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AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican‐3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time‐to‐event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16(MESF)) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time‐to‐event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 μg ml(−1) and high CD16(MESF) level (>5.26 × 10(5) MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16(MESF) level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

BACKGROUND: Identification of pathogenic germline alterations (PGAs) has important clinical and therapeutic implications in pancreas cancer. We performed comprehensive germline testing (GT) in an unselected prospective cohort of patients with exocrine pancreatic neoplasms with genotype and phenotype association to facilitate identification of prognostic and/or predictive biomarkers and examine potential therapeutic implications. METHODS: Six hundred fifteen unselected patients with exocrine pancreatic neoplasms were prospectively consented for somatic tumor and matched sample profiling for 410–468 genes. GT for PGAs in 76 genes associated with cancer susceptibility was performed in an “identified” manner in 356 (57.9%) patients and in an “anonymized” manner in 259 (42.1%) patients, using an institutional review board–approved protocol. Detailed clinical and pathological features, response to platinum, and overall survival (OS) were collected for the identified cohort. OS was analyzed with Kaplan-Meier curves. RESULTS: PGAs were present in 122 (19.8%) of 615 patients involving 24 different genes, including BRCA1/2, ATM, PALB2, and multiple additional genes associated with the DNA damage response pathway. Of 122 patients with germline alterations, 41.8% did not meet current guidelines for GT. The difference in median OS was not statistically significant between patients with and without PGA (50.8 months, 95% confidence interval = 34.5 to not reached, two-sided P = .94). Loss of heterozygosity was found in 60.0% of BRCA1/2. CONCLUSIONS: PGAs frequently occur in pancreas exocrine neoplasms and involve multiple genes beyond those previously associated with hereditary pancreatic cancer. These PGAs are therapeutically actionable in about 5% to 10% of patients. These data support routinely offering GT in all pancreatic ductal adenocarcimona patients with a broad panel of known hereditary cancer predisposition genes.

The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.

Brain metastases (BM) from pancreatic ductal adenocarcinoma (PDAC) are an infrequent event. We identified n=25 pts from MSKCC with BM and PDAC; median age 58years. Median time to the development of BM was 17 months (range 0 to 79). Median overall survival from the time of BM development was 1.5 months (1 to 31). Six patients had germline testing; with BRCA1 (n=1) or BRCA2 (n=2) alterations detected. Seven patients had molecular profiling with KRAS, TP53 and MYC amplification most frequent. BACKGROUND: The purpose of this study was to assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM) as well as the somatic and germline molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germline testing where performed in the subset of patients that had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8 gene panel). Overall survival (OS) was calculated from date of diagnosis to either date of last follow up or death. Survival post brain metastasis was calculated from date of diagnosis of brain metastases by radiology or pathology to either date of last follow up or death. RESULTS: From a total of 5,824 patients with PDAC identified from January 2000 to January 2016, twenty-five (0.4%) patients had brain metastases. Median age of PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (0 to 79). Median OS following BM diagnosis was 1.5 months (range 1 to 31). OS for patients that had craniotomy (n=4) was 11 months (1 to 31 months) with two long term survivors; 21 and 31 months respectively. Four patients had leptomeningeal disease. 6/25 pts had germline testing, 3 had BRCA mutations; BRCA1 (n=2) and BRCA2 (n=1). Somatic profiling identified KRAS mutations in 100%; G12D (n=4), G12V (n=2) and Q61K (n=1). CONCLUSION: BM from PDAC is a rare event. We identified a speculitive association of germline BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival post BM development is poor with prolonged survival in selected patients via a multidisciplinary approach.

Conflicts of Interest: A.N.S.: Research funding from Bristol-Myers Squibb. The other authors have no conflicts of interest to declare.

Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study. Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili)

Background Providing an estimate of the percentage of cancer in Lebanon by 2018 that is due to the exposure to risk factors in 2008. Factors include: smoking, body mass index (BMI), physical inactivity, dietary factors, alcohol consumption, infections, and air pollution in adults. Method Population Attributable Fraction (PAF) was calculated using the proportion of the population exposed and relative risks for each risk factor from meta-analyses. The PAF estimates the proportion of cases in which exposure may have played a causal role. Results Smoking caused most cancer cases, and it will further add a total of 1800 new cases by 2018. Among many other cancers, lung cancer had the largest proportion attributable of around 75%. BMI is expected to increase colorectal, liver and gastric cardia carcinoma specifically in males. High physical activity has a an average of 15% protection rate on cancer on colorectal cancer. Minimal adherence to Mediterranean diet will affect gastric cancer incidence by 7%. Cases of oropharyngeal and esophageal cancer will be the result of alcohol consumption mainly in males. H.Pylori infection is expected to result in half of the gastric cases by 2018. The high exposure to air pollution is expected to contribute by 13% to lung cancer cases in 2018. Conclusion The highest benefits can be achieved by controlling tobacco smoking. Interrelated and small changes in weight, physical activity and healthy diet with limited alcohol consumption can protect against several GI cancers in the long run. These results can be used to determine public health interventions that target important risk factors in the general population.

Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%-9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52-2.97; P

Purpose: Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy. Experimental Design: Archival or prospectively acquired FFPE samples and matched normal DNA from N = 336 patients with pancreatic cancer were analyzed using a hybridization capture–based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles. Results: The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results. Conclusions: The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. Clin Cancer Res; 23(20); 6094–100. ©2017 AACR.

ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1.A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/mEighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/mADI-PEG 20 was well tolerated in combination with gemcitabine and nab-paclitaxel. Activity was observed in previously treated and untreated patients with advanced pancreatic cancer and in patients with ASS1-deficient and -proficient tumors. Cancer 2017;123:4556-4565. © 2017 American Cancer Society.

Background Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. Trial registration number NCT00940225.

Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0–1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Despite a few global regions with increased incidence, cancers of the biliary tract remain a rare entity. Cholangiocarcinoma has been referred to as an ‘orphan’ cancer, given its relative infrequency in the Western population.

Western and Eastern perspectives on therapeutic guidelines for hepatocellular carcinoma (HCC) have many commonalities but may also differ in certain aspects, as described in this article. In view of the limited therapeutic options for advanced HCC, evidence-based therapies are few, and thus there is a dependence on consensus-based guidelines. This article focuses on the Italian Association for the Study of the Liver guidelines and the Japanese approaches to therapy, while drawing attention to certain controversies from other academic bodies where applicable and appropriate.

Purpose: Despite a challenging prognosis, modern cytotoxic therapy can induce tumor responses and extend life in pancreatic adenocarcinoma (PDAC). Pharmacogenomic (PGx) modeling of tumor tissue can predict the efficacy of chemotherapeutic agents in preclinical cancer models. We hypothesized that PGx profiling of circulating tumor and invasive cells (CTIC) isolated from peripheral blood could predict tumor response, progression, and resistance. Experimental Design: A PGx model was created and validated in preclinical models. A prospective clinical trial was conducted. Fifty patients with advanced PDAC were enrolled. Before treatment, 10 mL of peripherally drawn blood was collected. CTICs isolated from this blood sample were expression profiled and the PGx model was used to predict effective and ineffective chemotherapeutic agents. The treating physicians were blinded to PGx prediction. Results: We found that CTICs could be reliably isolated, total RNA extracted and profiled from 10 mL of peripheral blood from patients with unresectable PDAC before chemotherapy treatment and at disease progression. Using previously created PGx models to predict chemotherapy sensitivity, we found that clinical benefit was seen for study participants treated with chemotherapy regimens predicted to be effective versus chemotherapy regimens predicted to be ineffective with regard to progression-free (10.4 mo vs. 3.6 mo; P < 0.0001; HR, 0.14) and overall survival (17.2 mo vs. 8.3 mo; P < 0.0249; HR, 0.29). Conclusions: These findings suggest that PGx profiling of CTICs can predict treatment response. Clin Cancer Res; 20(20); 5281–9. ©2014 AACR.

The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined.We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma.Eligible patients were screened using computed tomography-pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m intravenously over 100 minutes and oxaliplatin 80 mg/m intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies.Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17-NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19-NA).This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key. Clinical trials identification: NCT00536874.

Hepatocellular carcinoma is a common malignancy with a poor prognosis. Sorafenib is the only systemic therapy known to improve the overall survival of patients with advanced disease. The clinical benefit of sorafenib is modest and the mechanistic basis for its activity is unknown. Four phase 3 clinical trials have failed to improve on sorafenib in the frontline setting and no agent has been shown to impact outcomes after sorafenib failure. Several factors have contributed to this recent stall in drug development but new approaches hold promise and currently are being investigated. This review will focus on the current pipeline of experimental therapeutics for patients with advanced hepatocellular carcinoma and shed a light on scientific limitations that hamper the advancement of new therapies for this disease, and ways around it.

comorbidities, such as liver cirrhosis or chronic hepatitis infection. The following report presents highlights from a roundtable discussion between 4 leading experts in HCC: Jorge Marrero, MD, from the University of Texas Southwestern Medical Center, Mary A. Maluccio, MD, from the Indiana University Melvin and Bren Simon Cancer Center, Heather McCurdy, RN, from the VA Ann Arbor Healthcare System, and Ghassan K. AbouAlfa, MD, from the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College at Cornell University. The panel members share insights into how they stage and monitor patients, their treatment strategies for early-, intermediate-, and advanced-stage HCC, and promising novel therapies on the horizon. In addition, case studies are used to demonstrate selected therapeutic strategies in real-world scenarios.

Importance Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC). Objective To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. Design, Setting, and Participants This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group–American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS. Interventions or Exposures Patients received either 60 mg/m2of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL. Main Outcomes and Measures The primary end point was OS, and progression-free survival (PFS) was a secondary end point. Results Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib. Conclusions and Relevance This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. Trial Registration ClinicalTrials.gov identifier:NCT01015833

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 Lysosome has been described as target of interest for cancer therapy. GNS561 is a new lysosomotropic small molecule which displays meaningful activity against several tumor types, specifically in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Herein, we report preliminary results of the Phase 1b/2a study of GNS561 in advanced primary liver cancer patients. Methods The Phase 1b portion is a non-randomized, one arm (3 + 3 design) clinical trial with a maximum enrolment of 36 patients. GNS561 was administered orally to histologically confirmed HCC or iCCA adult patients not eligible for curative therapy in 4 week cycles. The objectives are to assess the safety and pharmacokinetics (PK) of GNS561 and to determine the recommended phase 2 dose. Early safety, PD and PK data from patients of the 4 first dose levels are reported. Results As of May 2019, 13 patients were enrolled with 10 patients having completed the study with at least one cycle of treatment. Median patient age was 66 years (range 31 - 80), 3 (23%) were female, 6 (46%) had HCC; median number of prior systemic therapies was 1 (range 1-5). Patients received a median number of 2 cycles of GNS561. Six (46%) patients interrupted treatment because of tumor progression, 31% (n = 4) for investigator decision, and 7.7% (n = 1) for serious adverse event. Thus far, no dose limiting toxicity (DLT), or DLT equivalent toxicity have been observed. Most of related-AEs are digestive toxicities (grade 1-2 nausea, vomiting and diarrhea), fatigue and blood parameters abnormalities. The 400 mg cohort is currently ongoing. 70% (n = 7) patients were evaluable for tumor imaging assessment: 43% of them (n = 3) were stable at the beginning of Cycle 3, among which 2 patients had stable disease at the beginning of Cycle 5. Patients showed increasing exposure to GNS561 along with the dose in blood and liver, with dose-proportionality in plasma. Liver concentrations are at least 200 fold higher than in plasma. Conclusions Current data show patients that oral GNS561 displays a favorable safety profile, and exposure in blood and liver throughout the dosing interval. Enrollment in Phase 1b is continuing before extension to Phase 2a. Clinical trial identification 2017-003585-27. Legal entity responsible for the study Genoscience Pharma. Funding Genoscience Pharma. Disclosure A.H. Awada: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. J.J. Harding: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. N. Kotecki: Honoraria (institution): Genoscience Pharma. P.G. Aftimos: Honoraria (institution): Genoscience Pharma. T. Decaens: Honoraria (institution): Genoscience Pharma. C. Dreyer: Honoraria (institution): Genoscience Pharma. C. Ansaldi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma. M. Rachid: Full / Part-time employment: Genoscience Pharma. C. Serdjebi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma. P. Halfon: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Genoscience Pharma. G.K. Abou-Alfa: Honoraria (institution), Advisory / Consultancy: Genoscience Pharma. E. Raymond: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Full / Part-time employment: Genoscience Pharma.

Background Nivolumab (NIVO), a programmed death-1 (PD-1) inhibitor, is approved in several countries for sorafenib-treated patients (pts) with advanced hepatocellular carcinoma (aHCC) based on CheckMate040. We report findings on exploratory biomarker analyses. Methods In CheckMate040, pts with aHCC received NIVO regardless of programmed death ligand 1 (PD-L1) status and HCC etiology. Baseline tumor samples were analyzed by IHC for expression of PD-L1, PD-1, T-cell markers (CD3, CD4, CD8, FOXP3), and macrophages (CD68, CD163), and (in a subset of pts) by RNA sequencing for inflammatory signatures (ISs). Results were correlated with clinical outcomes: response (complete response [CR]/partial response [PR]/stable disease [SD]/progressive disease [PD]) and overall survival (OS). Associations with etiology and geographical region (non-Asia vs Asia) were assessed. Data cutoff: June 2018. Results In 184 pts with evaluable data, increased tumor cell PD-L1 expression was associated with response (CR+PR vs SD [P = 0.00009]; CR+PR vs PD [P = 0.0007]) and OS (P = 0.03), as was increased PD-1 expression (CR+PR vs SD [P = 0.05]; CR+PR vs PD [P = 0.009]; OS [P = 0.05]). Of the T-cell markers assessed, CD3 was associated with response (n = 182, CR+PR vs SD; P = 0.05). In pts positive for CD3 or CD8, there was a trend toward improved OS (P = 0.08). There was no association between CD68 and CD163 expression and clinical outcomes. For 37 pts with RNA sequencing data available, median Bristol-Myers Squibb (BMS) IS score was higher in pts with PR vs SD (P = 0.05) and was correlated with improved OS (P = 0.01). For all inflammation markers assessed, there was no association with etiology or geographical region. Conclusions In pts with aHCC, improved OS and response to NIVO may be associated with higher PD-L1, PD-1, and CD3 expression, and higher BMS IS scores, supporting the role of PD-1 inhibition in HCC treatment. Further investigation of these biomarkers is required. Originally presented at the AACR 2019.

Gallbladder cancer is an aggressive cancer that continues to be an important health care issue in certain regions of the world such as Southeast Asia and Latin America. Most patients are diagnosed at an advanced, unresectable stage and systemic therapy is their only option. Gallbladder cancer patients have traditionally been included in clinical trials for biliary tract cancer. Thus, systemic chemotherapy options for this cancer are similar to those for cholangiocarcinoma, including gemcitabine and cisplatin in the first line and FOLFOX in the second-line setting. Ongoing phase III clinical trials may change the systemic therapy paradigm for this cancer. Molecular profiling has indicated important genetic differences between gallbladder cancer and cholangio-carcinoma, which affects choice of targeted therapy. Her2/neu amplification, PIK3CA mutations and DNA repair genetic aberrations are relatively frequent and represent actionable targets for this cancer.

Introduction: Nivolumab (NIVO), a programmed death-1 (PD-1) inhibitor, demonstrated durable responses, manageable safety, and promising long-term survival in patients (pts) with advanced hepatocellular carcinoma (HCC), regardless of etiology, with/without prior sorafenib treatment in CheckMate 040 (El-Khoueiry, Lancet 2017). NIVO is approved in several countries for the treatment of sorafenib-experienced pts with advanced HCC. We report findings on additional exploratory biomarker analyses from NIVO-treated pts with advanced HCC from CheckMate 040. Methods: In CheckMate 040, pts with advanced HCC received NIVO monotherapy in the phase 1/2 dose-escalation (ESC; 0.1–10 mg/kg) and dose-expansion (EXP; 3 mg/kg) phases every two weeks, regardless of programmed death ligand 1 (PD-L1) status and HCC etiology. For pts in the ESC and EXP phases receiving NIVO 3 mg/kg, baseline tumor biopsy samples were analyzed using immunohistochemistry for the following markers: expression of PD-L1, PD-1, T-cell markers (CD3, CD4, CD8, FOXP3), and macrophages (CD68, CD163). Baseline tumor biopsy samples from a subset of pts in the ESC and EXP phases were evaluated using RNA sequencing to assess inflammatory signatures. Results were correlated with clinical outcomes: response (complete response [CR] + partial response [PR] vs stable disease [SD] or progressive disease [PD]) and overall survival (OS). Associations with characteristics such as etiology and geographical region (non-Asia vs Asia) were also assessed. The data cutoff date was June 2018. Results: In pts with evaluable data (n = 184), increased tumor cell PD-L1 expression was significantly associated with response (CR+PR vs SD [P = 0.00009]; CR+PR vs PD [P = 0.0007]) and OS (P = 0.03). Increased PD-1 expression was also significantly associated with response (CR+PR vs SD [P = 0.05]; CR+PR vs PD [P = 0.009]) and OS (P = 0.05). Of the T-cell markers assessed, CD3 expression was significantly associated with response (n = 182, CR+PR vs SD; P = 0.05). In pts positive for CD3 or CD8, there was a trend towards improved survival (P = 0.08). No association between CD68- and CD163-expression and clinical outcomes was observed. For the subset of pts for whom RNA sequencing data was available (n = 37), the median Bristol-Myers Squibb (BMS) inflammatory signature score was significantly higher in pts with a PR vs SD (P = 0.05) and was correlated with improved OS (P = 0.01). For all of the inflammation markers assessed, there was no association with HCC etiology or geographical region. Conclusions: In pts with advanced HCC, improved survival and response to nivolumab may be associated with higher PD-L1, PD-1 and CD3 expression, and higher BMS inflammatory signature scores. These data support the role of PD-1 inhibition in the treatment of HCC. Further investigation of these biomarkers is required. Citation Format: Ignacio Melero, Jaclyn Neely, Bruno Sangro, Richard Finn, Ghassan K. Abou-Alfa, Ann-Lii Cheng, Thomas Yau, Junji Furuse, Joong-Won Park, Samir Wadhawan, Hao Tang, Christine Delacruz, Carlos Baccan, Zach Boyd, Anthony El-Khoueiry. Assessment of inflammation biomarkers in relation to clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma in CheckMate 040 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2675.

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.

TPS4155 Background: Cholangiocarcinoma is the most common biliary tract malignancy with approximately 5,000–10,000 new cases annually in the USA. The fibroblast growth factor receptor (FGFR) family plays an important role in cholangiocarcinoma, with FGFR2 gene fusions detected in about 15% of patients with cholangiocarcinoma. Infigratinib is an ATP-competitive, FGFR1–3-selective oral tyrosine kinase inhibitor. First-line treatment with chemotherapy offers only modest benefit and more effective treatment options are needed. Based on preliminary response data of infigratinib in relapsed/refractory cholangiocarcinoma with FGFR2 fusions/translocations (Phase 2 Study CBJG398X2204), the PROOF trial is evaluating infigratinib versus gemcitabine + cisplatin in front-line patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations. Methods: Patients with advanced/metastatic or inoperable cholangiocarcinoma are randomized 1:1 to oral infigratinib once daily for 21 days of a 28-day treatment cycle versus IV gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Treatment will continue until confirmed progressive disease by central review, intolerance, withdrawal of informed consent, or death. After 8 cycles of gemcitabine + cisplatin, patients can continue treatment if the investigator considers that they are deriving continued benefit. Patients on the gemcitabine + cisplatin arm who progress can cross-over to infigratinib. The primary endpoint is progression-free survival (PFS, per RECIST v1.1 central review). Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, disease control rate, duration of response, and safety. Quality of life, PK and exploratory genetic alterations/biomarkers will also be measured. Current status: The study was initiated in February 2019 with planned enrollment of 350 patients with confirmed FGFR2 gene fusions/translocations. Clinical trial information: NCT03773302.

4088 Background: Class-specific AEs occurring with tyrosine kinase inhibitors have been associated with improved efficacy outcomes in several tumor types including aHCC. In the phase 3 CELESTIAL trial (NCT01908426), C, an inhibitor of VEGFR, MET, and AXL, improved overall survival (OS) and progression-free survival (PFS) vs placebo (P) in pts with previously treated aHCC. Here, we retrospectively evaluate the association of palmar-plantar erythrodysaesthesia (PPE) and hypertension (HTN) with OS and PFS for C in the CELESTIAL trial. Methods: 707 pts with aHCC were randomized 2:1 to receive 60 mg C or P once daily. Eligible pts had Child-Pugh score A, ECOG PS ≤1, must have received prior sorafenib, and could have received up to two prior regimens of systemic therapy for HCC. OS and PFS with C were evaluated for pts with any grade PPE or grade ≥3 HTN within the first 8 weeks of study treatment. Results: Overall, 374 (80%) pts in the C arm and 179 (76%) pts in the P arm completed ≥8 weeks of treatment. In the first 8 weeks, 188 (40%) of C-treated pts developed any grade PPE vs 11 (5%) of P-treated pts, and 61 (13%) of C-treated pts developed grade ≥3 HTN vs 3 (1%) of P-treated pts. Median OS with C was 14.4 mo for pts with any grade PPE vs 8.4 mo for pts without PPE (HR 0.59, 95% CI 0.47-0.74), and median PFS with C was 6.5 mo vs 3.7 mo, respectively (HR 0.63, 95% CI 0.51-0.78). Median OS with C was 16.1 mo for pts with grade ≥3 HTN vs 9.5 mo for pts without grade ≥3 HTN (HR 0.56, 95% CI 0.39-0.80), and median PFS with C was 7.4 mo vs 4.4 mo, respectively (HR 0.59, 95% CI 0.43-0.82). Some imbalances in baseline characteristics were present. Pts with PPE had better ECOG PS (60% vs 47% ECOG 0), better liver function (48% vs 34% ALBI grade 1), and less macrovascular invasion (24% vs 30%) than those without. Likewise, pts with grade ≥3 HTN had better ECOG PS (61% vs 51% ECOG 0), better liver function (56% vs 37% ALBI grade 1), and less macrovascular invasion (20% vs 29%) than those without. Conclusions: The development of PPE or grade ≥3 HTN with C was associated with prolonged OS and PFS in pts with previously treated aHCC although some imbalances in baseline characteristics between comparator groups were present. Clinical trial information: NCT01908426.

4132 Background: HRD is an emerging biomarker for platinum therapy in PDAC. The clinical implications regarding differences in outcome between germline and somatic HRD in advanced PDAC treated with 1L platinum is unexplored. Methods: We evaluated overall survival (OS) for advanced PDAC (stage III/IV) based on their pathogenic germline (gHRD) and somatic HRD (sHRD) using integrated genomic profiling from MSK-IMPACT and 1L platinum use. HRD defined by pathogenic alterations from the following genes: BRCA1/2, PALB2, ARID1A/B/2, ATR, ATRX, ATM, BAP1, RAD50/51C/D, BRIP1, NBN, CHECK1/2, FANCA/C, CDK12, and MRE11. Results: Advanced PDAC patients (n=461) treated at MSK enrolled in a prospective database, were evaluated. Median follow-up was 27.6 months (95% CI, 24.6-30.6). Both germline and somatic profilings were available for n=350 (76%) but only somatic profiling was available for n=111 (24%). We identified n=52 patients with gHRD (11.3%), n=42 patients with sHRD (9.1%), and 48 patients with somatic VUS for HRD genes. From all 461 patients, the OS was not different between 1L non-platinum vs. 1L platinum groups (19 M vs. 19.3 M), regardleess of their HRD status. (Table) The OS was superior for gHRD vs. non-gHRD (28.7 M vs. 18.2 M), regardless of 1L treatment choice. However, similar significant OS superiority was neither observed in sHRD vs. non-sHRD, nor in VUS sHRD vs. non-VUS sHRD. In a subgroup analysis of 1L platinum treated patients, the OS was superior in gHRD vs. non-gHRD (NR vs. 17.9 M); however, there was no OS difference between sHRD and non-sHRD. Conclusions: In advanced PDAC patients, only gHRD predicted better overall survival for first-line platinum chemotherapy. These findings emphasize the importance of germline mutation testing of HRD in PDAC. Biomarker validation and functional definition of HRD such as loss of heterozygosity analysis is underway. [Table: see text]

4096 Background: FGFR2 alterations are present in 14% of cholangiocarcinomas (CCA) and are promising targets of investigational FGFR-directed therapies. Cell-free DNA profiling has emerged as a non-invasive approach to monitor disease and longitudinally characterize tumor evolution. We describe the use of circulating tumor DNA (ctDNA) among patients (pts) with FGFR2-altered CCA receiving FGFR-targeted therapy in the identification of acquired FGFR2 mutations (mut) at resistance. Methods: Serial blood samples were collected from 8 pts with FGFR-altered CCA for ctDNA isolation and next generation sequencing. Plasma ctDNA collected at baseline and resistance to FGFR-targeted therapy were sequenced using a custom ultra-deep coverage cfDNA panel, MSK-ACCESS, incorporating dual index primers and unique molecular barcodes to enable background error suppression and high-sensitivity mut detection. The assay was enhanced to include all protein-coding exons and relevant introns of FGFR2. In 5/8 pts, genomic profiling of an initial tumor biopsy was performed. Results: 8 pts with FGFR2-altered CCA (7 gene fusions, 1 amplification) were treated with FGFR-targeted therapies. 7/8 pts exhibited stable disease or partial response. 19 total acquired mut in FGFR2 were detected at resistance in 5/8 pts (between 1-9 unique mut identified in each sample). All mut were located in the kinase domain. Conclusions: Acquired mut in FGFR2 are seen in pts who have developed resistance to targeted therapy. CtDNA can be used to identify these mut at the time of acquired resistance. The multitude of FGFR2 mut observed within individual pts suggest heterogeneity and evolutionary convergence of resistance mechanisms. Our results illustrate the utility of ctDNA as a less invasive way to monitor for signs of resistance and to identify other potential targetable alterations. [Table: see text]

TPS477 Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in HCC models. A prior phase 1 study of FOLFOX6 and ADI-PEG 20 established the safety and recommended phase 2 dose of the combination in pts with advanced gastrointestinal tumors (Harding et al. CCP 2018). For 23 treatment-refractory HCC pts who were treated at the recommended phase 2 dose on an expansion cohort of the phase 1, the objective response rate (ORR) was 21% (95% CI 7.5-43.7) and median progression-free survival (PFS) was 7.3 months. These data were favorable when compared to historic data for FOLFOX alone where the ORR was ~8% and PFS was 2.93 months and suggest greater clinical activity of the combination (Qin et al. JCO 2013). Prospective confirmation of these results is required. Methods: This is an international, multicenter, single-arm, open-label phase 2 trial of ADI-PEG 20 and FOLFOX6 for advanced HCC pts with Child-Pugh A liver function who progressed on ≥ 2 prior lines of prior systemic therapy (NCT02102022). The primary objective is to define the ORR by RECIST 1.1 as assessed by blinded independent central review. Secondary objectives include determination of safety, disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), serum arginine, citrulline and anti-ADI-PEG 20 levels over 24 weeks, and alpha-fetoprotein response. Eligible pts receive intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 36 mg/m.2 Cross-sectional imaging will be completed every 8 weeks until progression of disease. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. Clinical trial information: NCT02102022.

207 Background: In patients previously treated for aHCC, cabozantinib (cabo) led to longer overall survival and progression-free survival vs placebo (pbo) in the randomized, phase 3 CELESTIAL trial (NCT01908426; N = 707). CELESTIAL was stopped early for benefit at the second interim analysis. This post hoc analysis estimated the incremental quality-adjusted life years (QALYs) accrued in CELESTIAL. Methods: Health utility was elicited at each study visit using the EQ-5D-5L quality of life questionnaire. (completed by 82–100% of patients overall). UK crosswalk tariffs were applied for health states. Cumulative QALYs by patient were calculated by linear interpolation; for patients who were censored (31% of patients; including 9% within 100 days of randomization), the last observed utility value was carried forward to study end. The difference in restricted mean QALYs was calculated using generalized linear models, accounting for baseline utility, and with 0.06–0.08 QALYs considered the minimal important difference. Results: At day 50 after randomization (acute treatment phase), cabo was associated with a small reduction in mean total QALYs vs pbo (difference −0.003; 95% CI −0.005 to −0.002; p ≤ 0.001; n = 601 [cabo, n = 389; pbo, n = 212]). At day 100, there was a numerical benefit in mean total QALYs for cabo (difference +0.007; 95% CI −0.001 to 0.015; p = 0.103; n = 627 [cabo, n = 410; pbo, n = 217]), and at day 150 the difference was +0.032 QALYs (95% CI 0.017 to 0.047; p ≤ 0.001; n = 629 [cabo, n = 412; pbo, n = 217]) in favor of cabo. Over the entire follow-up, patients randomized to cabo accrued a mean of +0.092 (95% CI 0.016 to 0.169; p = 0.018; n = 700 [cabo, n = 465; pbo, n = 235]) additional QALYs compared with those receiving pbo. Using alternative Devlin weights for health states, the mean accrued QALYs with cabo was +0.115 vs pbo (95% CI 0.032 to 0.198; p = 0.007). Conclusions: Cabo was associated with an initial, small reduction in health utility. However, with continued treatment, health utility increased and at the end of the study there was a clinically and statistically significant benefit in mean QALYs in favor of cabo. Clinical trial information: NCT01908426.

423 Background: AFP response, defined as a decrease in serum levels of the tumor marker AFP after therapy, may be associated with improved survival of patients (pts) with HCC treated with locoregional or systemic therapy, and high baseline AFP levels may be associated with poor prognosis. In the phase III CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus P in pts with previously treated advanced HCC. Here we evaluate clinical outcomes with C in CELESTIAL based on AFP response or progression on treatment. Methods: 707 pts were randomized 2:1 to receive C (60 mg daily) or P. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤ 1. Pts received prior sorafenib and ≤ 2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for pts with baseline AFP ≥ 20 ng/mL based on AFP response ( ≥ 20% decrease from baseline) or progression ( ≥ 20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies. Results: Overall, 331 pts (70%) in the C arm and 160 (68%) in the P arm had baseline AFP ≥ 20 ng/mL; among these pts, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at week 8. Among evaluable pts, 117 pts (50%) in the C arm vs 14 (13%) in the P arm had an AFP response, and 72 (31%) vs 75 (68%) had AFP progression. Median OS with C was 16.1 mo for pts with an AFP response versus 9.1 mo for pts without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with C was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For pts with AFP progression, median OS with C was 8.1 mo, and median PFS with C was 3.6 mo. Hazard ratios for OS and PFS with C also favored AFP responders over non-responders when analyzed using best response through week 24. Conclusions: The AFP response rate was higher with C versus P, and AFP response was associated with longer OS and PFS with C for pts with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response. Clinical trial information: NCT01908426.

TPS462 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR genetic alterations is implicated in many cancers, including cholangiocarcinoma (CCA). FGFR2 translocations with fusion partners occur in ≈10% to 20% of intrahepatic CCA tumors. Pemigatinib is a selective oral inhibitor of FGFR-1, 2, 3. Preliminary data from the ongoing phase 2 study show efficacy and tolerable safety in patients (pts) with CCA with FGFR2 translocations. We present the design for a phase 3, open-label, randomized trial investigating pemigatinib monotherapy versus gemcitabine plus cisplatin chemotherapy in the first-line treatment of pts with advanced/metastatic or unresectable CCA with FGFR2 rearrangement. Methods: Eligible pts (target, N = 432) are ≥ 18 years (≥ 20 years for Japanese pts) and have ECOG performance status ≤ 1 and histologically confirmed advanced (locally advanced, metastatic, or recurrent) CCA with a documented FGFR2 rearrangement. Key exclusion criteria include prior systemic therapy, excluding adjuvant/neoadjuvant treatment completed ≥ 6 months before enrollment; current evidence of clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues; and known, untreated CNS metastases or history of uncontrolled seizures. Pts are randomized 1:1 and stratified by geographic region and tumor burden into 2 treatment groups: pemigatinib starting dose 13.5 mg once daily continuously on a 3-week cycle; or gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) administered intravenously on days 1 and 8 of every 3-week cycle for up to 8 cycles until disease progression or unacceptable toxicity. Crossover to pemigatinib may be allowed once progressive disease is confirmed. The primary endpoint is progression-free survival (based on independent central review using RECIST v1.1). Secondary endpoints include overall response rate, overall survival, duration of response, disease control rate, safety and tolerability, and impact on quality of life. Clinical trial information: NCT03656536.

305 Background: C significantly improved overall survival vs placebo in pts with previously treated advanced HCC in the phase 3 CELESTIAL trial (NCT01908426). In a previous single dose PK study, increased C exposure was observed in healthy volunteers (HV) with mild or moderate hepatic impairment (Nguyen, J Clin Pharmacol, 2016). An integrated PopPK model was recently developed to characterize C concentration data from HV and pts with various cancers, including renal cell carcinoma, castration-resistant prostate cancer, and medullary thyroid cancer (MTC) (Lacy, Cancer Chemother Pharmacol, 2018). Here, we update the model to include data for pts with advanced HCC from CELESTIAL and a prior phase 2 trial. Methods: The updated PopPK model was developed using nonlinear mixed effects modeling methodology (NONMEM v7.3) and incorporated data from 10 clinical studies with 9510 measurable C concentrations from 2023 subjects, including 489 pts with advanced HCC. Eligible pts with HCC were Child-Pugh class A. Evaluated covariates included age, gender, race, body weight, cancer type, and liver dysfunction as defined by the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG). Results: Overall, 70% of pts had normal hepatic function by NCI-ODWG criteria; 28% had mild, 1% had moderate, and

408 Background: Standard of care for CCA/GBC is C-G therapy. MAbs (ATZ, pembrolizumab) targeting PD-L1 show promise in treating CCA/GBC. Hyaluronan (HA), which may impede drug and immune cell access, is high (67%) in CCA/GBC tumors. PEGPH20 enzymatically degrades HA. HALO 110-101 (NCT03267940) evaluates safety and activity of PEG-C-G-ATZ or PEG-C-G versus C-G in CCA/GBC pts. Methods: This study comprises two parts. In Run-In (RI) six pts were enrolled in PEG-C-G arm, then six pts in PEG-C-G-ATZ arm. Eight additional pts may be enrolled for tolerability. In Expansion (EX), up to 50 pts will be enrolled for efficacy. Treatment (Tx) cycle is 21 days (d). PEGPH20 dose is 3 μg/kg on d1, eight and 15 and ATZ dose is 1200 mg (one–three hours after PEGPH20) on d1 (PEG-C-G-ATZ only). C-G is dosed at 25 mg/m2 C and 1000 mg/m2 G on d2 and nine. In C-G arm (EX only), C-G is dosed on d1 and 8. Primary endpoints are ORR (RECIST v1.1), AEs (NCI CTCAE v4.03), laboratory/safety (RI only); secondary endpoints are PK; DOR, DCR, PFS; OS, OS by PD-L1 expression; ORR and DOR (imRECIST). Results: Eighteen pts have been enrolled (nine in each arm). The mean (SD) age is 57 (12.2) yrs in PEG-C-G and 69 (8.8) yrs in PEG-C-G-ATZ. 56% were men. All pts experienced ≥ 1 AE. The most common AEs are nausea, fatigue (50% each); decreased appetite (44%); anemia, constipation (39% each); thrombocytopenia, oedema peripheral, AST increased, myalgia (33% each). To date, there has been one dose-limiting toxicity (febrile neutropenia) in the PEG-C-G arm. There have been no deaths due to AEs. Conclusions: The overall safety profile of PEGPH20 + C + G ± ATZ is acceptable and consistent with safety observed for the individual components. There were no DLTs resulting in a dose reduction of PEGPH20, which is being dosed at 3 μg/kg in the EX phase. Clinical trial information: NCT03267940. [Table: see text]

Background: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. Methods: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m−2 and cisplatin 25 mg m−2 on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m−2, cisplatin 20 mg m−2 and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. Results: A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes. Conclusion: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Despite the successful FDA approval of sorafenib as the standard of care therapy in patients with advanced hepatocellular carcinoma (HCC), its clinical benefits have been modest. The mortality rate remains high and prognosis poor for patients with advanced-stage HCC. The exact mechanism of sorafenib in the treatment of HCC and its resistance at the molecular levels are largely unknown. There are no other treatment options in first-line therapy and there is currently no standard of care second-line therapies available. Thus, there is a critical need for novel therapeutic approaches for the treatment of advanced HCC, and thus a clear justification for the already reported, currently ongoing, and planned clinical trials.

The recommendation of sorafenib as standard of care in advanced hepatocellular carcinoma has lent support to the increased use of antiangiogenic therapies. However, in three phase 3 randomised trials that compared other antiangiogenics with sorafenib, results did not show superiority or non-inferiority of the new therapies. The 10-month median overall survival shown in these studies for patients given sorafenib might be a ceiling for single-agent antiangiogenic therapy. Strategies to increase survival time include combination therapies that pair antiangiogenic treatment with biological therapy or chemotherapy. The combination of sorafenib and erlotinib was not superior to sorafenib alone, which suggests no positive interaction between antiangiogenics and tyrosine kinase inhibitors in the treatment of advanced hepatocellular carcinoma. A combination of sorafenib and doxorubicin is being assessed in a randomised phase 3 trial. Differences in patient outcome with sorafenib because of disease cause and the ethnic origin of patients suggest that sorafenib's multitarget capacity, including RAF kinase inhibition, might be important. MET inhibitors cabozantinib and tivantinib are drugs that might also bypass the so-called antiangiogenic ceiling and have led to selective treatment of patients that overexpress MET with these drugs. Although this intense period of research activity has not yet resulted in significant improvements in survival for patients with advanced hepatocellular carcinoma, we are certainly closer to a customised treatment, which should increase the antiangiogenic survival ceiling.

Cardiopulmonary resuscitation (CPR) is an important advance directive (AD) topic in patients with progressive cancer; however such discussions are challenging.This study investigates whether video educational information about CPR engenders broader advance care planning (ACP) discourse.Patients with progressive pancreas or hepatobiliary cancer were randomized to an educational CPR video or a similar CPR narrative. The primary end-point was the difference in ACP documentation one month posttest between arms. Secondary end-points included study impressions; pre- and post-intervention knowledge of and preferences for CPR and mechanical ventilation; and longitudinal patient outcomes.Fifty-six subjects were consented and analyzed. Rates of ACP documentation (either formal ADs or documented discussions) were 40% in the video arm (12/30) compared to 15% in the narrative arm (4/26), OR=3.6 [95% CI: 0.9-18.0], p=0.07. Post-intervention knowledge was higher in both arms. Posttest, preferences for CPR had changed in the video arm but not in the narrative arm. Preferences regarding mechanical ventilation did not change in either arm. The majority of subjects in both arms reported the information as helpful and comfortable to discuss, and they recommended it to others. More deaths occurred in the video arm compared to the narrative arm, and more subjects died in hospice settings in the video arm.This pilot randomized trial addressing downstream ACP effects of video versus narrative decision tools demonstrated a trend towards more ACP documentation in video subjects. This trend, as well as other video effects, is the subject of ongoing study.

Biliary tract cancers represent an uncommon, heterogenous malignant group of tumors that include gallbladder cancers (GBC) and cholangiocarcinomas that are frequently detected in the locally advanced or metastatic setting. The randomized phase III ABC-02 trial established the combination regimen of cisplatin plus gemcitabine as standard of care therapy. Nevertheless, despite prior and subsequent attempts utilizing a variety of treatment strategies clinical outcomes for these cancers remains disappointing, necessitating the innate call for improvements in treatment approaches. In this article, we provide an overview of prior first line studies of single, doublet and triplet systemic chemotherapy regimens as well as attempts to incorporate agents that target the EGFR and VEGF pathways in combination with a cytotoxic backbone and the current role of chemotherapy in the second line setting. Additionally, molecular profiling has the capability to identify genetic alterations to help guide rational treatment approaches; we highlight the molecular diverse profile within biliary cancer and the prior, current and emergent role of targeted therapy in biliary cancers as well as the ongoing investigational assessment of immunotherapy. Overall, combination therapy is superior to single agent therapy in the first line setting. For second line therapy, enrollment on to clinical trials is paramount as no standard of care currently exists and no specific regimen has shown a significant better outcome. Limitations of chemotherapy have been exposed and future trials must have a logical design with incorporation of biomarkers that can aid prognosis or predict benefit to therapy. Advances in genomic sequencing can allow identification of potential actionable targets that can be exploited therapeutically which is already underway with the targeting of FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma (IHCC). With these approaches there is potential to gain improvements in outcomes for patients affected by these adverse group of cancers.