Jiang, Ping

TPS592 Background: For advanced CCA, standard of care 1L systemic treatment is GEM + CIS. Genetic alterations in intrahepatic CCA provide potential therapeutic targets. Fibroblast growth factor receptor (FGFR) 2 gene rearrangements driving CCA tumorigenesis were identified almost exclusively in intrahepatic CCA patients (pts) (incidence, 10–16%). In phase 2, PEM (INCB054828), a selective, potent, oral FGFR1–3 inhibitor elicited an objective response rate (ORR) of 35.5% and median progression-free survival (PFS) of 6.9 months (mo) in previously treated, locally advanced or metastatic CCA with FGFR2 rearrangements (NCT02924376). FIGHT-302, a randomized, open-label, phase 3 study will evaluate efficacy and safety of 1L PEM vs GEM + CIS in unresectable/metastatic CCA with FGFR2 fusions or rearrangements (NCT03656536). Methods: Eligible pts are adults with confirmed unresectable/metastatic CCA; no prior systemic therapy for advanced disease < 6 mo before enrollment; radiographically measurable/evaluable disease (per RECIST v1.1); ECOG PS ≤1; documented FGFR2 fusions or rearrangements. Exclusions include clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification; untreated CNS metastases or history of uncontrolled seizures. Pts will be randomized (1:1; stratified by region and tumor burden) to PEM 13.5 mg QD on a 21-day (d) cycle or GEM (1000 mg/m2) + CIS (25 mg/m2) on D1 and D8 of 21-d cycles (max 8). Crossover to PEM allowed after confirmed progression. PEM titration to 18 mg from cycle 2 allowed for pts without hyperphosphatemia (serum phosphate > 5.5 mg/dL) and Grade ≥2 treatment-related adverse events during cycle 1. Hyperphosphatemia will be managed with diet modifications, phosphate binders, diuretics, or dose adjustments. Treatment will continue until progression or unacceptable toxicity. Primary endpoint is PFS (by independent review). Secondary endpoints are ORR, overall survival, duration of response, disease control rate, safety, and quality of life. Four pts (target N = 432) are enrolled as of Sep 25, 2019. Clinical trial information: NCT03656536.

248 Background: Improved understanding of TME in CCA may allow for development of novel therapeutics targeting stromal components. Hyaluronic acid (HA) is a polysaccharide that has been found in the TME of a number of solid tumors characterized by desmoplastic stroma, such as pancreatic cancer. Elevated HA levels were prognostic in these malignancies. HA prevalence and association with clinic-pathological features in CCA is unknown. Methods: A retrospective study was conducted using clinically annotated formalin-fixed paraffin embedded tissue from resected intrahepatic CCA samples. Specimens were analyzed for HA, scored using a positive pixel count algorithm (Aperio Imagescope) and positivity was calculated as % of total pixel count. Clinical variables were examined by chi-square or ANOVA F-test. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier method and compared via log-rank test. Multivariate analysis was conducted using Cox proportional hazards regression models. Results: 142 patient samples were stained for HA. HA was identified in all samples (100%), with a range of HA positivity of 32.8 – 91.8%. Median HA value was 67.1% and 95% of patients had HA positivity ≥ 45%. Factors associated with higher than median HA ( > 67%) included perineural invasion (PNI) (40% vs. 21%, p = 0.011), necrosis (67% vs. 41%, p = 0.003), lymph node positivity (32% vs. 14%, p = 0.027), and small tumor size ( < 6.8 cm vs. > 8.4cm, p = 0.014). Stratification of HA staining by median positivity value was not an independent predictor of survival based on multivariate analysis. OS for patients with HA > 67% was 40.1 months (mo) vs 48.5 mo with HA ≤ 67%, p = 0.537. PFS for patients with HA > 67% was 14.4 mo vs. 25.7 mo with HA ≤ 67%, p = 0.177. Conclusions: Prevalence of HA staining in resected CCA is higher than seen in many solid tumors and is ubiquitous in our study. Absence of statistically significant association with OS and PFS might be attributable to ubiquitous prevalence, narrow signal range, and association with known negative prognostic factors. Further pre-clinical and clinical evaluation would be warranted.