In a phase Ib clinical trial, cabozantinib (anti-VEGFR2, c-MET, AXL) and nivolumab (anti-PD-1) were used as a neoadjuvant therapy in patients with HCC that was not eligible for resection. Neoadjuvant therapy enhanced tumor resectability. 12 patients were able to undergo surgical resection; 1 achieved a complete pathological response and 4 achieved major pathological responses. Responders showed signs of increased antitumor immunity, including increased tertiary lymphoid structures and T cells, and decreased HCC cells. Aggregates of B cells were associated with responses, while Arg-1+ macrophages were associated with resistance.
Contributed by Lauren Hitchings
ABSTRACT: A potentially curative hepatic resection is the optimal treatment for hepatocellular carcinoma (HCC) but most patients are not candidates for resection and most resected HCCs eventually recur. Until recently, neoadjuvant systemic therapy for HCC has been limited by a lack of effective systemic agents. Here, in a single-arm phase 1b study, we evaluated the feasibility of neoadjuvant cabozantinib and nivolumab in patients with HCC, including patients outside of traditional resection criteria (ClinicalTrials.gov ID NCT03299946). Of 15 patients enrolled, 12 (80%) underwent successful margin-negative resection and 5 out of 12 (42%) had major pathological responses. In-depth biospecimen profiling demonstrated an enrichment in effector T cells, as well as tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders compared to nonresponders, indicating an orchestrated B cell contribution to antitumor immunity in HCC.