Therapy Areas: Oncology
New Data from Investigational Study of Lenvima and Keytruda Combination in Three Different Tumor Types Presented at the Society for Immunotherapy of Cancer's 33rd annual meeting
13 November 2018 - - Japanese drugmaker Eisai Co., Ltd. and US-based Merck (NYSE: MRK) have received results from presentations of new data and analyses of Lenvima (lenvatinib), an orally available kinase inhibitor discovered by Eisai, in combination with Merck's anti-PD-1 therapy Keytruda (pembrolizumab) in three different tumor types metastatic non-small cell lung cancer (NSCLC), metastatic melanoma and metastatic urothelial carcinoma, the companies said.

These data from the Study 111/KEYNOTE-146 Phase 1b/2 trial will be presented at the 33rd annual meeting of the Society for Immunotherapy of Cancer in Washington, DC from November 9-11.

In the interim analyses of the studies across three tumor types, the Lenvima and Keytruda combination demonstrated encouraging anti-tumor activity.

These data support further evaluation of the combination. Lenvima and Keytruda are not approved for use in combination in any cancer types.

Study 111/KEYNOTE-146 is a multi-center, open-label, single-arm, Phase 1b/2 basket trial (ClinicalTrials.gov, NCT02501096) evaluating the combination of Lenvima (20 mg/day) with Keytruda (200 mg intravenously every three weeks) in patients with selected solid tumors (metastatic endometrial cancer, metastatic head and neck cancer, metastatic melanoma, metastatic NSCLC, metastatic renal cell carcinoma and metastatic urothelial carcinoma).

Patients were not preselected based on PD-L1 tumor expression status. The primary endpoint of the Phase 1b study was to determine the maximum tolerated dose of Lenvima and Keytruda in combination.

The primary endpoint of the Phase 2 portion is investigator-assessed objective response rate at week 24 based on immune-related RECIST (irRECIST). The secondary efficacy endpoints included ORR, progression-free survival and duration of response for patients with complete or partial responses.

Data from Study 111/KEYNOTE-146 are being presented at SITC's 33rd annual meeting from the metastatic NSCLC, metastatic melanoma and metastatic urothelial carcinoma cohorts.

As of data cutoff on March 1, 2018, 21 patients with metastatic NSCLC who either had no prior therapy or had received up to two prior lines of therapy were enrolled in this Phase 2 cohort. The primary endpoint of ORR at week 24 per irRECIST was 33.3% (95% CI: 14.6-57.0).

For secondary endpoints, median PFS per irRECIST was 5.9 months (95% CI:2.3-13.8), and the PFS rate at 12 months per irRECIST was 29.0% (95% CI: 10.2-51.0). Median DOR was 10.9 months (95% CI:2.4-not estimable).

Grade 3 treatment-related adverse events (TRAEs) occurred in 10 patients, and Grade 4 TRAEs occurred in one patient. The most common TRAEs (any grade) ≥30% were decreased appetite, fatigue, hypothyroidism, diarrhea, proteinuria, arthralgia and hypertension.

There was one treatment-related death.

As of March 1, 2018, 21 patients with metastatic melanoma who either had no prior therapy or had received up to two prior lines of therapy were enrolled in this cohort.

The primary endpoint of ORR at week 24 per irRECIST was 47.6% (95% CI:25.7-70.2). For secondary endpoints, median PFS was 5.5 months (95% CI:2.6-15.8), and the PFS rate at 12 months was 34.7% (95% CI: 14.5-56.0). In addition, median DOR was 12.5 months (95% CI:2.7-not estimable).

All patients experienced at least one TRAE. Grade 3 or 4 TRAEs occurred in 14 patients. The most common TRAEs (any grade) ≥30% were fatigue, decreased appetite, diarrhea, hypertension, dysphonia, nausea, arthralgia and proteinuria.

There were no treatment-related deaths.

As of March 1, 2018, 20 patients with metastatic urothelial cancer who either had no prior therapy or had received up to two prior lines of therapy were enrolled in this cohort.

The primary endpoint of ORR at week 24 per irRECIST was 25% (95% CI: 9-49). For secondary endpoints, median PFS was 5.4 months (95% CI: 1.3-not estimable). Eighteen patients experienced TRAEs. Grade 3 or 4 TRAEs occurred in 10 patients.

The most common TRAEs (any grade) ≥30% were proteinuria, diarrhea, hypertension, fatigue and hypothyroidism.

There was one treatment-related death.

Lenvima, discovered and developed by Eisai, is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor receptors VEGFR1, VEGFR2, and VEGFR3.

Lenvima inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.

The combination of lenvatinib and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells.

Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

US Merck has the industry's largest immuno-oncology clinical research programme. There are currently more than 850 trials studying Keytruda across a variety of cancers and treatment settings.

The Keytruda clinical program seeks to understand the role of Keytruda across cancers and the factors that may predict a patient's likelihood of benefiting from treatment with Keytruda, including exploring several different biomarkers.

Founded in 2011, MedDay is an international biopharmaceutical company targeting brain metabolism to treat nervous system disorders. The lead product, MD1003, is a patented formulation of high dose pharmaceutical grade biotin developed and under study in progressive multiple sclerosis and other demyelinating diseases.
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