310 - A Phase II Study of Durvalumab and Tremelimumab with Radiation Therapy in Patients with Advanced Hepatocellular Carcinoma and Biliary Tract Cancer
Presenter(s)
J. L. Koenig1, Z. L. Cosner2, Z. Guan3,4, P. S. Pathak5, B. Y. Yeap3,6, J. N. Allen5, A. X. Zhu4, L. Goyal7, J. Franses8, K. S. Lau-Min4, L. C. Drapek1, D. P. Ryan4, J. W. Clark5, E. P. Walsh4, A. Foster3, C. Bolton3, J. Seidenberg3, H. J. Roberts1, A. R. Parikh4, T. S. Hong1, and J. Y. Wo1; 1Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2Johns Hopkins School of Medicine, Baltimore, MD, 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 4Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 5Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 6Department of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 7Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford School of Medicine, Stanford, CA, 8Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
Purpose/Objective(s):
This study evaluated the combination of radiation therapy (RT) with durvalumab (D; anti-PD-L1)/tremelimumab (T; anti-CTLA-4) in patients (pts) with hepatocellular carcinoma (HCC) and biliary tract cancer (BTC).Materials/Methods:
This is an open-label, single-arm, phase 2 study (NCT03482102) of pts with locally advanced/metastatic HCC or BTC, Child-Pugh A/B7 cirrhosis, prior treatment with/refusal of sorafenib (HCC) or gemcitabine-based chemotherapy (BTC), one unirradiated lesion amenable to RT, and another unirradiated lesion outside of the RT field. Pts received D/T q 4 wks for 4 cycles followed by D monotherapy with doses determined during the safety run-in. RT (24 Gy/3 fx) began on C2D1. Dose limiting toxicity (DLT) was assessed through C2 in a safety run-in. The primary endpoint was the overall response rate (ORR) by irRECIST. We planned to enroll 55 HCC/15 BTC pts. The HCC cohort closed after 2 pts, and the BTC cohort expanded to 40 pts before closing early. HCC pts were excluded from the primary analysis. The study was designed to test if the addition of RT to D/T is associated with an ORR of 30%, requiring at least 9/40 pts to achieve a response. Secondary endpoints included the disease control rate (DCR), duration of response (DOR), time to disease progression (TTDP), PFS, OS, and safety per CTCAE v 4.03.Results:
We enrolled 33 BTC pts from 5/2018 to 3/2024. Median age was 63 yrs (range 40-84). 32 pts had metastatic disease. 25 had Child-Pugh A. Pts received a median of 2 prior systemic therapies (range 0-6), and 7 had prior anti-PD-1/PD-L1 therapy. Somatic alterations were identified in IDH1 (7), KRAS (7), BRAF (3), FGFR2 (2), NTRK (1), and ERBB2 (1). TMB was high (>10 mut/Mb) in 2 pts. In the first safety run-in (D 1500 mg), 3/6 pts had DLT, exceeding the 33% threshold. A second run-in (D 1125 mg) had DLT in 1/6 pts, allowing continued enrollment. 85% of pts completed RT. Pts received a median of 2 cycles of D (range 1-80) and T (range 1-4). With a median follow-up of 11.3 months (mos) among 7 surviving pts (range 0.7-73.3), the ORR was 15% (5/33; 95% CI, 5-32%; CR 1, PR 4, SD 5, 23 PD) and DCR was 30% (10/33; 95% CI, 16-49%). DOR was 34.2 mos, 2.9 mos (95% CI, 1.7-NA mos), and 1.8 mos (95% CI, 0.9-NA mos) for patient(s) with CR, PR, and SD, respectively. Median TTDP, PFS, and OS were 1.7 mos (95% CI, 1.5-3.1 mos), 1.7 mos (95% CI, 1.6-2.7 mos), and 5.8 mos (95% CI, 3.3-10.5 mos), respectively. At 1 year, PFS was 9% and OS was 30%. 11 of 31 (35%) progressing pts continued D past progression for a median of 3.1 mos. 18/33 pts had grade 3+ AEs and five pts had SAEs (one in first safety run-in), including ARDS, ascites, increased bilirubin, delirium, fatigue, hyperkalemia, hyponatremia, thrombocytopenia, and renal tubular acidosis. Conclusion: While adding RT to D 1125mg/T 75mg did not show significant activity in advanced, pretreated BTC, RT with D/T at this dosing was found to be tolerable. Biomarker selection, ablative RT doses, and earlier RT in cycle 1 may improve the efficacy of this approach.