Eisai and Merck Present First Clinical Data from Two LEAP Studies Evaluating Lenvatinib Plus Pembrolizumab Across Seven Tumor Types

TOKYO and KENILWORTH, N.J., Oct. 12, 2020 /PRNewswire/ -- Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito; hereinafter referred to as “Eisai”) and Merck & Co., Inc. (Kenilworth, N.J., USA; known as MSD outside the United States and Canada) announced the latest data from two trials evaluating LENVIMA (an oral multi-targeted tyrosine kinase receptor inhibitor developed by Eisai) in combination with KEYTRUDA (Merck’s anti-PD-1 therapy) as part of the LEAP (Lenvatinib Plus Pembrolizumab) clinical research program. In the Phase II LEAP-004 trial, the objective response rate (ORR) for LENVIMA combined with KEYTRUDA was 21.4% (95% confidence interval [CI]: 13.9–30.5) in patients with unresectable or advanced melanoma who had experienced disease progression following prior anti-PD-1/PD-L1 therapy. In the Phase II LEAP-005 trial, the ORR for LENVIMA combined with KEYTRUDA ranged from 9.7% to 32.3% (95% CI: 2.0–51.4) in patients with previously treated triple-negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (non-microsatellite instability-high [non-MSI-H]/proficient mismatch repair [pMMR]), glioblastoma multiforme (GBM), and biliary tract cancer (BTC). The results of LEAP-004 (Abstract No. LBA44) and LEAP-005 (Abstract No. LBA41) were accepted as late-breaking abstracts for presentation and reporting at the 2020 European Society for Medical Oncology (ESMO) Annual Congress.

Dr. Scot Ebbinghaus, Vice President of Clinical Research at Merck Research Laboratories, stated, “These new data from the LEAP clinical program demonstrate encouraging antitumor activity of KEYTRUDA in combination with LENVIMA across several aggressive cancer types, providing deeper insights into the potential of this combination regimen and helping more patients with these cancers.” Dr. Ebbinghaus further added, “This marks the first presentation of clinical data from two LEAP trials, reflecting significant progress in our ongoing exploration of the potential of this combination for patients in need of new treatment options, particularly for those with advanced melanoma who have experienced disease progression following prior anti-PD-1 or PD-L1 therapy.”

Dr. Takashi Owa, Vice President of Eisai, Chief Medical Creation Officer and Chief Discovery Officer of the Oncology Business Division, stated, “To date, we are encouraged by the growing body of research findings across 13 different cancer types, which support the potential of the combination therapy of LENVIMA and KEYTRUDA. Currently, we are evaluating this combination in 19 clinical trials.” Dr. Owa further remarked, “These data not only help deepen our understanding of treatment regimens but also strengthen our resolve to address the unmet medical needs of these patients.”

Lenvatinib (len) in combination with pembrolizumab (pembro) Treatment receivedPD-1orPD-L1Advanced melanoma with disease progression following inhibitor therapy (MEL）：LEAP-004(Abstract No.LBA44) Preliminary Results

LEAP-004 (ClinicalTrials.gov, NCT03776136) is a Phase II, single-arm, open-label trial evaluating LENVIMA in combination with KEYTRUDA in patients with unresectable or advanced melanoma who experienced disease progression within 12 weeks of receiving anti-PD-1/PD-L1 therapy. Patients received oral LENVIMA 20 mg once daily and intravenous KEYTRUDA 200 mg once every 3 weeks for up to 35 cycles (approximately 2 years), until unacceptable toxicity or disease progression occurred. The primary endpoint was objective response rate (ORR), assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints included progression-free survival (PFS) and duration of response (DOR) (assessed by BICR according to RECIST v1.1), overall survival (OS), and safety.

As of the data cutoff date (June 10, 2020), a total of 103 patients were enrolled and received treatment. The median follow-up duration was 12 months (range: 8.7–15.6). The overall objective response rate (ORR) assessed by BICR for LENVIIMA in combination with KEYTRUDA was 21.4% (n=22) (95% CI: 13.9–30.5), with a complete response rate of 1.9% (n=2) and a partial response rate of 19.4% (n=20). In the overall study population, the median duration of response (DOR) was 6.3 months (range: 2.1+ to 11.1+), and 72.6% (95% CI: 46.2–87.6) of patients maintained a response for at least 6 months. The median progression-free survival (PFS) was 4.2 months (95% CI: 3.5–6.3); 73.8% of patients experienced disease progression or death, and the 9-month PFS rate was 26.2% (95% CI: 17.4–35.9). The median overall survival (OS) was 13.9 months (95% CI: 10.8–not reached [NR]); 44.7% of patients died, and the 9-month OS rate was 65.4% (95% CI: 55.2–73.8).

Exploratory analysis indicated that, specifically, among the 29 patients who experienced disease progression after treatment with anti-PD-1/L1 plus anti-CTLA-4 therapy, the objective response rate (ORR) assessed by BICR was 31% (95% CI: 15.3–50.8), with a complete response rate of 3.4% (n=1) and a partial response rate of 27.6% (n=8). In these patients, the disease control rate (DCR) assessed by BICR was 62.1% (95% CI: 42.3–79.3). In the overall study population, the DCR assessed by BICR was 65% (95% CI: 55.0–74.2).

Treatment-related adverse events (TRAEs) led to discontinuation of LENVIMA and/or KEYTRUDA in 7.8% of patients. Grade 3–5 TRAEs occurred in 44.7% of patients (Grade 3: 39.8%; Grade 4: 3.9%; Grade 5: 1.0%), and serious TRAEs occurred in 18.4% of patients. The most common TRAEs of any grade (≥30%) in the overall study population were hypertension (56.3%), diarrhea (35.9%), nausea (34.0%), hypothyroidism (33.0%), and decreased appetite (31.1%).

LEAP-005: Lenvatinib in combination with pembrolizumab for the treatment of patients with previously treated advanced solid tumorsIIPhase Study (Abstract No.LBA41）

LEAP-005 (ClinicalTrials.gov, NCT03797326) is a Phase II, single-arm, open-label trial evaluating LENIVIMA in combination with KEYTRUDA in selected patients with previously treated advanced solid tumors. The study cohorts include patients with triple-negative breast cancer (TNBC), ovarian cancer, gastric cancer, colorectal cancer (non-MSI-H/pMMR), glioblastoma (GBM), and biliary tract cancer (BTC). Patients received oral LENIVIMA 20 mg once daily concurrently with intravenous infusion of KEYTRUDA 200 mg every 3 weeks for up to 35 cycles (approximately 2 years), until unacceptable toxicity or disease progression occurred. The primary endpoints were objective response rate (ORR), assessed by blinded independent central review (BICR) according to RECIST v1.1 or the Response Assessment in Neuro-Oncology (RANO) criteria (for GBM only), and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), all assessed by BICR according to RECIST v1.1 or RANO criteria (for GBM only), and overall survival (OS).

As of the data cutoff date (April 10, 2020), a total of 187 patients were enrolled and received treatment. At a median follow-up duration of 8.6 months (range: 1.9–13.1), the confirmed objective response rate (ORR) across six different tumor types, along with efficacy and safety results, were as follows:

TNBC 2L/3L（n=31）

Ovarian Cancer4L（n=31）

Gastric Cancer3L（n=31）

Colorectal Cancer3L（n=32）

BTC 2L（n=31）

GBM 2L（n=31）

ORR，%

（95% CI）

29.0

32.3

9.7

21.9

9.7

16.1

(14.2-48.0)

(16.7-51.4)

(2.0-25.8)

(9.3-40.0)

(2.0-25.8)

(5.5-33.7)

DCR，%

（95% CI）

58.1

74.2

48.4

46.9

67.7

58.1

(39.1-75.5)

(55.4-88.1)

(30.2-66.9)

(29.1-65.3)

(48.6-83.3)

(39.1-75.5)

DOR, Median (Range), Months

NR

NR

NR

NR

5.3

3.2

(0.0+ to 8.4+)

(1.5+ to 7.9+)

(2.1+ to 2.3+)

(2.1+ to 10.4+)

(2.1+ to 6.2)

(2.5 to 4.9+)

≥3GradeTRAE，%（n）

55

68

42

50

48

35

(17)

(21)

(13)

(16)

(15)

(11)

Due toTRAEDeath,%（n）

3

3

3

3

0

3

(1)

(1)

(1)

(1)

(0)

(1)

Due toTRAEDiscontinue treatment,%（n）

10

13

6

9

6

6

(3)

(4)

(2)

(3)

(2)

(2)

+=No disease progression (PD) observed as of the last disease assessment; DCR=disease control rate (best confirmed response: complete/partial response; stable disease); DOR=duration of response; NR=not reached.

The most common (≥20%) treatment-related adverse events (TRAEs) of any grade observed in the overall study population were hypertension (39.0%), fatigue (29.4%), diarrhea (26.7%), decreased appetite (25.1%), hypothyroidism (27.8%), and nausea (21.9%). Based on these preliminary results, the trial will be expanded to enroll approximately 100 patients per cohort.

LENVIMA^®(Lenvatinib) Capsules Introduction

LENVIMA is a multi-targeted receptor tyrosine kinase inhibitor discovered and developed by Eisai, which inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). In addition to normal cellular functions, LENVIMA also inhibits other kinases involved in pathological angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor (FGF) receptors FGFR1-4, platelet-derived growth factor receptor α (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, lenvatinib in combination with an anti-PD-1 antibody reduced tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated enhanced antitumor activity compared to either agent administered alone. Currently, LENVIMA has been approved as monotherapy for the treatment of thyroid cancer in more than 65 countries (including Japan, the United States, Europe, and certain countries in Asia), and as monotherapy for the treatment of unresectable hepatocellular carcinoma in more than 65 countries (including Japan, the United States, certain countries in Europe, China, and other parts of Asia). Furthermore, LENVIMA has also been approved in more than 55 countries (including the United States and certain countries in Europe [under the brand name Kisplyx^®[Approved for the treatment of renal cell carcinoma] and in certain Asian countries) in combination with everolimus for patients with advanced renal cell carcinoma who have previously received anti-angiogenic therapy. Meanwhile, LENVIMA has also been approved in countries including the United States, Australia, and Canada for use in combination with KEYTRUDA to treat patients with advanced endometrial cancer that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have experienced disease progression following prior systemic therapy and are not candidates for curative surgery or radiation therapy. The continued approval of this indication is contingent upon the verification and characterization of clinical benefit in confirmatory trials.

KEYTRUDA^®(Pembrolizumab) Injection Introduction

KEYTRUDA is an anti-PD-1 therapeutic agent that functions by enhancing the human immune system’s ability to detect and combat 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 that may affect both tumor cells and healthy cells.

MSD is currently conducting the largest immuno-oncology clinical research program in the industry. There are currently more than 1,200 trials investigating KEYTRUDA across multiple cancer types and treatment settings. The KEYTRUDA clinical program aims to understand the role of KEYTRUDA in cancer and identify factors that may predict the likelihood of patient benefit from KEYTRUDA therapy, including the exploration of several different biomarkers.