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427 Background: Derazantinib, a potent anti- FGFR1-3 oral kinase inhibitor, has shown clinically meaningful anti-tumor activity (21%), durable responses (median, 6.4 months), and progression-free survival (median, 8.0 months) in patients (pts) with FGFR2 fusion (FGFR2F)-positive intrahepatic cholangiocarcinoma (iCCA), and with a manageable toxicity profile. Herein, we report an interim analysis of the clinical efficacy data of derazantinib for pts with iCCA harboring FGFR2 mutations or amplifications (FGFR2M/A), a potential therapeutic option currently not addressed by FGFR inhibitors. Methods: Study FIDES-01 enrolls in a dedicated cohort pts with FGFR2M/A+ advanced iCCA who received previous chemotherapy. Pts receive 300 mg derazantinib daily until disease progression, death or intolerance. The primary endpoint is the proportion of pts alive and free of disease progression at 3 months (PFS3; RECIST 1.1, central imaging review) using a Simon’s two-stage sample-size minimizing statistical design. The interim analysis population comprises 23 pts dosed (intention to treat) who had at least one post-baseline tumor assessment (or clinical progression, or died) by June 3, 2021, using investigator assessments based on RECIST 1.1. Results: To date, 28 pts have been enrolled and dosed. FGFR2M/A observed in these pts included missense point mutations (78%), other short variants (11%) and amplifications (11%). Transition from stage 1 to stage 2 of the study was achieved earlier than planned after 8 (67%) of 12 pts were assessed as PFS3 based on central imaging review. In 23 pts included in this interim analysis for efficacy, the best overall response (investigator assessment) was confirmed partial response in two (8.7%) and stable disease in additional 15 pts (65.2%), resulting in a disease control rate of 73.9% (95% CI, 51.6–89.8). Using Kaplan-Meier analyses, the median PFS was 7.3 months (95%CI, 3.5–16.7) and the probability of being progression-free at 3 months and at 6 months were 76.3% (95%CI, 51.9–89.4) and 50.3% (95%CI, 21.7–73.4), respectively. Clinically meaningful anti-tumor efficacy was observed across all types of genetic aberrations. The safety profile of derazantinib in FGFR2M/A+ iCCA pts was consistent with that previously reported for FGFR2F+ iCCA pts. Conclusions: This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment. Clinical trial information: NCT03230318.

388 Background: IVO—a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) protein, found mainly in intrahepatic CCAs (̃13% of patients globally)—is an FDA-approved therapy for the treatment of previously treated, locally advanced or metastatic mIDH1 CCA based on the results of the randomized, double-blind, phase 3 ClarIDHy study (NCT02989857). In this study, IVO significantly improved progression-free survival vs placebo (PBO) (HR = 0.37, p < 0.0001), resulted in a favorable overall survival trend vs PBO, and was well tolerated (Zhu JAMA Oncol 2021; Abou-Alfa Lancet Oncol 2020). Herein we describe the longitudinal assessment of HRQoL. Methods: A total of 126 and 61 patients were randomized to IVO 500 mg daily or PBO, respectively, with crossover to IVO permitted at radiographic disease progression. HRQoL was a secondary endpoint based on assessments with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Cholangiocarcinoma and Gallbladder Cancer module (QLQ-BIL21). Three domains of interest were prespecified: physical functioning (PF), pain, and appetite loss. After a protocol amendment, HRQoL was assessed predose on Cycle (C) 1 Day (D) 1, every 4 weeks on the first day of subsequent cycles until end of treatment (EOT), and every 12 weeks thereafter until start of new anticancer therapy (vs every 6 weeks between C1D1 and EOT in the original protocol). Mixed-effect models with repeated measurements were conducted on subscale score changes from baseline (BL). Results: At BL, EORTC QLQ-C30 and QLQ-BIL21 scores were available for 114 and 108 IVO patients and 53 and 52 PBO patients, respectively. Sample sizes for HRQoL analyses decreased in both arms over time, in part due to rapid disease progression, which is typical of CCA. No HRQoL assessments were available for PBO after C8 (Week 28), while change scores were available for some IVO patients beyond Week 52 (QLQ-C30 n = 17 at Week 52). From BL to C27D1, patients remaining on IVO tended to maintain their HRQoL, with no QLQ-C30 PF subscale change scores exceeding the threshold for clinically meaningful decline estimated from study data (12-13 points). For the small number of PBO patients with post-BL HRQoL assessments, clinically meaningful PF deterioration was observed at multiple cycles (C2D1, C3D1, C4D1, C5D1, C8D1). Similar preservation for IVO patients was observed on other prespecified subscales based on the published threshold of 10 points, indicating clinically meaningful change (ClarIDHy-based thresholds not estimable due to sample sizes). Conclusions: In ClarIDHy, patients with advanced mIDH1 CCA treated with IVO were likely to maintain their HRQoL over the duration of treatment, including those treated for relatively long periods of time (eg, 1 year). Clinical trial information: NCT02989857.

436 Background: The phase 2 Study 22 trial (NCT02519348) investigated durvalumab (anti-programmed cell death ligand-1 [PD-L1] antibody) and tremelimumab (anti-cytotoxic T-lymphocyte associated antigen 4 antibody) as monotherapy, or durvalumab in combination with tremelimumab or bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody), for the treatment of patients with unresectable hepatocellular carcinoma (uHCC). Results of Study 22 that evaluated durvalumab and tremelimumab as monotherapy or in combination were reported previously. PD-L1 inhibition plus VEGF inhibition with bevacizumab may exhibit an additive effect to improve clinical activity. Herein, we report results from a single-arm cohort of Study 22, evaluating durvalumab plus bevacizumab as first-line treatment in patients with uHCC. Methods: Patients with uHCC who had not received any prior systemic therapy were administered durvalumab 1120 mg plus bevacizumab 15 mg/kg once every 3 weeks. Adequate endoscopic therapy according to institutional standards was required for patients with a history of gastrointestinal bleeding for >12 months or those at high risk for esophageal varices. The primary endpoint was safety. Secondary endpoints included confirmed objective response rate (ORR; assessed by blinded independent central review [BICR] according to RECIST v1.1), duration of response (DoR; RECIST v1.1 by BICR) and overall survival (OS). Results: At the data cut-off (November 6, 2020), 47 patients were allocated to receive treatment. Median total treatment duration was 6.2 months (durvalumab) and 4.1 months (bevacizumab). Thirty-three (70.2%) patients experienced an adverse event possibly related to treatment (TRAE). Grade 3 or 4 TRAEs occurred in 4 (8.5%) patients; serious TRAEs occurred in 5 (10.6%) patients, including gastric ulcer perforation, ascites, and liver tumor rupture, possibly related to bevacizumab, and raised creatinine and pneumonitis, possibly related to durvalumab. There were 3 (6.4%) discontinuations and no deaths associated with TRAEs. Objective responses (RECIST 1.1 by BICR) were confirmed in 10 patients (ORR, 21.3%; 95% CI, 10.7–35.7); median DoR (RECIST 1.1 by BICR) was not reached. Median OS was not reached (95% CI, 12.52 months–non-estimable). Conclusions: Durvalumab plus bevacizumab was well tolerated and showed promising clinical activity in patients with uHCC. Durvalumab with or without bevacizumab in combination with transarterial chemoembolization is being investigated as locoregional therapy in patients with HCC not amenable to curative treatment in the phase 3 EMERALD-1 study (NCT03778957), and durvalumab with or without bevacizumab is being investigated in patients with HCC at high risk of recurrence after curative treatment in the phase 3 EMERALD-2 study (NCT03847428). Clinical trial information: NCT02519348.

BACKGROUND Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. RESULTS At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P

Importance Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor–associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy. Objective To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors. Design, Setting, and Participants In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021. Main Outcomes and Measures Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution. Results A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor–associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was −0.1 (−0.2 to −0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (−0.03 to 0). No patient discontinued drug therapy on account of their retinopathy. Conclusions and Relevance FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.

We describe a case of primary acinar cell carcinoma (ACC) originating in the liver in a 54-year-old female, diagnosed following persistent abnormal elevated liver function. Imaging revealed two masses, one dominant lesion in the right hepatic lobe and another in segment IVA. A right hepatectomy was performed to remove the larger lesion, while the mass in segment IVA was unresectable due to its proximity to the left hepatic vein. Immunohistochemical staining showed positivity for trypsin and chymotrypsin. Postoperatively the patient underwent hepatic arterial embolization of the other unresectable lesion followed by FOLFOX chemotherapy. At 20 months from diagnosis the patient is currently under observation with a decreasing necrotic mass and no other disease evident. Based on histology, immunohistochemistry and radiological findings a diagnosis of primary ACC of the liver was made. Genomic assessment of somatic mutations within the patient’s tumor was also performed through next generation sequencing and findings were consistent with an acinar malignancy. This case highlights a rare tumor subtype treated with a combination of therapeutic modalities through a multidisciplinary approach.

BACKGROUND 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. METHODS 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/m2) and nab-paclitaxel (125 mg/m2) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m2 weekly (cohort 1) or at 36 mg/m2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. RESULTS Eighteen 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/m2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95% confidence interval, 5.3-11.2 months), and the median overall survival time was 11.3 months (95% confidence interval, 6.7 months to not reached). CONCLUSIONS ADI-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. © 2017 American Cancer Society.

Background A continued rise of hepatocellular carcinoma (HCC) incidence is noted. HCC main risk factors are hepatitis B, C, alcohol, and nonalcoholic steatohepatitis. The majority of biliary tumors are adenocarcinomas. Biliary tumors have been classically understood as three different diseases: gallbladder cancer, extrahepatic, and intrahepatic biliary tumors, with different clinical and biological characteristics. Methods Presenting the basic scientific components and clinical premises is supplemented by a thorough review of the new oncoming data especially for advanced disease is reported. This particularly true for the incredible advents in the treatment of advanced HCC. Results Surgery, liver transplantation, and radiofrequency ablation (RFA), are the sole proven curative therapies for HCC. Locally advanced disease is generally treated with different forms of local therapies, including but not limited to, transarterial embolization, chemoembolization, radioembolization, and radiation therapy. Novel five tyrosine kinase inhibitors are now added to sorafenib, and two of them are already FDA approved, being lenvatinib and regorafenib. Checkpoint inhibitors and combination of checkpoint inhibitors is another key advent. For biliary cancers, a novel approach to differentiate the three diseases based on biology and pathways is evolving. Surgery remain the sole curative approach. Capecitabine is now validated as an adjuvant treatment after resection. Several mutational taregts are being further investigated for the treatment of biliary cancers, particularly cholangiocarcinoma and gallbladder cancer. Principal conclusions Screening programs for HCC continue to evolve. Pathology evaluation may help distinguish variants or combined HCC and cholangiocarcinoma. Novel therapies are helping move the field forward at a fast pace.

Background: Patients with liver cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC). Due to the low accuracy of current methods, new non-invasive strategies for early HCC diagnosis in cirrhotic patients are needed. Methods: A case-control study recruited a total of 2,250 patients with liver cirrhosis (LC), 508 with HCC, and 476 healthy controls (CTRL), from 13 hospitals in 11 provinces of China. Four genomic features of cell-free DNA (cfDNA), including nucleosome footprint, fragmentation, base mismatch and 5-hydroxymethylcytosines were profiled. Training and validation cohorts helped develop the integrated diagnostic model, and a test cohort was used to evaluate its performance. Findings: We established a classifier of each feature for HCC against non-HCC (cirrhosis & healthy control). By integrating these four genomic features, we developed a novel diagnostic model (HIFI, 5-Hydroxymethylcytosines/base mIsmatch/Fragmentation/nucleosome footprInt), and achieved a higher accuracy in differentiating HCCs from liver cirrhosis (AUC=0.997 [0.994-0.999], sensitivity 95.42%, specificity 97.67% in test set) than AFP or PIVKA-II, irrespective of the following demographics and clinical features, age, HBV status, Child-Pugh score, BCLC stage, tumor size, and AFP status. In AFP positive (AFP>20ug/L) liver cirrhosis patients and AFP/PIVKA-II negative (AFP 400μg/L: 100% in liver cirrhosis patients; AFP

Purpose: The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes. Patients and Methods: Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics. Results: Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62–1.04] for patients with baseline AFP Conclusions: Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib.

PURPOSE Chemotherapy-induced thrombocytopenia (CIT) leads to delay or reduction in cancer treatment. There is no approved treatment. METHODS We conducted a phase II randomized trial of romiplostim versus untreated observation in patients with solid tumors with CIT. Before enrollment, patients had platelets less than 100,000/μL for at least 4 weeks, despite delay or dose reduction of chemotherapy. Patients received weekly titrated romiplostim with a target platelet count of 100,000/μL or more, or were monitored with usual care. The primary end point was correction of platelet count within 3 weeks. Twenty-three patients were treated in a randomization phase, and an additional 37 patients were treated in a single-arm, romiplostim phase. Resumption of chemotherapy without recurrent CIT was a secondary end point. RESULTS The mean platelet count at enrollment was 62,000/μL. In the randomization phase, 14 of 15 romiplostim-treated patients (93%) experienced correction of their platelet count within 3 weeks, compared with one of eight control patients (12.5%; P < .001). Including all romiplostim-treated patients (N = 52), the mean platelet count at 2 weeks of treatment was 141,000/μL. The mean platelet count in the eight observation patients at 3 weeks was 57,000/μL. Forty-four patients who achieved platelet correction with romiplostim resumed chemotherapy with weekly romiplostim. Only three patients (6.8%) experienced recurrent reduction or delay of chemotherapy because of isolated CIT. CONCLUSION This prospective trial evaluated treatment of CIT with romiplostim. Romiplostim is effective in correcting CIT, and maintenance allows for resumption of chemotherapy without recurrence of CIT in most patients.

Biliary tract cancer (BTC) is comprised of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC). These tumors arise in the biliary epithelium, share histological characteristics and are associated with grim prognosis even when diagnosed at early stages. Moreover, its relatively low incidence in developed countries has precluded the development of clinical trials addressing specific differences among BTC subgroups in terms of their biology, treatment response and clinical outcomes. In this scenario, the development of effective treatment strategies for patients has been rather modest. To date, the combination of cisplatin plus gemcitabine remains as the standard first line therapy in advanced disease and after progression to this regimen there are limited treatment options. Next generation sequencing (NGS) studies have assessed the distribution of driver genes and potentially actionable genomic alterations among ICC, EHC and GBC. Here, we outline genomic differences among these subsets and describe key milestones in order to develop novel targeted drugs against BTCs. Although the early results of several studies are promising, international collaboration is critical to conduct adequately-powered trials, enrolling patients from high-incidence countries.

Thank you for your interest in this special edition of Chinese Clinical Oncology , and welcome to this in-depth discussion and analysis of data on gallbladder cancer. This special edition would not have been possible without the dedication and contributions of all our dear colleagues from every corner of the planet, and thus represents a very global perspective and series of insights on this disease.

The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further.

Lessons LearnedTKM-080301 showed a favorable toxicity profile at the studied dose. TKM-080301 targeting PLK1 through small interfering RNA mechanism did not demonstrate improved overall survival in patients with advanced hepatocellular carcinoma compared with historical control. Preliminary antitumor activity as shown in this early-phase study does not support further evaluation as a single agent.BackgroundPolo-like kinase 1 (PLK1) is overexpressed in hepatocellular carcinoma (HCC). Knockdown of PLK1 expression by PLK1 small interfering RNA (siRNA) in an HCC cell line showed reduced expression in RNA-induced silencing complex and a reduction in cell proliferation.MethodsA 3 + 3 dose escalation plus expansion cohort at the maximum tolerated dose (MTD) was implemented. Patients with HCC, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and Child-Pugh score A received TKM-080301 as an intravenous infusion once every week for 3 consecutive weeks, repeated every 28 days.ResultsThe study enrolled 43 patients. The starting dose of TKM-080301 was 0.3 mg/kg, and MTD was declared at 0.75 mg/kg. Following the development of grade 4 thrombocytopenia in two subjects on the expansion cohort, the MTD was redefined at 0.6 mg/kg. Four patients did not have any evaluable postbaseline scan. Of the other 39 subjects who had received at least 0.3 mg/kg, 18 subjects (46.2%) had stable disease (SD) by independent RECIST 1.1 criteria. By Choi criteria, eight subjects (23.1%) had a partial response (PR). For 37 assessable subjects, with 2 subjects censored, median progression-free survival (PFS) was 2.04 months. Median survival for the whole study population was 7.5 months.ConclusionTKM-080301 was generally well tolerated. In this early-phase study, antitumor effect for TKM 080301 was limited. Further evaluation as a single agent in large randomized trials is not warranted.

Background Although gemcitabine plus platinum chemotherapy is the established first-line regimen for advanced biliary cancer (ABC), there is no standard second-line therapy. This study evaluated current practice and outcomes for second-line chemotherapy in patients with ABC across 3 US academic medical centers. Methods Institutional registries were reviewed to identify patients who had received second-line chemotherapy for ABC from April 2010 to March 2015 along with their demographics, diagnoses and staging, treatment histories, and clinical outcomes. Overall survival from the initiation of second-line chemotherapy (OS2) was estimated with Kaplan-Meier methods. Results This study identified 198 patients with cholangiocarcinoma (intrahepatic [61.1%] or extrahepatic [14.1%]) or gallbladder carcinoma (24.8%); 52% received at least 3 lines of systemic chemotherapy. The median OS2 was 11 months (95% confidence interval [CI], 8.8-13.1 months). The median OS2 for patients with intrahepatic cholangiocarcinoma was 13.4 months (95% CI, 10.7-17.8 months), which was longer than that for patients with extrahepatic cholangiocarcinoma (6.8 months; 95% CI, 5-10.6 months) or gallbladder carcinoma (9.4 months; 95% CI, 7.2-12.3 months; P = .018). The median time to second-line treatment failure was 2.2 months (95% CI, 1.8-2.7 months), and it was similar across tumor locations (P = .60). Conclusions In this large cohort of patients with ABC treated across 3 academic medical centers after the failure of first-line chemotherapy, the time to treatment failure on standard therapies was short, although the median OS2 was longer than has been reported previously, and more than half of the patients received additional lines of treatment. This multicenter collaboration represents the largest cohort studied to date of second-line chemotherapy for ABC and provides a contemporary benchmark for future clinical trials.

Esophageal carcinoma is an aggressive malignancy and outcomes remain poor. Immune checkpoint inhibitors are a standard-of-care in the third-line and beyond settings, although benefit is modest. Herein, we report the case of a patient who achieved a partial response to salvage chemotherapy following treatment with an immune checkpoint inhibitor despite having chemo-refractory disease. A 41-year-old male, with a history of Crohn's disease, was diagnosed with Her2-positive metastatic esophageal adenocarcinoma to lungs and lymph nodes. The patient received multiple lines of systemic therapy including: first-line modified DCF (docetaxel/cisplatin/5-fluorouracil) with trastuzumab, second-line trastuzumab/afatinib on a clinical study, third-line carboplatin/irinotecan/ramucirumab and fourth-line treatment with a Her2 antibody-drug conjugate, DS-8201A, on a phase I study. While the patient was not a candidate for clinical trials evaluating immune checkpoint inhibitors due to his history of Crohn's disease, the latter was well controlled. Thus, the patient commenced pembrolizumab as fifth-line of treatment 2 years since diagnosis. After 3 cycles of therapy, the patient developed grade 3 immune-related colitis and treatment was discontinued. The patient maintained a good performance status and commenced a sixth-line of carboplatin/irinotecan/ramucirumab. Subsequent imaging demonstrated a partial response which was maintained over a 6-month period. This case demonstrates a response to previously administered chemotherapy following immune checkpoint inhibitor therapy, despite prior progression on this chemotherapy regimen. To our knowledge, this has not been previously reported in esophagogastric carcinoma (EGC). Post-immune checkpoint inhibitor chemotherapy may be a feasible treatment strategy. Research is needed to evaluate the role of post-immune checkpoint inhibitor chemotherapy in patients with metastatic EGC.

Hepatocellular carcinoma (HCC) is a common illness that affects patients worldwide. The disease remains poorly understood though several recent advances have increased the understanding of HCC biology and treatment. A literature review was conducted to understand the role of biomarkers in HCC clinical practice and highlight areas of critical investigation. Candidate biomarkers may include differential alterations in HCC genomics, epigenomics, gene expression and transcriptomic profiles, protein expression, cellular composition of the microenvironment, and vasculature. To date no circulating or tumor diagnostic markers have been established in this disease. Likewise, prognostication is currently adjudicated by clinicopathologic features and it remains unclear if the incorporation of any biomarkers may help enhance the prognostic understanding following curative intents like surgery, transplant, and select regional therapy or palliative treatment including embolization or systemic therapy. Predictive biomarkers are investigational and are under evaluation for molecular pathways like TOR, MET, VEGFA, and FGF19. Tumoral genomics, HLA allele diversity and tumoral immune activation as predictive markers for immune checkpoint inhibitors are key focuses of ongoing research. Diagnostic, prognostic, and predictive tumor and circulating biomarkers for HCC have not been defined though several markers have been proposed to guide patient care.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) fusions occur in 13–17% of intrahepatic cholangiocarcinomas (IHC). A multicenter, open-label, phase II study (NCT02150967) evaluated the antitumor activity of infigratinib, an ATP-competitive FGFR1–3-selective oral tyrosine kinase inhibitor, in patients (pts) with previously-treated advanced IHC containing FGFR2 fusions. METHODS: Pts received infigratinib 125 mg orally daily for 21 days of 28-day cycles until unacceptable toxicity, disease progression, investigator discretion, or withdrawal of consent. Primary endpoint: investigator-assessed confirmed overall response rate (cORR, RECIST 1.1). Secondary endpoints: progression-free survival (PFS), disease control rate (DCR), best overall response, overall survival (OS), safety, pharmacokinetics. RESULTS: Seventy-one pts (62% women; median age 53 years; median 2 prior lines of therapy) were included. At the prespecified data cutoff (8th, Aug, 2018), median duration of treatment was 5.5 months, median duration of follow-up was 8.4 months, and 62 pts had discontinued treatment. The ORR (confirmed and unconfirmed) was 31.0% (95% CI, 20.5–43.1%) and the cORR (in pts with potential for confirmation) was 26.9% (95% CI, 16.8–39.1%). Other efficacy findings: cORR in pts receiving ≤1 prior lines of treatment was 39.3% (n=28), and ≥2 17.9% (n=39); DCR 83.6% (95% CI, 72.5–91.5%); median duration of response 5.4 (95% CI, 3.7–7.4) months; median PFS 6.8 (95% CI, 5.3–7.6) months; median OS 12.5 (95% CI, 9.9–16.6) months. Most common any-grade treatment-emergent adverse events (TEAEs): hyperphosphatemia (73.2%), fatigue (49.3%), stomatitis (45.1%), alopecia (38.0%), constipation (35.2%). Grade 3/4 TEAEs occurred in 47 pts (66.2%), including hypophosphatemia (14.1%), hyperphosphatemia (12.7%), and hyponatremia (11.3%). CONCLUSIONS: Infigratinib-associated toxicity is manageable, and our efficacy findings suggest clinically meaningful activity after chemotherapy in pts with IHC containing FGFR2 fusions. The efficacy of infigratinib in this study supports FGFR2 as a therapeutic target in FGFR2-fusion IHC.

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

3030 Background: Diarrhea, HFS, and hypertension are common toxicities of sorafenib. No markers are validated to predict patients at risk of these toxicities. This study aimed to identify genetic predictors of sorafenib-induced toxicities. Methods: A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) and genotyped for 1040 single-nucleotide polymorphisms (SNPs) in 56 genes. The three most statistically significant SNPs associated with grade ≥2 composite toxicity (either hypertension, diarrhea, HFS, or other skin toxicities, CTCAE v.3.0) were tested for association with grade 3 composite toxicity (either hypertension, diarrhea, or HFS, CTCAE v.4.0) in a validation set of 240 hepatocellular carcinoma patients from Alliance/CALGB 80802 treated with sorafenib (400 mg twice daily) alone or with doxorubicin. Associations between SNPs and composite toxicity was performed by logistic regression, with adjusting covariates (age, gender, race, and treatment arm, the latter two covariates for the validation set only). A meta-analysis odds ratio (OR) of each SNP-grade 3 toxicity association between the discovery and validation sets was obtained by inverse variance to point toward effects specific to a type of toxicity. Results: In the discovery set, the top three SNPs associated with grade ≥2 composite toxicity were rs12366035 (C>T, minor allele frequency, MAF 0.34) in VEGFB (p 0.0007), rs4035887 (G>A, MAF 0.49) in EPAS1 (p 0.0021), and rs4864950 (T>A, MAF 0.23) in KDR (p 0.0058). These SNPs were genotyped in the validation set and only rs4864950 in KDR was replicated. No grade 4 toxicities were reported. Similar to the discovery set (OR 2.41, 95% CI 1.29-4.51), the A allele of rs4864950 increased the risk of grade 3 composite toxicity (p 0.032, OR 2.12, 95% CI 1.70-4.27) in the validation set. Grade 3 toxicity prevalence in the discovery and validation sets were 3.6% and 7.4% diarrhea, 8.6% and 12.3% HFS, 3.6% and 8.8% hypertension, respectively. The meta-analysis of the two datasets showed that the A allele of rs4864950 increased the risk of grade 3 diarrhea (p 0.045, OR 3.09, 95% CI 1.03-9.29), grade 3 HFS (p 0.012, OR 2.57, 95% CI 1.24-5.37), but not grade 3 hypertension (p 0.207, OR 0.51, 95% CI 0.18-1.45). Conclusions: We provide the first evidence of clinical validity of a marker of sorafenib-induced diarrhea and HFS. Sorafenib inhibits VEGFR2 (coded by KDR), leading to epithelial hypoxia and causing diarrhea and HFS. Variant rs4864950 might affect the function VEGFR2, which, during VEGFR2 inhibition, increases the risk of diarrhea and HFS. This SNP is common and can be genotyped in patients before receiving sorafenib for a better risk assessment. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ClinicalTrials.gov Id: NCT01015833.

6580 Background: Outcomes for patients (pts) with cancer may vary widely based on accessibility and quality of care. Subspecialized expert care is associated with improved outcomes yet access to this scarce resource is limited. Providing SEO opinions in legacy ways is time-consuming and difficult to scale. We hypothesized that summarizing comprehensive pt records could enhance efficiency of a remote opinion process. In this prospective pilot, oncologists (MDs) at Memorial Sloan Kettering (MSK) tested the NCDM, a clinically-validated, semi-automated system which abstracts pertinent data elements from medical records into a structured summary to support SEO decision making for remote opinions. Methods: From July to December 2020, 12 MSK MDs provided remote opinions to consecutive pts from an international second opinion service who were specifically seeking MSK expertise. NCDM summaries, with relevant DICOM imaging, were provided to MDs via web and mobile app. MDs answered a brief survey about their experience after each opinion. Time spent to read and respond to an NCDM summary was tracked electronically. Pt feedback was collected by prospective phone follow up. Results: N = 101 remote opinions. Cancer type (N): breast (24), gastrointestinal (15), heme malignancy (14), prostate (12), renal (8), gynecologic (7), head & neck (11), lung (9) and skin (1). 92% MD response rate. Pt characteristics: median age (60 years, range 17-83); stage of disease (early stage 41%, advanced 59%); 86% of pts had received prior treatment. MDs survey responses: median time to complete record review and render opinion = 4.8 min (IQR 2.7 – 7.9 min); NCDM provided adequate information needed to make a decision in this case = 95.7% (89/93); Decision making was easy in this case with data presented in the NCDM format = 96.8% (90/93). Pt survey responses (71/88): 92% shared recommendation with local MD; 87% received the recommended treatment; 99% stated they would recommend a NCDM enabled remote opinion service to others. Conclusions: NCDM summaries enabled subspecialized MSK cancer experts to provide oncology remote opinions with ease. Patients reported high satisfaction with the experience. Technology assisted abstraction and case summary can facilitate access to subspecialized expert opinions at a global scale.

e16169 Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value > 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from > 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( < 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with > 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia > 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis. Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether hyperammonemia is related to FLC tumor biology.

e16175 Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]

BACKGROUND AND AIM In recent years, several novel immunotherapeutic approaches were developed and investigated in patients with hepatocellular carcinoma (HCC). We designed this systematic review, to evaluate clinical efficacy of specific immunotherapy in patients with HCC, according to the guidelines of Border of Immune Tolerance Education and Research Network (BITERN) and Cochrane collaboration. METHODS We searched Medline, Scopus, CENTRAL, TRIP, DART, OpenGrey, and ProQuest through the 9th of December 2015. One author reviewed and retrieved citations from these seven databases for irrelevant and duplicate studies, and two other authors independently extracted data from the studies and rated their quality. We collated study findings and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 12144 references in seven databases of which 21 controlled studies with 1885 HCC patients in different stages were included in this systematic review after the primary and secondary screenings. Overall, patients undergoing specific immunotherapy had significantly higher overall survival than those in control group (HR = 0.59; 95% CI = 0.47-0.76, P

Hepatocellular carcinoma (HCC) is becoming an important cause of mortality in patients with HIV, attributed to coinfection with hepatitis C virus, hepatitis B virus, and the longer survival advantage these patients are achieving after introducing the highly active antiretroviral therapy (HAART) regimens.In addition to hepatitis infection, immunosuppression secondary to HIV infection, direct impact of the virus on liver parenchyma, and the use of hepatotoxic antiretroviral drugs, all contribute to HCC pathogenesis. Screening is very important in this particular population; data on population-specific guidelines are still controversial and scarce. Liver transplantation remains the treatment of choice in eligible patients. Trials on sorafenib have not included patients with HIV; yet, we know from small retrospective series that it might be safe and effective.In the HAART era, HCC is arising as a common non-AIDS defining cancer with high impact on morbidity and mortality of HIV-infected patients. Candidates for liver transplantation should be offered this option regardless of HIV infection. Safety and efficacy of sorafenib and other treatment modalities should be further studied and offered as deemed applicable to HIV patients diagnosed with HCC.

Gastroduodenal artery (GDA) aneurysm is a very rare condition. It is divided into false and true aneurysms where pseudoaneurysms are associated with pancreatitis and true aneurysms are secondary to celiac trunk stenosis. We report a 24 year old female patient who was diagnosed with pancreatic head neuroendocrine tumor and was incidentally found to have multiple GDA aneurysms in the absence of celiac artery stenosis. A decision to embolize the aneurysms was taken in view of the presumed high risk of bleeding. The procedure was successful with a follow up CT scan showing no recurrence.

276 Background: CCA is associated with poor prognosis and reduced QoL. In the phase 2 FIGHT-202 study (NCT02924376) of the selective oral FGFR1–3 inhibitor pemigatinib, 35.5% and 46.7% of pts with previously treated advanced CCA and FGFR2 fusions/rearrangements (RE) had a complete or partial response (CR/PR) and stable disease (SD), respectively; 14.9% had progressive disease (PD) [Abou-Alfa et al., Lancet Oncology 2020;21:671-684]. QoL was an exploratory endpoint. Methods: Pts received pemigatinib 13.5 mg once daily (21-day cycle; 2 weeks on, 1 week off). QoL was assessed longitudinally by best overall response (BOR) per RECIST with the EORTC-QLQ-C30 and the biliary tract cancer-specific EORTC-QLQ-BIL21 questionnaires. QoL scores and longitudinal changes from baseline (BL) were analyzed using descriptive statistics. Treatment-related changes in QoL were a priori expected to be evident by cycle 6 day 1 (week 16). Results: Of 107 pts with FGFR2 RE, 100 (93%) were evaluable for QoL, including36, 48, and 15 with CR/PR, SD, and PD, respectively. From BL to week 16, QLQ-C30 overall health status was maintained in pts with CR/PR and SD and worsened in pts with PD (Table). Emotional functioning remained stable and similar in pts with CR/PR and SD but worsened in pts with PD. All subgroups showed decline in role and social functioning. Pts with CR/PR and SD experienced decreases in QLQ-BIL21 pain and anxiety; all subgroups showed increases in QLQ-BIL21 treatment side effects. Conclusions: In these pts with advanced CCA, those with an SD as BOR had a similar pattern of changes in QoL as those with CR/PR to pemigatinib. Changes in QoL were directionally more favorable in pts with CR/PR or SD than pts with PD. Clinical trial information: NCT02924376. [Table: see text]

303 Background: Most patients (pts) with cholangiocarcinoma (CCA) are diagnosed with advanced disease and are ineligible for surgery. FGFR2 fusions/rearrangements are oncogenic drivers and are present almost exclusively in pts with intrahepatic CCA (iCCA; 10–16% of pts); however, little is known about the effects of FGFR2 status on response to systemic chemotherapy. Memorial Sloan Kettering (MSK) obtains genomic sequencing data from almost all iCCA pts treated at the institution. This provides a unique, rich database from which genomic profiling data can be overlaid with clinical data to facilitate a meaningful understanding of pt outcomes, and to suggest potential therapeutic options. This retrospective analysis evaluated progression free survival (PFS) and overall survival (OS) in pts receiving standard systemic chemotherapy (CXT) for iCCA harboring FGFR2 fusions/rearrangements ( FGFR2 +), or harboring wild-type FGFR2 ( FGFR2wt). Methods: Clinical and genomic data were obtained from the MSK database for all iCCA pts to determine disease history and exposure to prior lines (PL) of CXT in the advanced setting. Only pts with complete data for PL of CXT were analyzed. Median PFS and OS were calculated using the Kaplan-Meier method. OS was calculated from diagnosis until death; PFS was calculated from first dose of first line of CXT until progression, death, last visit, relevant dates of later CXT lines; pts with unconfirmed outcomes were censored at last known follow-up date. Results: One-hundred-thirty-two pts were included in this analysis (median age at diagnosis: 62.0 y; 54.5% female; FGFR2+, n = 15; FGFR2wt, n = 115; other FGFR2 alterations, n = 2). Among pts receiving first-line CXT, median PFS was 7.1 months (95% CI: 5.0–8.3) for all pts (n = 124), 6.2 months (2.0–16.8) for FGFR2+ pts (n = 15), and 7.2 months (5.0–8.3) for FGFR2wt pts (n = 107). Among pts with ≥2 PL of CXT (n = 90), median PFS on second-line chemotherapy was 5.6 months (95% CI: 2.8–10.3) for FGFR2+ pts, and 3.7 months (2.6–5.6) for FGFR2wt pts. Median OS was numerically longer in FGFR2+ pts compared with FGFR2wt pts (31.3 months [95% CI: 5.8–not estimable] vs 21.8 months [16.7–26.6]). Conclusions: Among pts receiving standard systemic chemotherapy for iCCA, median PFS was similar in pts harboring FGFR2+ vs FGFR2wt receiving first-line chemotherapy, and relatively longer in pts harboring FGFR2+ receiving second-line chemotherapy. Median OS was longer in FGFR2+ vs FGFR2wt pts. Compared with recently published data in molecularly unselected CCA pts (Lowery. Cancer. 2019; 125: 4426), PFS was similar in pts receiving first-line chemotherapy, and slightly longer for second-line chemotherapy. Data interpretation is limited by the retrospective nature of this analysis of investigator-reported data, the study size, and by the possibility that the analysis population may not reflect the general population of pts with CCA.

TPS349 Background: TACE is the most widely used locoregional therapy recommended for patients with intermediate-stage HCC (Barcelona Clinic Liver Cancer stage B). Despite the significant tumor responses that can be achieved with TACE, tumors commonly recur, progress, or are refractory. Clinical trials have explored the combination of TACE with tyrosine kinase inhibitors; however, these have not reported improved outcomes. HCC possesses a unique immunosuppressive microenvironment, which makes it an attractive target for immunotherapies, particularly immune checkpoint inhibitors. Furthermore, there is evidence that locoregional interventions induce changes in the immune environment that could promote synergy with checkpoint inhibitors. Preliminary data for the combination of TACE with nivolumab indicate an acceptable safety profile and promising efficacy (Harding et al. ASCO-GI 2020). NIVO monotherapy and NIVO+IPI combination therapy are both approved in the United States for patients with HCC previously treated with sorafenib. Together, these findings support investigation of TACE plus NIVO, IPI, or NIVO+IPI to address the therapeutic needs of patients with intermediate HCC. Methods: CheckMate 74W is a global, double-blind, placebo-controlled, 3-arm, randomized phase III trial. Patients with tumors that exceed the Beyond Milan and Up-to-7 criteria (7 being the sum of size [in centimeters] and number of tumors), eligible for TACE, with Eastern Cooperative Oncology Group performance status of 0 to 1 are eligible for enrollment. Patients must not have received prior locoregional therapies. Approximately 765 patients will be randomized in a 1:1:1 ratio to NIVO+IPI+TACE (arm A), NIVO+IPI placebo+TACE (arm B), or NIVO placebo+IPI placebo+TACE (arm C). Primary endpoints are the time to TACE progression (TTTP), assessed by blinded independent central review, and overall survival in arm A versus arm C. Secondary endpoints are TTTP and overall survival in arm B versus arm C, event-free survival, and progression-free survival. Clinical trial registry: NCT04340193. Clinical trial information: NCT04340193.

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as < 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p < 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]

313 Background: In a phase II study in uHCC (Study 22, NCT02519348), a novel, priming combination regimen of tremelimumab (T; anti-CTLA-4) and durvalumab (D; anti-PD-L1) (T300+D) has shown favorable clinical activity vs each agent as monotherapy or vs another combination (T75+D). The analyses presented here assess the pharmacokinetics (PK) and relationships between tremelimumab exposure, as monotherapy or in combination, and safety, efficacy, and pharmacodynamics (PD) in this study. Methods: Overall, 216 pts were included in these analyses (T, n=65; T300+D, n=72; T75+D, n=79). Safety, antitumor activity, PK, PD, and immunogenicity were analyzed using standard pharmacometrics methods. A previously developed population PK model for T across solid tumors was validated using T monotherapy and combination therapy data from Study 22, including a post-hoc covariate analysis to assess the impact of covariates on individual PK parameters. Population PK and PD models related individual T exposures to safety parameters, PD, and efficacy (overall survival, OS; progression-free survival, PFS; and objective response rate, ORR). The E-R relationships for time-to-event variables OS and PFS were explored by Kaplan-Meier estimates and analyzed by Cox proportional-hazards models (CPHM). Results: For T monotherapy and T+D combinations, no significant E-S relationships were observed for grade 3/4 treatment-related adverse events (TRAEs), grade 3/4 TRAEs of special interest, and AEs leading to treatment discontinuation. Analyses of each quartile of T exposure suggest pts with higher exposure (3rd and 4th quartile) may have longer OS vs lower quartiles. The CPHManalysis showed that after accounting for prognostic factors (baseline albumin and neutrophil-to-lymphocyte ratio), neither AUC nor Cmin appeared to be a significant factor for OS hazard. There was no significant relationship between response and ORR, PFS and any T PK exposure metric in T-treated pts. Saturable relationships (described by Emax) were observed for maximum change from baseline for proliferating T-cell counts as functions of exposure. Conclusions: The observed PK data are generally consistent with predictions based on a historical population PK model, suggesting the PK of T in uHCC pts is consistent with pts with other solid tumors. No significant relationships were observed between E-S and E-R; therefore, PK is not a significant predictor to evaluate for T efficacy or safety. Considering the small sample size limitation, still the saturable relationships observed in proliferating T-cells appear to support a dose of T300. Future studies of pooled data from Study 22 and the larger phase III HIMALAYA study (NCT03298451) will be conducted to further the characterization of E-R relationships and the development of the T300+D regimen. Clinical trial information: NCT02519348.

310 Background: FLC, a rare liver cancer of young adults, has no effective systemic therapies. Surgical resection is used extensively with non-curative intent. FLC is associated with a DNAJB1- PRKACA chimeric transcript that produces a fusion protein with retained kinase activity and increased expression of several oncogenic signaling pathways including, but not limited to, HER2 ( ERBB2). Methods: N (240 mg oral daily) was studied in FLC pts in the SUMMIT study (NCT01953926); and later under compassionate use for N-based combinations (combo): P (2 mg/kg q3w), E (7.5 mg daily), and V (240 mg q2w) in doublet or triplet regimens. Eligible pts: ≥12y; histologically confirmed FLC; adequate organ function; any number of prior therapies. Primary endpoint: objective response rate (ORR; RECIST v1.1). Secondary endpoints: duration of response; clinical benefit rate (CBR); safety (CTCAE v4.0); somatic and germline sequencing (MSK IMPACT). Results: As of 03-Sep-2020, 15 pretreated pts received N in SUMMIT (confirmed ORR 0%; CBR 13%). Efficacy data for 5 pts from SUMMIT and 2 more pts receiving combo under compassionate use (4 male, 3 female, median age 26 years, median 0 [range 0–4] prior systemic therapies) are in shown in the table. The most common adverse events (AE) with single-agent N (n = 5) were diarrhea (grade 1 80%; grade 2 20%) and nausea (grade 1 60%); other AEs were grade ≤1 in ≤20% of pts. Conclusions: N monotherapy had limited benefit as a single agent in FLC pts. Several case studies evaluating N-based combo with checkpoint inhibitors administered under compassionate use demonstrated that NP led to 1 PR, and the triplet of NPE to prolonged SD. These are case-limited observations but are critical and worth evaluating further in upcoming clinical trials given the continued lack of a standard of care therapy for pts with FLC. Clinical trial information: NCT01953926. [Table: see text]

265 Background: Treatment options for cholangiocarcinoma (CCA) after progression on first-line gemcitabine-based therapy are limited. Fibroblast growth factor receptor 2 ( FGFR2) gene fusions occur in 13–17% of intrahepatic CCA. A single-arm, phase II study (NCT02150967) evaluated infigratinib, an ATP-competitive FGFR1–3-selective oral tyrosine kinase inhibitor, in previously-treated advanced CCA with FGFR fusions/rearrangements. Methods: Adult patients with advanced/metastatic CCA with progression on ≥1 line of systemic therapy received infigratinib 125 mg orally for 21 days of each 28-day cycle until unacceptable toxicity or disease progression. All patients received prophylaxis with the oral phosphate binder sevelamer. Primary endpoint: objective response rate (ORR) by independent central review per RECIST v1.1, with duration of response (DOR). Secondary endpoints: progression-free survival (PFS), disease control rate, overall survival, safety, pharmacokinetics. Approximately 160 patients are planned (120/20/20 patients in Cohorts 1/2/3). This analysis focuses on Cohort 1 (patients with FGFR2 gene fusions or rearrangements without receiving a prior FGFR inhibitor). Results: As of 31 March 2020, 108 patients, including 83 (77%) with FGFR2 fusions, received infigratinib: median age 53 years (range 23–81 years); 54% had received ≥2 prior treatment lines. Median follow-up was 10.6 months (range 1.1–55.9 months). 96 patients (88.9%) discontinued treatment (12 ongoing). Centrally reviewed ORR was 23.1% (95% CI 15.6–32.2) including 1 CR and 24 PRs; median DOR was 5.0 months (range 0.9–19.1 months). Among responders, 8 (32.0%) patients had a DOR of ≥6 months. Median PFS was 7.3 months (95% CI 5.6–7.6 months). Prespecified subgroup analysis: ORR was 34% (17/50) in the second-line setting and 13.8% (8/58) in the third-/later-line setting (3–8 prior treatments). Most common treatment-emergent adverse events (TEAEs, any grade) were hyperphosphatemia (76.9%), eye disorders (67.6%, excluding central serous retinopathy/retinal pigment epithelium detachment [CSR/RPED]), stomatitis (54.6%), and fatigue (39.8%). CSR/RPED occurred in 16.7% of patients (including 1 G3 event; 0 G4). Other common grade 3/4 TEAEs were stomatitis (14.8%; all G3), hyponatremia (13.0%; all G3), and hypophosphatemia (13.0%; 13 G3, 1 G4). Conclusions: Infigratinib is associated with promising anticancer activity and a manageable AE profile in patients with advanced, refractory CCA with an FGFR2 gene fusion or rearrangement. A phase III study of infigratinib versus gemcitabine/cisplatin is ongoing in the front-line setting (NCT03773302). Clinical trial information: NCT02150967.

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.