307 - Phase IB/II Study of Trifluridine/Tipiracil Hydrochloride (FTD/TPI) Plus Radiation Therapy for the Treatment of the Liver in Patients with Hepatic Metastases from Colorectal and Pancreatic Cancer
Presenter(s)
J. Y. Wo1, Z. Guan2, B. Y. Yeap3, H. J. Roberts4, L. C. Drapek1, L. Morris5, A. R. Parikh6, H. Willers7, L. S. Blaszkowsky6, J. N. Allen6, C. Weekes6, J. W. Clark6, and T. S. Hong1; 1Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 3Department of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 4Columbia University College of Physicians and Surgeons, New York, NY, 5Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 7Department of Radiation Oncology, Mass General Brigham/ Massachusetts General Hospital, Boston, MA
Purpose/Objective(s): Stereotactic body radiotherapy (SBRT) for liver metastases (LM) has emerged as a viable option for treatment of unresectable disease. Among patients with colorectal (CRC) and pancreatic cancer (PDAC) LM, however, recent phase II data demonstrated a 1-year local control (LC) rate with SBRT of 60%, suggesting need for novel strategies to enhance radiosensitivity. FTD/TPI is an orally administered FDA approved regimen for refractory metastatic CRC. In this current study, we report our combined Phase IB/II results where we sought to determine efficacy of FTD/TPI administered with liver SBRT.
Materials/Methods: Patients were enrolled on an investigator-initiated, industry sponsored, prospective, single arm study (NCTXXXXXXX). Key eligibility included: confirmed diagnosis of CRC or PDAC with 1-4 unresectable LM, at least 1 lesion measuring = 1 cm, = 800 ml of uninvolved liver, and ECOG PS 0-1. Prior TACE, RFA, chemotherapy, or targeted agents allowed. Prior liver directed RT, including SIRT, was not permitted. Patients were treated with liver RT in 5-6 fractions over 2-3 weeks with RT dose determined by Veff (30-50 Gy in 5 fractions, or 31.8-54 Gy in 6 fractions). FTD/TPI dosing occurred on day 1-5 and 8-12. Our prior Phase IB study (n=12) established DLT of FTD/TPI at 30 mg/m2 with liver SBRT. The primary hypothesis of the phase II component was to demonstrate improvement of 1-year LC with SBRT from 60% to 80% with addition of FTD/TPI. Secondary endpoints included PFS, OS, and toxicity.
Results: From 10/2017 to 12/2023, 52 patients were enrolled (n=12 in Phase I, n=40 in Phase II), of whom 51 were analyzed (1 died prior to treatment). Median age was 66 (range: 32-88), and 31 patients were male (61%). In total, 27 (53%) and 24 (47%) patients had a diagnosis of CRC and PDAC, respectively. Median RT dose was 50 Gy (range: 30-54). Median follow-up was 23 (range: 10-29) months among 20 patients still alive. The 1 and 2-year LC rates were 78% and 68% for the entire cohort, 78% and 61% among patients with CRC, and 79% and 79% among patients with PDAC. The 1 and 2-year PFS rates were 16% and 8% for the entire cohort, 19% and 9% for CRC, and 12% and 8 % for PDAC, respectively. The 1 and 2-year OS rates were 63% and 37% for the entire cohort, 78% and 43% for CRC, and 45% and 31% for PDAC, respectively. Rates of grade 3+ toxicity (acute or late) for non-hematologic and hematologic were 6% and 57%, respectively (43% with grade 3+ lymphopenia). Smaller lesion size (baseline sum of longest tumor diameters) was a significant predictor of improved PFS (p=0.03). Among 22 patients with known KRAS mutation status, wildtype KRAS (50%) was a significant predictor of improved PFS (p=0.04) and OS (p=0.01).
Conclusion: In our phase IB/II study, FTD/TPI in combination with liver SBRT was well tolerated. Although not quite meeting the prespecified study endpoint, FTD/TPI with liver SBRT demonstrated promising efficacy in improving LC among patients with CRC and PDAC LM. Limited long term PFS and OS suggest need for further improvements in systemic therapies.