Aims: Lenvatinib is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, and other targets; pembrolizumab is an anti–PD-1 antibody. We report exploratory biomarker analyses from a phase 1b/2 study in advanced endometrial cancer (EC) and preclinical rationale for the activity of lenvatinib+pembrolizumab.
Methods: 41 Candidate serum biomarkers were assessed using immunoassay panels in 38 patients with EC receiving lenvatinib+pembrolizumab at baseline; cycle 1, day 15 (C1D15); and cycle 2, day 1 (C2D1). Data cutoff: May 31, 2017. Tumor-associated macrophages (TAM) were assessed by flow cytometry and immunohistochemistry. RNAseq transcriptomes of tumors from mice treated with lenvatinib, anti–PD-1, or lenvatinib + anti–PD-1 were subjected to pathway enrichment analyses.
Results: At C1D15 and C2D1 of lenvatinib+pembrolizumab, significant changes were seen in the levels of 16/41 and 18/41 biomarkers, respectively, including increased levels of interferon (IFN)-γ and IFN-γ–regulated chemokines (CXCL9, CXCL10, CXCL11; all P < 0.05). Significant associations were found between increases in CXCL9 and CXCL10 and patients with complete, partial, or unconfirmed partial responses (all P < 0.05). Preclinical experiments showed that lenvatinib alone significantly depleted the TAM population in excised tumors (P < 0.01). Transcriptome analyses of tumors from mice treated with lenvatinib + anti–PD-1 showed that genes specifically regulated by the combination were significantly enriched for involvement in signaling pathways associated with immune modulation, including IFN signaling (FDR P as low as 1.50 x 10-9).
Conclusions: In patients with advanced EC, lenvatinib+pembrolizumab was associated with changes in several biomarkers, including IFN-γ–regulated chemokines, some of which may be associated with clinical response. Preclinical experiments suggest that lenvatinib monotherapy may modulate tumor microenvironment by decreasing the local TAM population, whereas lenvatinib + anti–PD-1 may act via a mechanism that includes the IFN signaling pathway. Overall, these findings provide preclinical rationale for the activity of lenvatinib+pembrolizumab.