Analysis Of Serum Biomarkers (Bm) In Patients (Pts) From A Phase 3 Study Of Lenvatinib (Len) Vs Sorafenib (Sor) As First-Line Treatment For Unresectable Hepatocellular Carcinoma (Uhcc)

Background: LEN is an oral multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. LEN was noninferior to SOR in overall survival (OS) in a phase 3 study in pts with uHCC (medians: LEN, 13.6 mos vs SOR, 12.3 mos; HR: 0.92; 95% CI, 0.79–1.06). We performed BM analyses to identify potential markers of benefit to each agent. Methods: 954 Pts with uHCC, untreated in first-line, were randomized 1:1 in this open-label study to oral LEN (weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or SOR 400 mg twice daily. Primary endpoint was OS. Archival tumor tissue and blood samples were collected pretreatment and at specified time points. The BM analysis set (BAS; n = 119) included pts who provided both archival tissue and serum samples. Serum samples from 114 pts were analyzed at baseline and over time with ELISA or chemiluminescence for VEGF, ANG2, FGF21, FGF23, and PIVKA-II. Gene-expression profiling was performed on tissue samples with nCounter® (NanoString). Results from BM analyses were correlated with OS. Results: Of 119 pts in the BAS, 58 tissues passed quality assurance. Clinical characteristics of the BAS were similar to the ITT except most pts in the BAS were from the West. For serum assays, 66 pts in the LEN arm and 48 pts in the SOR arm were analyzed. At baseline, there was a trend that lower VEGF, ANG2, and FGF21 serum levels were associated with better outcomes with both LEN and SOR. Data with FGF19 and FGF23 were not consistent. An increase in serum VEGF over time was seen with both drugs, but was greater for LEN. Only LEN showed modulation of ANG2, FGF19, and FGF23 levels. Gene-expression analysis was performed in 58 pts (34 LEN, 24 SOR). Supervised clustering using angiogenic and growth-factor pathway gene expression based on 36 genes identified 3 groups. Median OS was longer with LEN in pts with higher VEGF- and FGF-family gene-expression levels but was longer with SOR in pts with lower expression levels. Conclusions: LEN was noninferior to SOR in OS in pts with uHCC. Serum BM and gene expression levels appear to correlate with outcomes in the BAS. Change in BM levels after LEN and SOR differs by treatment. These results are hypotheses generating and need confirmation. Clinical trial identification: NCT01761266 Legal entity responsible for the study: Eisai Inc. Funding: Eisai Inc. Disclosure: R.S. Finn: Reports grants/personal fees/nonfinancial support from Eisai Inc during the conduct of the study. Reports grants/personal fees/nonfinancial support from Bayer, Pfizer, Novartis, Bristol-Myers-Squibb, and Merck outside the submitted work. M. Kudo: Reports and Honoraria from health care company: Bayer, Eisai, MSD, EA Pharma. A-L. Cheng: Reports personal fees from BMS, personal fees from Ono, personal fees from Novartis, personal fees from Bayer, personal fees from MERCK, personal fees from MSD, during the conduct of the study. L. Wyrwicz: Sponsored Research for Eisai. J-F. Blanc: Reports personal fees from Bayer SP, personal fees from Lilly Oncology, personal fees from Novartis, personal fees from BMS, outside the submitted work. A.D. Baron: Report Research Funding from Eisai Inc., M. Ikeda: Advisory boards: Eisai, Bayer Yakuhin, Eli Lilly Japan, BMS, Kyowa Hakko Kirin. Corporate-sponsored research: Bayer Yakuhin, Kyowa Hakko Kirin, Taiho, Eli Lilly, Ono Pharma, Eisai, Chugai, Kowa. Honoraria: Bayer Yakuhin, BMS, Abbott, Eisai, Nippon Kayaku. F. Piscaglia: Reports personal fees from Eisai during the conduct of the study. Reports grants and personal fees from Bayer and personal fees from Bracco outside the submitted work. K-H. Han: Reports grants and other from Eisai co., during the conduct of the study; grants and other from Kowa, other from Bayer, outside the submitted work; . Y. Minoshima: Employee of Eisai Co., Ltd. Y. Funahashi: Employee of Eisai Co., Ltd M. Ren, P. Sachdev, T. Tamai, C. Dutcus: Employee of Eisai Inc. R. Dairiki: Employee of Eisai Co Ltd., T.R.J. Evans: “Other” from Eisai during conduct of study. Other from BMS, Clovis, Karus Therapeutics, Baxalta, Bayer, Celgene, GlaxoSmithKline, Otsuka, Roche/Genentech, TC Biopharm, Immunova, Basilea, eTherapeutics, Immunocore, Vertex, Verastem, Daiichi, Merck. All other authors have declared no conflicts of interest.