A phase IIa clinical trial of first-line cyclical therapy alternating gemcitabine, cisplatin, and durvalumab with pemigatinib for advanced biliary tract cancers with <i>FGFR2</i> -alterations.

TPS645 Background: Unresectable biliary tract cancer (BTC) has a poor prognosis. Frontline chemo-immunotherapy (C-IO) for advanced BTC leads to ~25% overall survival (OS) at 24-month, but 93-99% of patients reported adverse events (AEs), and 13-19% of patients stopped treatment drugs due to AEs. FGFR kinase inhibitors (FGFRi) are second-line therapy for 10% of BTC with FGFR2 fusions. However, clinical trials of upfront FGFRi have not accrued well. Cumulative toxicities frequently interrupt treatment and limit feasibility of concurrent C-IO + FGFRi. Over time, side effects from each of therapies have a negative impact on patients’ quality of life (QoL). We previously treated two FGFR2 -altered BTC patients with cyclical chemotherapy (CT) and FGFRi and observed prolonged survival with better QoL. By monitoring serial circulating tumor DNA (ctDNA), we observed development of FGFRi-resistant subclones while on FGFRi and their subsequent clearance after resuming CT. Thus, we have developed a clinical trial to validate our hypothesis that upfront cyclical therapy alternating between C-IO and FGFRi can improve therapeutic efficacy and QoL. Alternating therapy is hypothesized to avoid accumulating toxicities and treat emerging resistance subclones. Methods: In this single-center, single-arm, Phase IIa trial, all treatment-naive patients with FGFR2 -altered advanced BTCs, PS ≤ 1, are eligible. Patients will receive cyclical therapy alternating between two therapy-blocks, starting from C-IO block (2 cycles of gemcitabine, cisplatin and durvalumab, 28-day/cycle), then FGFRi block (3 cycles of pemigatinib on day 1-14 of 21-day/cycle). Block-switch continues until progressive disease (PD), and then we will continue alternated block until the next PD. A sample size of 30 is calculated based on an expected 12-month OS rate of ≥ 55%. The trial is anticipated to enroll the first patient in early 2025. Results: The primary objective is 12-month OS rate. Secondary objectives are overall response rate, progression-free survival, AEs. We will stratify patients to PD-L1 CPS &lt;1 or ≥ 1 to assess if cyclical therapy can enhance IO. Exploratory objectives are (1) assessing dynamics of FGFR2 -ctDNA variants throughout therapy correlating with clinical outcomes, using a custom liquid biopsy (FGFR-Dx) developed at the Ohio State University; (2) assessing QoL scores with EORTC-QLQ-C30 and -BIL21 questionnaires, correlating with clinical outcomes. Results will be compared to historical controls from TOPAZ-1 trial. Conclusions: Cyclical therapy will be one of the first to combine alternating C-IO and targeted therapy in cancer. This strategy can be validated in other tumors if it is proven effective in our trial. Cyclical therapy holds great promise to introduce FGFRi earlier into treatment for BTC and improve both efficacy and QoL.