DeLeon, Thomas

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

Abstract Background Treatment patterns for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) differ, but limited studies exist comparing them. This study examines differences in molecular profiling rates and treatment patterns in these populations, focusing on use of adjuvant, liver-directed, targeted, and investigational therapies. Methods This multicenter collaboration included patients with ICC or ECC treated at 1 of 8 participating institutions. Retrospective data were collected on risk factors, pathology, treatments, and survival. Comparative statistical tests were 2-sided. Results Among 1039 patients screened, 847 patients met eligibility (ICC = 611, ECC = 236). Patients with ECC were more likely than those with ICC to present with early stage disease (53.8% vs 28.0%), undergo surgical resection (55.1% vs 29.8%), and receive adjuvant chemoradiation (36.5% vs 4.2%) (all P &lt; .00001). However, they were less likely to undergo molecular profiling (50.3% vs 64.3%) or receive liver-directed therapy (17.9% vs 35.7%), targeted therapy (4.7% vs 18.9%), and clinical trial therapy (10.6% vs 24.8%) (all P &lt; .001). In patients with recurrent ECC after surgery, the molecular profiling rate was 64.5%. Patients with advanced ECC had a shorter median overall survival than those with advanced ICC (11.8 vs 15.1 months; P &lt; .001). Conclusions Patients with advanced ECC have low rates of molecular profiling, possibly in part because of insufficient tissue. They also have low rates of targeted therapy use and clinical trial enrollment. While these rates are higher in advanced ICC, the prognosis for both subtypes of cholangiocarcinoma remains poor, and a pressing need exists for new effective targeted therapies and broader access to clinical trials.

Abstract Background:Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations.Methods:This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results:Twelve patients were enrolled prior to early termination of the trial. Clinical benefit (defined as complete/partial response + stable disease) of 45.5% was observed. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed.Conclusions:Ponatinib as a single agent in FGFR altered BTC is tolerable with very modest clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

580 Background: Though studies indicate that the genomic profiles of ICC and ECC are distinct, the clinical features that differentiate them still remain to be well characterized. The purpose of this study was to further analyze these differences and patient treatment patterns in a multi-center cohort. Methods: A retrospective chart review was performed at 8 institutions on patients (pts) with ICC or ECC diagnosed after June 2009. Data on demographics, risk factors, treatments, pathology and overall survival (OS) were collected. Tumor genotyping results from CLIA-certified tissue assays were analyzed. Fisher’s exact, Wilcoxon rank sum and log-rank tests were used to compare sub-groups. Results: In a database of 737 pts with cholangiocarcinoma, 538(73%) had ICC and 199(27%) had ECC. Pts with ICC more often presented in later stages, had tumors > 5cm at resection (p < 0.0001) and had metastases to the liver, lymph nodes, lung and/or bone (p < 0.01). Pts with ICC more often received liver directed therapy, targeted therapy and multiple lines of systemic therapy and they more often enrolled in a clinical trial (all p < 0.01). Pts with ECC were more likely to be male, undergo surgery, receive adjuvant chemotherapy and/or chemoradiation (all p < 0.05). Mutation profiling performed in 381 (52%) pts (ICC/ECC = 301/80) showed that pts with ICC were more likely to have IDH1 mutations and FGFR2 fusions, whereas pts with ECC were more likely to have KRAS, APC, SMAD4, WNT, TGFb and TP53 mutations (all < 0.05). Factors that did not differ significantly between pts with ICC and ECC include race, rates of primary sclerosing cholangitis, median diagnosis CA19-9 levels and R1 resection rate. Median OS from diagnosis was 18.9 months in ICC and 17.3 months in ECC (p = 0.8471). Conclusions: While pts with ICC and ECC have some similarities in their clinical features, differences in metastases patterns and molecular profiling significantly impact their management such that pts with ICC receive more liver-directed therapy, targeted therapy and more lines of systemic therapy. Further prospective studies are needed as referral patterns to tertiary care centers may have impacted these results.

Abstract BACKGROUND Radiation is an integral component of the multidisciplinary treatment of patients with intracranial metastasis (ICM) from melanoma. The risk of radiation necrosis (RN) post-treatment can range from 5–25%. We retrospectively evaluated pre- and post-radiation clinical and radiographical characteristics in patients with ICM from melanoma to identify potential risk factors for RN. METHODS After IRB approval, patients with ICM from melanoma who received radiation at our institution between 2013 and 2018 were retrospectively reviewed. We recorded demographics, intracranial metastasis (burden and location), systemic therapy, resection, stereotactic radiosurgery versus whole brain radiation, and outcomes. Brain MRI was evaluated using the Response Assessment in Neuro-Oncology criteria (RANO). RESULTS A total of 27 patients were included in the study. RN was diagnosed in 14 patients (52%) at one month to three years following radiation. Cerebellar location (n=7) was significantly associated with RN (p=0.0058). Metastasis-associated hemorrhage was present in 7 patients, 6 of which developed RN (43% vs 8%, p=0.08). Surgical resection prior to radiation was performed in 9 patients, 7 of which developed RN (50% vs 15%, p=0.1). RN appeared to be less often diagnosed when ICM were treated with higher doses of radiation (24 Gy vs 20 Gy, p=0.07). Systemic treatment was administered prior to radiation in 25 patients and we found no relationship with systemic therapy type and RN. Presumed RN was treated in 12 of 14 patients (86%). Steroids or surgical resection were the primary treatment modalities, with laser ablation used in 1 case. Following treatment, improvement was noted in 3 patients radiographically and in 1 of these clinically. CONCLUSIONS This series of patients with radiotherapy-treated brain metastases from melanoma reveals cerebellar involvement, hemorrhage, and prior surgical resection as potential risk factors for radiation necrosis. Neoadjuvant systemic treatment did not appear to be a risk factor in our review.

TPS532 Background: Recent studies have shown that FGFR2 fusions may represent recurrent (prevalence ~10-15% in larger cohorts) driver events amenable to therapeutic targeting in patients with advanced, intrahepatic cholangiocarcinoma. Methods: This single arm pilot study (NCT02265341) is being conducted at 3 centers (Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester; enrollment initiated December 2014). Next-generation sequencing based assays and a FISH-break apart assay are used to identify tumors with FGFR2 fusions. Patients must additionally have histologically/cytologically confirmed cholangiocarcinoma, ECOG performance score 0-2, measurable disease, preserved hematologic/renal and hepatic function and absence of cardiac events/stroke in the preceding 6 months. Ponatinib is administered at 45 mg once daily. Patients will be treated until disease progression, intolerable toxicity or patient decision to not pursue further therapy. The primary objective of the study is to estimate the clinical benefit rate (defined as composite of partial response rate, complete response rate and stable disease rate ≥ 4 months; as defined by RECIST criteria v1.1). Secondary endpoints include estimation of progression-free survival, overall survival, CA19-9 response rate (defined as > 50% reduction from baseline) and evaluation of the overall adverse event profile of ponatinib in this patient population. Translational objectives include serial circulating DNA (ct-DNA) monitoring, target knockdown assessments in tumor tissue (p-FGFR2, p-FRS2, p-Akt and p-ERK) and evaluation of mechanisms of resistance through comparison of baseline and progression biopsy samples using multi-platform sequencing (exome, RNA-Seq and methyl-Seq). Additionally, quality of life assessments will be evaluated using EORTC-QLQ-C30 and BIL21 tools. A total of 30 patients will be enrolled into the study (12 of 30 patients have been enrolled). The trial is designed using an underlying assumption of clinical benefit rate (CBR) of 5% with significance level of 0.15 and 80% power to detect a 20% CBR. Clinical trial information: NCT02265341.

355 Background: In this study, we sought to determine the prognostic factors impacting survival of patients with NELM who underwent LT at Mayo Clinic. Methods: We performed a three-site retrospective analysis of patients with unresectable NELM treated with LT from 1990 -2017. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, timing of diagnosis and transplant, extent of liver involvement, and tumor grade, were extracted. Extent of liver involvement was calculated using previously validated standardized volumetry with high defined as > 25% increase in the weight of the extracted liver at the time of the transplant as compared to the standard liver volume. Survival was calculated using the Kaplan–Meier method. Results: We identified 37 patients. Median age at LT was 47 (range 17.0-64.0), male: female (73% vs. 27%, respectively). Primary tumor site was in the pancreas in 51.3% and in the small bowels in 43.2%; 78.4% had NELM at presentation. While primary tumor resection was done at the time of LT in 5 (13.9%) cases, most patients (80.6%) had ˃6-months interval between primary tumor resection and LT surgery. Prior to LT, 25 (74.3%) patients received somatostatin analogues and 18 (61.3%) had liver-directed therapy. Median time from diagnosis to transplant was 33.6 months (0-246). High extent of liver involvement was identified in 12 patients (33.3%). Disease-Free Survival (DFS) at 3, 5, and 10 years was 56.8%, 43.1%, and 22.4% respectively. Overall-survival (OS) at 3, 5, and 10 years was 86.9%, 79.6%, and 52.6% respectively. High extent of liver involvement at the time of transplantation was associated with inferior DFS and OS and patients˃45 years-old at the time of transplantation had worse DFS. Patients whose disease met the OPTN (Organ Procurement and Transplantation Network) criteria for NELM transplantation had significantly better DFS and OS with median 10-year OS of 80.7 % vs. 17%. Conclusions: LT is a reasonable therapeutic option for selected patients with unresectable NELM with 10-year OS of 52.6%. High extent of liver involvement was associated with worse long-term outcomes while meeting OPTN criteria resulted in best outcomes.

328 Background: Patients with a history of solid organ transplants have been excluded from PD-1/PD-L1 inhibitor clinical trials due to concern for graft rejection. Only 2 case reports of PD-1 inhibitor use in patients with liver transplantation (LT) have been reported thus far. Here, we report our experience with using checkpoint inhibitors in metastatic cancer patients with LT. Methods: A single center pilot evaluation was conducted to evaluate the safety and efficacy of PD-1/PD-L1 inhibitors in patients with LT. PD-L1 staining on both the tumor and allograft were assessed if there was available tissue. The primary endpoint was evaluation of the risk for allograft rejection. Secondary endpoints included RECIST v1.1 and Immune-Related Response criteria (iRC) response rates, progression free survival (PFS) and overall survival (OS). Translational objectives included the relationship of PD-L1/PD-1 staining of tumor/allograft with response and rejection. Results: Six metastatic cancer patients with a history of LT received PD-1 inhibitor therapy (hepatocellular n=5, melanoma n=1). 3 patients were on mTOR inhibitor as immunosuppressive regimen and 3 on calcineurin inhibitor. Overall, allograft rejection was observed in 1/6 patients (on mTOR inhibitor). One patient achieved a CR (melanoma), 3 patients had PD and 2 patients discontinued therapy prior to restaging assessments. A single response (by both RECIST v1.1 and iRC) and rejection were reported in patients who received mTOR inhibitors (1 of 3). Three patients were tested for PD-L1 staining in the allograft tissue and all of them were negative (0% staining) with no graft rejections observed. Four patients had tumor PD-L1 evaluated (2 patients tested positive with 1 patient obtained a CR). The median OS, PFS and duration of therapy were 1.2, 1.8 and 1.2 months respectively. Conclusions: In this pilot evaluation of PD-1/PD-L1 inhibitors in LT patients both preliminary efficacy (1 of 4) and allograft rejection (1 of 6) was exhibited. Larger, prospective trials are needed to elucidate optimal patient and immunosuppressive regimen selection in these patients.

e21057 Background: BRAF, NRAS, CDKN2A and P53 mutations are commonly observed pathogenic mutations in cutaneous melanoma. The influence of mutations such as BRAF, NRAS, CDKN2A and P53 on treatment response in the PD1 inhibitor era has not been well defined. Methods: This study included patients with melanoma with a cutaneous or unknown primary. All patients had genomic profiling with the Mayo Clinic 50-gene solid tumor mutation panel. Treatment response to first line immunotherapy with PD1, CTLA-4, or combination PD1/CTLA-4 inhibitors were assessed by response rate and time-to-progression (TTP) rate at 12 months. Each patient outcome was stratified by non-mutually exclusive gene mutation status into BRAF, NRAS, P53, CDKN2A, or quadruple negative (N4) groups. Results: Genomic profiling was performed on 208 patients, of whom 102 received first line immunotherapy. Most patients received a PD1 inhibitor (n = 62), followed by CTLA-4 inhibitor (n = 34), and combination therapy (n = 6). A trend towards improved outcomes was observed in CDKN2A and BRAF mutated patients with worse outcomes noted in P53, N4, and NRAS patients. The percent without progression at 12 months were BRAF 52.2%, CDKN2A 58.2%, NRAS 30.5%, P53 37.7%, and N4 26.7% (see table below). Response rates were BRAF 46.4%, CDKN2A 38.5%, NRAS 22.2%, P53 40.0%, and N4 33.3%. Conclusions: There is a trend towards improved outcomes with immunotherapy in BRAF and CDKN2A mutated patients while P53, NRAS and N4 patients have inferior outcomes. [Table: see text]

e15626 Background: FGFR2 fusions are found in 10-15% of intrahepatic cholangiocarcinomas. Individuals with FGFR2 fusions have a better prognosis and more indolent natural history. More recently FGFR2 fusions have been described as a predictive marker for tyrosine kinase inhibitors targeting the FGFR2 pathway. Texture analysis from CT imaging has been used in the past to estimate degree of fibrosis and angiogenesis in various tumors types; however, texture analysis has not been used in the past to detect FGFR2 rearrangements. Methods: This is a retrospective study of 33 patients with intrahepatic cholangiocarcinoma who were previously tested for FGFR2 fusions with either a FISH break apart assay or with clinically available next generation sequencing assays. All patients had a contrast enhanced CT performed. To address physiological and pathological variations, matched-size regions of interest (ROIs) over areas of non-necrotic tumor and unaffected liver during the portal venous phase were drawn. The paired ROIs for each patient were then processed via an imaging analytic pipeline for (1) ROI normalization, (2) texture panel creation, and (3) machine learning predictive model development. Results: Fifteen patients with FGFR2 fusions and 18 patients without FGFR2 fusions were included in the study. Using the developed predictive model, accurate FGFR2 fusion classification in 90% of cases was achieved (sensitivity = 87%, specificity = 94%). Conclusions: Utilizing advanced analytics with machine learning techniques, multi-textural data obtained from conventional CT images has the capability to detect genetic aberrations in intrahepatic cholangiocarcinoma, including FGFR2 gene fusions. Radiogenomic evaluation has several attractive benefits including the cost effective and expeditious detection of actionable mutations such as FGFR2 fusions as well as avoidance of invasive procedures such as percutaneous core biopsies. [Table: see text]