A phase II study of durvalumab (MEDI4736) in combination with a CSF-1R inhibitor (SNDX-6352) following chemotherapy or radio-embolization for patients with intrahepatic cholangiocarcinoma.
Authors: Baretti Marina , Ding Yingjun , Brancati Madalena , Parkinson Rose , Linden Sheila , Hong Kelvin , Liddell Robert , Zheng Lei 
Published: June 2023

e16217

Background: Intraarterial therapies (IAT) are treatment options for selected intrahepatic cholangiocarcinoma (iCCA), with reasonable effectiveness. CCA are abundantly infiltrated with macrophages and M2-tumor associated macrophages (TAM) are associated with the risk of metastasis. By binding to colony-stimulating factor 1 receptor (CSF-1R) and blocking activation by its ligands, SNDX-6352 (axatilimab) can affect the migration, differentiation and survival of TAMs. We aimed to investigate the safety and clinical activity of combining IAT plus anti-PDL1 and axatilimab in iCCA (NCT04301778). Methods: This was a phase 2 study for patients with liver-limited, unresectable iCCA. Patients received treatment with either trans-arterial chemo-embolization (cTACE) or radio-embolization (Y90) every 8 weeks. Durvalumab was started one week following the first IAT procedure. Beginning with the second cycle, durvalumab and axatilimab combination therapy was given on Day 1 (both drugs) and Day 15 (axatilimab only) of each 28-day cycle. Patients underwent biopsy at baseline, at weeks 4 (after durvalumab single agent) and at week 8, during the second IAT procedure. Major immune cell subtypes, including T cell and myeloid cell, were characterized by multiplex immunohistochemistry on the formalin-fixed paraffin-embedded tissue slides of these biopsy specimens. T cell exhaustion pathways, including TIGIT expression on T cells and its ligand PVR(CD155) expression on tumor epithelial cells, were examined. Results: The study was closed early due to slow accrual. At the time of data cut of (11/2022), 5 patients were enrolled. The median age was 60 years (range 39-64) and 2/5 were male. Grade 3 treatment-related adverse events were reported by 3 patients including elevated CK and AST in 2 patients, elevated ALT in one patient, femoral pseudoaneurysm and cellulitis in one patient. No grade 4-5 adverse events were observed. One patient had partial responses by RECIST 1.1, and 1 had stable disease. Two patients had partial response of target lesions, but overall progression due to appearance of new liver lesions. PVR was moderately to strongly expressed on tumor epithelial cells and TIGIT+ T cells were abundantly infiltrated in all cases at baseline. PVR expression and TIGIT+ T cell infiltration appeared decreased following durvalumab and axatilimab treatments, although these changes could be secondary to tumor regression. Conclusions: The combination of IAT, durvalumab and axatilimab was generally well tolerated in patients with advanced CCA, with some signal of activity observed. Correlative studies suggest TIGIT axis modulation as a potential target of combination immunotherapy in patients with CCA. Further investigations are needed to expand the applicability of combination of immunotherapy with local therapies in CCA. Clinical trial information: NCT04301778 .