF; 64/58% of patients had AFP ≥400 ng/mL. Median TTP was 12.0 weeks (90% CI: 7.1, 12.6) in the overall population (Arm A, 12.6 weeks; Arm B, 10.9 weeks). In SF-naïve patients, TTP was 18.3 weeks (90% CI: 6.3-non-estimable). TTP was higher in the non-alcohol compared to alcohol-only etiology group (median 12.1 vs. 6.1 weeks). Median baseline serum TGF-ß1 was 3.4 ng/mL (range: 1.4-3.7) and E-cadherin was 6.1 mg/mL (range: 1.9-17.3). AFP decline of >25% occurred in 21/106 patients (20%). Four patients discontinued treatment due to a drug-related AE. Most common grade 3/4 related AEs in patients were: neutropenia (n=3), GI bleeding (n=2), fatigue (n=2), and anemia (n=2). Preliminary PK analysis (51 patients) demonstrated moderate interpatient exposure variability (42%). Conclusions: Based on the manageable toxicity profile, the evidence for biomarker/TTP responses, and an analysis of the aggregate PK/PD data, the 300 mg/day dose was chosen for future studies in HCC. Clinical trial information: NCT01246986.

4014 Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n = 46. Study treatment consisted of erlotinib 100 mg + selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) > 6 weeks, 10 with SD > 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline > 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no study-related deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.

2517 Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3+3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ≥ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment >16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ≥50% decline in alpha-fetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other anti-angiogenic agents. Clinical trial information: NCT01271972.

2605 Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2+ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2+ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2+ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a >7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2+ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.

207 Background: Noninvasive biomarkers are urgently needed to improve diagnosis, prognosis, and molecular characterization in HCC. Detection of CTC by EpCAM-enrichment methods is associated with poor outcomes in other tumors. Approximately 35% of HCC are EpCAM+. We hypothesized that CTC are detectable in a subset of metastatic HCC but not in NMLD and that CTC DNA might serve as a source of tumor DNA for biomarker detection and discovery. Methods: Whole blood was obtained from (1) patients with metastatic HCC and (2) NMLD controls. CTC were enumerated using CellSearch by blinded investigators. If > 10 CTC/7.5 mL, immunomagnetic enrichment for EpCAM followed by fluorescence-activated cell sorting (FACS) was also performed to collect highly purified CTC for whole genome amplification (WGA) by GenomePlex WGA4 kit. NGS using 46-gene AmpliSeq Cancer Panel (Ion Torrent) was performed on DNA from CTC, formalin-fixed paraffin embedded tumor (FFPE), and peripheral blood mononuclear cells (PBMC) if available. Results: 20 HCC and 10 NMLD were enrolled. FFPE was available in 7 HCC. In HCC cohort, median alpha-fetoprotein (AFP) was 492 ng/mL (range: 3.8-587,134) and vascular invasion (VI) was present in 13/20 (65%). CTC ≥ 3/7.5 mL were detected in 6/20 (30%, 95% CI: 0.08, 0.52) HCC and 0/9 (95% CI: 0, 0) eligible NMLD (p=0.07). One NMLD had CTC > 3/7.5 mL but was found to have HCC on surveillance ultrasound and excluded. CTC ≥ 3/7.5 mL were associated with AFP ≥ 400 (p=0.01) and VI (p=0.05) by Fisher’s exact test. NGS identified mutations listed in COSMIC in the majority including TP53 and CTNNB1. Variants appeared more frequent in CTC than FFPE in this small sample. Coverage was significantly lower in CTC than FFPE (coverage 20x mean 50% vs 93%, p < 0.02 by unpaired t-test). Conclusions: CTC are a promising biomarker in metastatic HCC and merit further study, including non-EpCAM methods. CTC were associated with AFP and VI. NGS of CTC WGA DNA is feasible and identified characteristic mutations but was limited by coverage bias. Updated NGS findings including 5 cases with paired CTC, FFPE, and/or PBMC will be presented.

e14569 Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage II CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage II CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage II CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p

4102 Background: Mammalian target of rapamycin inhibitors added to SOR augment antitumor effect in HCC models. We developed a phase 1 trial to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of TEM plus SOR in HCC patients (pts). The study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support from Pfizer, Inc., and conducted at 2 NCCN centers. Methods: Eligibility: ≥1 measurable site. No prior systemic therapy (Tx). ECOG ≤2, Child Pugh ≤7, bilirubin ≤2 mg/dL, platelets (PLT) ≥75,000/mcL. Design: 3+3 escalation. Dose-limiting toxicity (DLT) window 28 days. MTD expansion cohort of 9 pts for PK and biomarkers. Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK for TEM. Exploratory: Tumor necrosis, alpha fetoprotein (AFP)-L3, des-γ-carboxyprothrombin, and circulating tumor cells (CTC) by slide-based assay. Results: 21 pts enrolled. Median age: 60 (47-77). Male/Female: 15/6. Etiology: HCV 9 (43%), HBV 4 (19%), HBV+HCV 2 (10%), ETOH 2 (10%), unknown 4 (19%). Toxicity: DL1: 1 DLT Grade (Gr) 3 PLT. All pts required reductions for adverse events (AE); de-escalated to DL-1 for intolerability. DL-1: 1 DLT Gr3 hand-foot syndrome (HFS). Most common related ≥Gr 3 AE: HypoPO4 (52%); PLT (24%); transaminitis (19%); diarrhea, fatigue, HFS (10% each). Possibly related serious AE (SAE): Gr4 tumor rupture, Gr4 urosepsis, Gr3 dental infection with Gr2 ANC, Gr2 pneumonia (1 pt, 5% each). Best response: Confirmed partial response (PR) 2/21 (10%), stable disease (SD) 11/21 (52%), progression 1/21 (5%), 7/21 (33%) not evaluable. Time on study: Range 50% decline. CTC were detected in 5/5 of tested samples. Decreased tumor enhancement on Tx was seen. Conclusions: DL-1 is MTD and RP2D, lower than a prior trial in pts without HCC; tolerability may be impacted by cirrhosis. Encouraging durable radiographic and AFP responses occurred. [Table: see text]

3006^ Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions. TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance. CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design. CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression. Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results: 28 subjects were treated across 5 dose levels: 7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8). The most common (> 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%). Dose-limiting toxicity (all grade 3) occurred in 4 subjects: hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg). The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg). Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an Emax model. Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD. Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions: CC-223 was well tolerated with toxicities comparable to other drugs in this class. Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR. Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.

4007 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. MET over-expression has been observed in advanced hepatocellular carcinoma (HCC). Anti-VEGF pathway agents have shown clinical benefit in pts w/ HCC. Simultaneous targeting of the MET and VEGF signaling pathways with cabo may therefore be a promising treatment strategy. Methods: Eligible HCC patients (pts) were required to have measurable disease per RECIST, ≤ 1 prior systemic regimen and Child-Pugh score of A. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). The primary endpoint was overall response rate (RR) per mRECIST in the Lead-in stage. Results: Enrollment has been completed (n = 41); all pts are unblinded. Median age: 61 years (33 to 83). Males: 76%; Asian: 37%. HCC etiology: Hep B 24%; Hep C 22%; alcohol abuse 20%; other 38%. Extra-hepatic spread observed in 70%. Median number of prior systemic treatments was 1; prior sorafenib was 51%. Median baseline AFP was 368 ng/mL (3 – 259,298); 86% had elevated AFP at baseline. Median follow-up was 5.5 mos (0.8 -18.5). 29 pts (71%) completed the Lead-in stage. Median PFS from Study Day 1 was 4.2 mos. 2/36 pts evaluable for tumor assessment at 12 weeks achieved a confirmed PR (cPR) by original RECIST (RR 5%). One more pt randomized at Week 12 achieved a cPR at 18 weeks. 28/36 pts (78%) with ≥1 post-baseline scan had tumor regression (with no apparent relationship to prior sorafenib therapy). The overall disease control rate (DCR = PR+SD) at Week 12: was 68% (Asian subgroup: 73%). AFP responses (defined as reduction from baseline of >50% in pts with elevated AFP at baseline) in 26 pts with ≥1 post-baseline result: 10/26 (38%). Most common Gr 3/4 AEs: diarrhea (17%), palmar-plantar erythrodyesthesia (15%), and thrombocytopenia (10%). Conclusions: Cabo treatment exhibits activity in HCC pts regardless of prior sorafenib treatment. The safety profile was comparable to that of other VEGFR TKIs.

285 Background: Building on strong preclinical data, we hypothesized that concomitantly targeting mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) signaling pathways will inhibit neuroendocrine tumors (NET) more effectively than targeting either pathway alone (thus improving likelihood of shrinkage). We initiated a prospective, phase II study to assess the safety and efficacy of RAD001 plus erlotinib in patients (pts) with advanced NET. Methods: Pts with well-differentiated NET were enrolled using a Simon 2-stage design with 2 groups: pancreatic NET (PNET) and other low-grade NET/ carcinoid (CARC). Eligibility criteria included histological diagnosis of a well- to moderately-differentiated NET and no prior mTOR- or EGFR-inhibitor. Pts treated with RAD001 5 mg PO QD and erlotinib 100 mg PO QD without scheduled breaks (1 cycle = 28 d). Pts followed for toxicity and radiographic response, with first planned analysis after 8 evaluable pt/group. Results: Since 6/09, 17 pt enrolled: M/F 9/8; PNET/CARC 8/9. Pts on octreotide remained on drug. All pt had PD at enrollment. Median # cycles: 12 in CARC (range 2-20); 5.5 (to date) in PNET (range 0.5-18). Excessive toxicity in first 7 pts prompted reduction in starting erlotinib dose from 150 to 100 mg/d, resulting in improved tolerability: Gr 3 stomatitis in 3/7 initial pts (43%) vs 1/10 (10%) after new starting dose. Overall, the most common side effects include diarrhea, stomatitis, rash, anorexia, and fatigue. Enrollment to CARC cohort stopped after first stage due to insufficient efficacy (7/9 SD, 2/9 PD; 0 PR). Conclusions: RAD001 plus erlotinib appears to be associated with radiographic stability, but not shrinkage, in CARC. Combining the two agents has proven challenging; toxicity precludes administration of either agent at full dose. Interim efficacy analysis for PNET stratum pending. Correlation with expression of mTOR pathway components in archived tissue planned.

4089 Background: FLL-HCC is rare and develops in young individuals of either gender in the absence of underlying liver disease. There are limited data on the demographics and outcome of FLL-HCC. Me...

e14665 Background: Most patients (pts) with pancreatic cancer are unresectable at diagnosis. About 70% of these pts will develop obstructive jaundice requiring intervention. Most commonly, relief o...

296 Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN). Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK. Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response. Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented. [Table: see text] [Table: see text]

4136 Background: GEM-based therapy remains the standard of care for APC and ABC. The addition of CAP to GEM has produced modest improvements in clinical outcomes compared to GEM alone in several ph...

TPS213 Background: The multikinase inhibitor SOR prolongs survival in patients with advanced HCC. Another pathway often active in HCC is mammalian target of rapamycin (mTOR). Preclinical studies su...