Citations

TPS600 Background: Pts with adv CCA have poor survival outcomes, and chemotherapy offers limited survival benefit (5-year survival rates, 5–10%; median overall survival [OS], 8–12 months). FGFR2 gene rearrangements are known to be early drivers of oncogenesis in ~15% of pts with intrahepatic (i) CCA. Futibatinib, an oral, highly selective, irreversible FGFR1-4 inhibitor has shown antitumor activity against a broad spectrum of FGFR-deregulated tumors in preclinical studies. In a previous study, futibatinib demonstrated clinical activity and tolerability in heavily pretreated pts with adv CCA harboring FGFR2 gene rearrangements. This phase 3 trial (FOENIX-CCA3) is designed to evaluate futibatinib vs gem-cis as 1L therapy for pts with adv iCCA harboring FGFR2 rearrangements. Methods: FOENIX-CCA3 is a multicenter, open-label, randomized phase 3 study that will be conducted in pts with metastatic or unresectable iCCA harboring FGFR2 rearrangements (assessed at screening by a central laboratory). Pts must have an ECOG performance status of 0 or 1 and should not have received previous systemic anticancer therapy for adv disease (adjuvant/neoadjuvant therapy ≥6 mo prior to randomization is permissible). Pts with clinically-significant alterations in calcium-phosphorus homeostasis or ectopic mineralization/calcification will be excluded. Approximately 216 pts will be randomized (1:1 ratio) to receive 20 mg futibatinib once daily until disease progression or other discontinuation criteria are met or gem-cis (on days 1 and 8 of a 21-day cycle) for 8 cycles or until disease progression, whichever occurs first. Pts will be stratified by prior surgical excision (yes vs no), geographic region, and locally adv vs metastatic disease. The primary endpoint is progression-free survival (PFS) assessed by independent central review (ICR). Secondary endpoints include objective response rate and disease control rate based on ICR, OS, PFS per investigator assessment, and safety. The anticipated start date is in April, 2020.

TPS468 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care palliative 1st-line therapy for advanced HER2+ GEJ/GC patients (pts). M, an Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. M coordinately enhanced both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. MGA012 (INCMGA00012) is a humanized, hinge-stabilized, IgG4 κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. MGD013 is a humanized Fc-bearing bispecific tetravalent protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC pts, and induced a 30% objective response rate (ORR). This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC pts. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study. The first single arm, CTX-free cohort A evaluates M+MGA012 in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) pts. After 40 pts are evaluated for response/safety, 60 more pts will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) pts are enrolled irrespective of PD-L1 status. Part 1 randomizes pts to 1 of 4 arms (50 pts each): control arm (T+CTX) or 1 experimental arm (M+CTX; M+CTX+MGA012; M+CTX+MGD013). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either MGA012 or MGD013, depending on results from part 1; with 250 pts each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival.

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.