PD-1 inhibitor combined with lenvatinib for unresectable liver cancer as the conversion therapy: An open-label, non-randomized, phase IV study.

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e16173 Background: The combination of lenvatinib and PD-1 inhibitor has shown to be a promising regimen for advanced hepatocellular carcinoma (HCC). We aimed to assess the feasibility of conversion therapy by lenvatinib combined with PD-1 inhibitor in unresectable HCC in a non-randomized phase IV study (ChiCTR1900023914). Methods: Eligible patients had histologically or cytologically confirmed unresectable HCC (AASLD); BCLC B or C; an ECOG status of 0 or 1 and Child-Pugh A-B. Patients received lenvatinib (8-12mg, oral QD) and PD-1 inhibitor (IV Q3W) until disease progression, unacceptable toxicity or satisfied for curative surgery. Surgical patients received maintenance therapy based on the pathological evaluation (pCR: PD-1 inhibitor 6-12m, pPR: combination therapy 6-12m, pPD: personalized). The primary endpoint was conversion rate for surgery based on radiological assessment. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), relapse-free survival (RFS) and overall survival (OS) by modified RECIST. Tumor tissue samples were collected at diagnosis and surgery. Immune cell subsets (CD8+ T cell, macrophage, NK cell) in tumor and stromal were measured by multiplex fluorescent immunohistochemistry. Whole exosome sequencing was performed with tumor samples and matched white blood cells. Results: and received the combination therapy. 49 patients were evaluated for the efficacy, 51.0% patients (5 CR, 17 PR and 3 SD) were conversed successfully based on their radiological evaluation after 3-7 cycles of combination therapy, among whom 15 patients (30.6%) actually received curative surgery upon comprehensive evaluation and patient preference. The median duration of follow-up was 271 days. The ORR was 53.1% (26/49, 5 CR and 21 PR) and the DCR was 69.4% (34/49). The median RFS and median OS of the 15 surgical patients were unreached. The 12-month OS was 74.1% and the 12-month RFS was 61.1%. Treatment-related adverse events occurred in 46.9% (23/49) of patients (grade ≥ 3, 6.1%). In both pre- and post-therapy tumor tissues, more CD8+ T cells (pre: p = 0.083, post: p = 0.007) and M1 macrophages (pre: p = 0.127, post: p = 0.120) were present in responders compared with non-responders. The conversion therapy could promote macrophage differentiating into M1 type in treatment-sensitive patients, as post-therapy tumoral M1/M2 ratio were higher in responders than non-responders (p = 0.073). Higher frequency of KMT2C mutation (missense and splicing, p = 0.040) were observed in response group. Conclusions: Combination of PD-1 inhibitor with lenvatinib as conversion therapy could benefit unresectable advanced HCC patients to achieve curative surgery. Tumor microenvironment and genomic characteristics may explain the potential mechanism of the clinical response. Clinical trial information: ChiCTR1900023914.