Poster Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2018

Biomarker results and preclinical rationale for combination lenvatinib and pembrolizumab in advanced endometrial carcinoma (#369)

Vicky Makker 1 , Allen Cohen 2 , Matthew Taylor 3 , Yukinori Minoshima 4 , Yu Kato 4 , Ryo Dairiki 4 , Michio Kanekiyo 5 , Ayako Yachie 6 , Kotaro Kodama 4 , Pallavi Sachdev 5 , Junji Matsui 5 , Yasuhiro Funahasi 4 , Louise Young 7 , Drew Rasco 8
  1. Memorial Sloan Ketting Cancer Center, New York, USA
  2. Rocky Mountain Cancer Center, Denver, CO, USA
  3. Oregon Health and Science University, Portland, Oregon, USA
  4. Eisai Co., Ltd, Tokyo, Japan
  5. Eisai Inc., Woodcliff Lake, New Jersey, United States of America
  6. The Systems Biology Institute, Tokyo, Japan
  7. Eisai Australia Pty Ltd, Melbourne, VIC, Australia
  8. START, San Antonio, Texas, USA

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.