IP Library › Granted Patent US 12,661,398
Granted Patent B2
US 12,661,398 · App. 17/772,468 · Granted Jun 23, 2026

Combination of a PD-1 antagonist, a VEGFR/FGFR/RET tyrosine kinase inhibitor and a CBP/beta-catenin inhibitor for treating cancer

Inventors: Yoichi Ozawa (Tsukuba, JP); Yasuhiro Funahashi (Tsukuba, JP); Yu Kato (Tsukuba, JP)
A61K39/3955A61K31/47A61K31/53A61P35/00
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Quick Facts
Patent No.
US 12,661,398
App. No.
17/772,468
Granted
Jun 23, 2026
Kind
B2
Abstract

The present disclosure describes a combination therapy comprising an antagonist of Programmed Death 1 receptor (PD-1), a lenvatinib or a pharmaceutically acceptable salt thereof, and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) or a pharmaceutically acceptable salt thereof, —and the use of the combination therapies for the treatment of a cancer.

Claims (14)

1 . A method for treating a cancer in a human subject comprising administering to the human subject a combination therapy which comprises:

(i) an antagonist of a Programmed Death 1 protein (PD-1) which is an anti-PD-1 antibody;

(ii) lenvatinib having the structure:

or a pharmaceutically acceptable salt thereof, wherein the lenvatinib is administered daily; and

(iii) (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (E7386) having the structure:

or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of: a renal cell carcinoma (RCC), a colorectal cancer (CRC), a hepatocellular carcinoma (HCC), a melanoma, and a bladder cancer.

2 . The method of claim 1 , wherein the cancer is a RCC.

3 . The method of claim 1 , wherein the anti-PD-1 antibody is pembrolizumab or nivolumab.

4 . The method of claim 1 , wherein the anti-PD-1 antibody is pembrolizumab.

5 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and pembrolizumab is administered once every three weeks.

6 . The method of claim 5 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 200 mg for an adult human subject or 2 mg/kg up to 200 mg for a pediatric human subject once every three weeks.

7 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate; and E7386 or a pharmaceutically acceptable salt thereof is E7386.

8 . The method of claim 1 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered daily; and the anti-PD-1 antibody is pembrolizumab and is administered once every six weeks.

9 . The method of claim 8 , wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 24 mg, 20 mg, 18 mg, 12 mg or 8 mg; and pembrolizumab is administered at a dose of 400 mg once every six weeks.

Continuity (3)
Provisional Application 62927334 · Oct 29, 2019
Provisional Application 62927576 · Oct 29, 2019
Related Publication 20220409724A1 · Dec 29, 2022
References Cited (40)
US 9174998B2 · Inoue et al. · 2015 [cited by applicant]
US 10259817B2 · Kushida et al. · 2019 [cited by applicant]
US 20180185395A1 · Odagami et al. · 2018 [cited by applicant]
CA 3044658A1 · 2018 [cited by applicant]
WO WO2016141218A1 · 2016 [cited by applicant]
WO WO2018147275A1 · 2018 [cited by applicant]
Broderick JM. FDA Grants Pembrolizumab/Lenvatinib Breakthrough Designation for RCC (https://www.onclive.com/view/fda-grants-pembrolizumablenvatinib-breakthrough-designation-for-rcc, Jan. 9, 2018) (Year: 2018). [cited by examiner]
Luke JJ et al. Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. (Journal of Clinical Oncology 2016 34(15), Supp 1Abstract No. 3004.) (Year: 2016). [cited by examiner]
Lee C. et al. A phase 1 b/2 trial of Lenvatinib plus pembrolizumab in patients with renal cell carcinoma. (Annals of Oncology 2017 28 (Supplement 5): v295-v329, ESMO 2017; Abstract 847O) (Year: 2017). [cited by examiner]
NCT02501096. A Trial of Lenvatinib (E7080) Plus Pembrolizumab in Participants With Selected Solid Tumors. (https://clinicaltrials.gov/study/NCT02501096?term=NCT02501096&rank=1&tab=history&a=15#version-content-panel, Jan… [cited by examiner]
Lala M et al. A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. (Journal of Clinical Oncology 2018 36(15 suppl) abstract 3062) (Year: 2018… [cited by examiner]
Adachi et al., E7386, a selective inhibitor of the interaction between [beta]-catenin and CREB-binding protein (CBP), enhances antitumor activity in combination with Lenvatinib (LEN), and LEN + anti-PD-1 antibody in a p… [cited by applicant]
Grunwald et al., Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale, Future Oncology, 15(9):929-941 (Mar. 2019). [cited by applicant]
Lee et al., 1187PD—Phase II study of lenvatinib plus pembrolizumab for disease progression after PD-1/PD-L1 immune checkpoint inhibitor in metastatic clear cell renal cell carcinoma (mccRCC): Results of an interim analy… [cited by applicant]
Makker et al., Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial, The Lancet Oncology, 20(5):1-8 (Mar. 25, 2019). [cited by applicant]
Shen et al., E7386, a Wnt/[beta]-catenin signaling modulator, suppresses the differentiation of regulatory T cells in combination with Lenvatinib plus anti-PD-1 antibody, Cancer Research, 84(6_Supplement):2022 (Mar. 22,… [cited by applicant]
Hori et al., E7386, an orally active CBP/beta-catenin modulator, induces T cells infiltration into tumor and enhances antitumor activity of anti-PD-1 mAb in Wnt1 tumor syngeneic mice model, Cancer Research, Abstract 517… [cited by applicant]
Sharpe, et al., The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. [cited by applicant]
Dong, et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion, Nat Med, 8(8):793-800, (Aug. 2002). [cited by applicant]
Yang et al., PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro, Invest. Ophthalmol. Vis. Sci., 49(6): 2518-2525, (2008). [cited by applicant]
Ghebeh et al., The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors, [cited by applicant]
Hamanishi et al., Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer, Proc. Natl. Acad. Sci., 104: 3360-3365, (2007). [cited by applicant]
Thompson et al., Significance of B7-H1 overexpression in kidney cancer, Clinical genitourin Cancer, 5: 206-211, (2006). [cited by applicant]
Nomi et al., Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer, Clinical Cancer Research, 13: 2151-2157, (2007). [cited by applicant]
Ohigashi et al., Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand 2 expression in human esophageal cancer, [cited by applicant]
Inman et al., PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression, Cancer, 109: 1499-1505, (2007). [cited by applicant]
Shimauchi et al., Augmented expression of programmed death-1 in both neoplasmatic and nonneoplastic CD4+ T-cells in adult T-cell Leukemia/ Lymphoma, [cited by applicant]
Gao et al., Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma, [cited by applicant]
Nakanishi et al., Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers, [cited by applicant]
Hino et al., Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma, Cancer, 1757-1766, (2010). [cited by applicant]
Ghebeh et al., Foxp3+ tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy, [cited by applicant]
Ahmadzadeh et al., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired, [cited by applicant]
Thompson et al., PD-1 is expressed by tumor infiltrating cells and is associated with poor outcome for patients with renal carcinoma, [cited by applicant]
Tamai et al., Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma, [cited by applicant]
El-Khoueiry et al., A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors, J. Clin. Oncol., 31(15): 2501, (May 2013). [cited by applicant]
Van Amerongen et al., Break the loop, escape the cycle?, [cited by applicant]
Broderick, FDA grants Pembrolizumab/Lenvatinib breakthrough designation for RCC, OncLive (Jan. 2018). [cited by applicant]
Luke et al., Correlation of WNT/b-catenin pathway activation with immune exclusion across most human cancers, J. Clin. Oncol., 34(15): 3004, (2016). [cited by applicant]
Lee et al., A phase 1 b/2 trial of lenvatinib plus pembrolizumab in patients with renal cell carcinoma, Annals of Oncology, 28(5 Suppl.): v295-v296 (2017). [cited by applicant]
Eisai, Inc., NCT02501096: A Trial of Lenvatinib (E7080) Plus Pembrolizumab in Participants With Selected Solid Tumors, ClinicalTrials.gov, (Jul. 2023). [cited by applicant]