Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC).
Authors: Yarchoan Mark , Zhu Qingfeng , Durham Jennifer N. , Gross Nicole , Charmsaz Soren , Leatherman James M. , Zhang Shu , Popovic Aleksandra , Weiss Matthew John , Philosophe Benjamin , Burkhart Richard A. , Burns William , Wilt Brad , Sugar Elizabeth , Fertig Elana J. , Laheru Dan , Anders Robert A , Jaffee Elizabeth M. , Ho Won Jin 
Published: January 2021

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Background: Only 10-15% of newly diagnosed HCC patients are candidates for a potentially curative resection, and most patients who receive resection eventually recur. Historical systemic therapies including sorafenib, as well as locoregional therapies, have not demonstrated benefit in the perioperative setting. Novel combinations of targeted therapies and immunotherapies demonstrate higher response rates than sorafenib in HCC. Here, we report the feasibility and efficacy of neoadjuvant combination therapy with cabozantinib plus nivolumab, followed by surgical resection, in patients with borderline resectable or locally advanced HCC. Methods: We conducted an open-label, single-arm, phase I study in patients with HCC with borderline resectable or locally advanced HCC (including multinodular disease, portal vein involvement, or other high-risk features). Patients received 8 weeks of therapy with cabozantinib 40 mg oral daily plus nivolumab 240 mg IV every two weeks, followed by restaging and possible surgical resection. The primary endpoint was feasibility, defined by the percentage of patients experiencing a treatment-related adverse event that precluded continuing on to surgery within 60 days of the planned date for surgical evaluation. Results: We enrolled 15 patients of whom 14 patients completed neoadjuvant therapy and underwent surgical evaluation. Adverse events were consistent with prior experience with these agents, and the trial met its primary endpoint, with no patients experiencing a treatment-related adverse event that precluded timely surgical assessment. Of patients completing neoadjuvant therapy, 1 patient declined surgery, 1 tumor could not be resected, and 12 patients underwent successful R0 surgical resection. 5/12 (41.7%) resected patients had a major or complete pathologic response. At a median follow up of one year, 4/5 pathologic responders are without recurrence. We performed an in-depth profiling of the surgical resection biospecimens and identified an enrichment of IFNγ+ effector memory CD4+ and granzyme B+ effector CD8+ T cells as well as tertiary lymphoid aggregates in the pathologic responders. We further analyzed the spatial relationships of cell types in responders and non-responders, which identified distinct spatial arrangement of B cells in responders, and proximity of arginase-1 expressing myeloid cells to T cells in nonresponders. Conclusions: This study is, to our knowledge, the first use of a targeted therapy in combination with an immune checkpoint inhibitor in the neoadjuvant setting in HCC, and the first use of modern systemic therapies to expand surgical resection criteria. Neoadjuvant cabozantinib and nivolumab is feasible, and may result in pathologic responses and long-term disease-free survival in a group of patients who may be outside traditional resection criteria. Clinical trial information: NCT03299946.