Li, Daneng

539 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with a unique FGFR-binding mechanism. It potently inhibits FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and early clinical studies in cholangiocarcinoma (CCA). Here we present the preliminary efficacy and safety of tinengotinib (TT-00420) in a phase II trial TT420C1206 (NCT04919642). Methods: Eligible patients (pts) with advanced/metastatic CCA exhausting standard treatment options received tinengotinib 10 mg QD. Pts were enrolled into four cohorts using historical FGFR alteration status: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor (FGFRi) (A1) or progression after prior response to FGFRi (acquired resistance) (A2); non-fusion FGFR alteration(s) (B); or FGFR wild-type (FGFRwt, C). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Safety, PK parameters, and biomarker profile were evaluated and reviewed jointly with the efficacy outcomes. Adverse events (AEs) were graded per CTCAE version 5.0. Results: As of Sep 13, 2022, 25 pts with CCA were enrolled and dosed; 7 in A1, 6 in A2, 2 in B and 10 in C. Median age 61 [range 24-82] years old, 64% female, 93.3% had ≥ 3 prior treatment lines. 13 patients with ECOG 0 and 12 patients with ECOG 1 at baseline. Among 15 patients with historical FGFR alterations (13 fusions/rearrangement and 2 mutations), 93.3% had ≥ 1 prior FGFRi, and 3 pts (20.0%) had 2 prior FGFRi treatments. Eighteen pts were evaluable for tumor assessment at data cutoff date, including 4 in A1, 6 in A2, 1 in B and 7 in C. The median follow up was 15 weeks. In A2, 2 out of 6 pts (33%) achieved PR with tumor reductions of 34% and 54%. Overall DCR (CR or PR+SD) was 90% (9/10) in FGFR2 fusion/rearrangement pts; 100% in FGFR primary mutation pt (1/1); and 71% (5/7) in FGFRwt pts. One PR and 5 SDs lasted for more than 16 weeks. Among 25 treated pts, drug-related AEs occurred in 20 (80%) pts, including 7 (28%) with Grade (G) 1-2 AEs, 12 (48%) with G3 AEs, and 1 (4%) with G4 AE. Most frequently occurred G3/4 AEs were hypertension in 6 (24%) pts, including 5 (20%) with G3 and 1 (4%) with G4, G3 fatigue in 2 (8%) and G3 neutrophil count decreased in 2 (8%) pts. No drug-related G5 was observed. The efficacy and safety results observed were consistent with the previous reported data ( NCT03654547 ) in CCA pts. The preliminary biomarker analysis suggests loss of resistant FGFR mutation on liquid biopsy post tinengotinib therapy. Further biomarker analysis will be updated at the presentation. Conclusions: Tinengotinib may result in promising clinical benefit for CCA pts in the setting of FGFRi-resistance. Tinengotinib-related toxicities were manageable. An ongoing phase II study will further provide safety, efficacy and biomarker evaluations for both FGFR resistant and FGFRwt CCA. Clinical trial information: NCT04919642 .

Abstract Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

TPS468 Background: Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from the intrahepatic bile duct. Standard treatment of unresectable, recurrent, or metastatic iCCA is with cytotoxic chemotherapy. FGFR2 gene fusions have been identified as oncogenic drivers in 10–20% of iCCA tumors, but no targeted agents have been established to date. TAS-120 is an investigational irreversible FGFR1–4 inhibitor in development as a once-daily oral treatment for iCCA. Based on initial studies in multiple tumor types expressing FGFR abnormalities, iCCA was identified as a tumor type with potential susceptibility to FGFR inhibition and high unmet need. A phase I portion of the trial with an iCCA expansion cohort demonstrated tolerability and preliminary evidence of clinical efficacy with TAS-120 as a continuous, once-daily oral treatment in patients with iCCA. The most common AEs in the phase I portion of the trial were hyperphosphatemia, a mechanism-based on-target side effect, cutaneous AEs, and gastrointestinal AEs. The phase I portion of the study is continuing to enroll, and final results are anticipated in early 2019. Based on preliminary findings, a phase II portion of the study (FOENIX-101; clinicaltrials.gov registration NCT02052778) has been initiated. Methods: The phase II portion of the trial is a global, single-arm study of TAS-120 in patients with iCCA harboring FGFR2 gene rearrangements. The study will enroll approximately 100 adult patients with locally advanced or metastatic iCCA that progressed after ≥ 1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy. Screening for FGFR2 gene rearrangements will be performed at a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life. Clinical trial information: NCT02052778.