— First presentation of LENVIMA/KEYTRUDA data in patients with unresectable hepatocellular carcinoma (HCC), which aims to be the first systemic combination of a TKI and immunotherapy for these patients, as well as squamous cell carcinoma of the head and neck (SCCHN)
— Updated results show antitumor activity with a consistent safety profile in advanced renal cell carcinoma (RCC) and advanced endometrial carcinoma (EC)
— The LENVIMA/KEYTRUDA combination was recently granted U.S. Food and Drug Administration (FDA) Breakthrough Therapy Designation for advanced RCC
— Phase 3 trials underway in advanced RCC (NCT02811861) and advanced EC (NCT03517449)
WOODCLIFF LAKE, NJ and KENILWORTH, NJ, USA I June 3, 2018 I Eisai Inc. and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced 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 four different tumor types: unresectable hepatocellular carcinoma (HCC) (Abstract #4076), squamous cell carcinoma of the head and neck (SCCHN) (Abstract #6016), advanced renal cell carcinoma (RCC) (Abstract #4560), and advanced endometrial carcinoma (EC) (Abstract #5596 and Abstract #5597). The data are included in presentations at the 54th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago from June 1-5. LENVIMA and KEYTRUDA are not approved for use in combination in any cancer types today.
“The data we have observed in the combination studies of LENVIMA plus KEYTRUDA have fueled our commitment to help meet the diverse health care needs of patients living with cancer through clinical studies and research in specific tumor types that are notoriously difficult to treat and continue to have a significant need for new therapeutic options,” said Alton Kremer, MD, PhD, Chief Clinical Officer and Chief Medical Officer, Oncology Business Group at Eisai. “We are pleased to share the activity observed in clinical studies of the LENVIMA plus KEYTRUDA combination, as well as rationale for the combination in advanced endometrial carcinoma through translational research.”
“With these data at ASCO, we are continuing to see encouraging overall response rates, as well as a safety profile that supports the scientific rationale of adding LENVIMA to KEYTRUDA,” said Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories. “These findings add to the growing body of evidence showing the potential of this combination regimen across a number of tumor types and underscore the strategy behind our collaboration with Eisai.”
This release discusses investigational uses for FDA-approved products. It is not intended to convey conclusions about efficacy and safety. There is no guarantee that any investigational uses of FDA-approved products will successfully complete clinical development or gain FDA approval.
Early phase results from Study 116/KEYNOTE-524 support further investigation in unresectable HCC
Study 116/KEYNOTE-524 is a Phase 1b open-label, single-arm multicenter study evaluating the tolerability and safety of the combination of LENVIMA (12 mg/day for patients weighing ≥ 60 kg, 8 mg/day for patients weighing < 60 kg) and KEYTRUDA (200 mg intravenously every 3 weeks) in patients with unresectable HCC, Barcelona Clinic Liver Cancer (BCLC) stage B (not eligible for transarterial chemoembolization [TACE]) or C, Child-Pugh class A, and ECOG performance status of 0 or 1. The primary endpoint was safety; secondary and exploratory endpoints included overall survival (OS), objective response rate (ORR), progression-free survival (PFS) and time to progression (TTP) using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Tumor assessments of complete or partial response (CR or PR) were confirmed greater than or equal to four weeks after initial response. Part 1 evaluated tolerability by assessing dose-limiting toxicities (DLTs) during the first cycle of treatment in patients for whom no other appropriate therapy was available. After tolerability was confirmed, additional patients with no prior systemic therapy for unresectable HCC were enrolled (Part 2). The expansion part of the study will evaluate ORR and duration of response as measured by mRECIST.
Data presented at ASCO are from one abstract:
- A Phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC) (Abstract #4076)
As of March 22, 2018, 30 patients were enrolled in this trial (Part 1, n=6; Part 2, n=24). No dose-limiting toxicities were reported. Four patients discontinued due to treatment emergent adverse events (TEAEs). The most common TEAEs (any grade) were decreased appetite (53.3%) and hypertension (53.3%), diarrhea (43.3%) and fatigue (40.0%). Tumor assessments were performed according to mRECIST by the investigators. At data cutoff, the ORR (including cases of unconfirmed CR and PR) was 42.3% (95% CI: 23.4-63.1). A second scan was performed at least four weeks following the initial response, which demonstrated a confirmed ORR of 26.9% (95% CI: 11.6-47.8). Median duration of PFS was 9.7 months (95% CI: 5.55-NE). None of the treated patients experienced progressive disease (PD) as best overall response (BOR). Twenty-three patients (Part 1, n=3, Part 2, n=20) are still undergoing study treatment. Based on the safety and efficacy data seen thus far, the protocol has been amended to enroll approximately 94 patients to the Part 2 expansion cohort.
New and updated results from Study 111/KEYNOTE-526 support further evaluation in SCCHN, RCC and EC, as well as biomarker analysis with clinical serum samples from patients with advanced EC to clarify combination rationale
Study 111/KEYNOTE-526 is a multicenter, open-label, single-arm Phase 1b/2 basket trial evaluating the combination of LENVIMA (20 mg/day) with KEYTRUDA (200 mg intravenously every three weeks) in patients with selected solid tumors. Patients were not preselected based on PD-L1 status. The primary endpoint of the Phase 1b study was to determine the maximum tolerated dose of KEYTRUDA and LENVIMA in combination. The primary endpoint of the Phase 2 portion is investigator-assessed ORR at week 24 based on immune-related RECIST (irRECIST). The secondary efficacy endpoints included ORR, PFS, and duration of response for patients with complete or partial responses.
Data presented at ASCO are from four abstracts:
- A Phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck (Abstract #6016)
As of December 1, 2017, 22 patients with measurable, confirmed metastatic SCCHN and ECOG performance status of 0 or 1 were enrolled in this cohort. 90.9% of patients received at least one prior anticancer therapy. At data cutoff, ORR at week 24 was 36.4% (95% CI: 17.2-59.3), overall ORR was 40.9% (including 1 CR and 8 PRs; 95% CI: 20.7-63.6), and PFS rate at 12 months was 41.9% (95% CI: 17.6-64.7). None of the treated patients experienced progressive disease (PD) as best overall response (BOR), and tumor size reduction was observed in the majority of the patients. Grade 3 or 4 TRAEs occurred in 72.7% of patients (Grade 4 TRAEs in 4.5%). The most common TRAEs (any grade) were fatigue (50.0%), hypertension (40.9%), diarrhea (36.4%), decreased appetite (31.8%), oropharyngeal pain (31.8%) and stomatitis (31.8%). Overall, the study demonstrated promising clinical activity, supporting further evaluation of the combination in patients with SCCHN.
- Lenvatinib + pembrolizumab in patients with renal cell carcinoma: updated results (Abstract #4560)
This cohort enrolled 30 patients with metastatic clear cell RCC and measurable disease per irRECIST. In addition to the assessments performed by investigators per irRECIST, these updated data include tumor assessments performed retrospectively by independent radiographic review (IRR) per irRECIST and RECIST 1.1, as well as the first report of PFS results in this cohort. ORR at week 24 was 63.3% (95% CI: 43.9–80.1), based on investigator assessment per irRECIST. At data cutoff on December 1, 2017, overall ORR was 70.0% (95% CI: 50.6-85.3) based on investigator assessment per irRECIST; median duration of response was 18.4 months (95% CI: 10.3-NE), and median PFS was not estimable (95% CI: 11.6-NE). Based on the IRR per irRECIST, ORR was 66.7% (95% CI: 47.2-82.7), median duration of response was not estimable (95% CI: 14.9-NE), and median PFS was 18.0 months (95% CI: 10.2-NE); per RECIST 1.1, ORR was also 66.7% (95% CI: 47.2-82.7), median duration of response was 16.6 months (95% CI: 8.9-NE), and median PFS was 18.0 months (95% CI: 9.6-NE). Grade 3 or 4 AEs occurred in 22 patients (73.3%), and eight patients (26.7%) discontinued treatment due to an AE. The most common AEs (any grade) were diarrhea (83.3%), fatigue (73.3%), hypothyroidism (70.0%), stomatitis (63.3%) and nausea (60.0%). A Phase 3 trial comparing the LENVIMA plus KEYTRUDA combination and the LENVIMA plus everolimus combination versus sunitinib monotherapy for the first-line treatment of advanced RCC is currently recruiting (CLEAR; NCT02811861; please visit clinicaltrials.gov for more information).
- Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: Updated results (Abstract #5596)
As of data cut-off of December 15, 2017, efficacy and safety analyses are summarized in the poster for 53 patients with histologically confirmed metastatic EC, irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status, and measurable disease per irRECIST. Four (7.5%) patients were MSI-high, 45 (85%) were non MSI-H (MSS), and four (7.5%) patients’ MSI status was not known. At data cutoff, ORR at week 24 based on investigator assessment was 39.6% (95% CI: 26.5-54.0); overall ORR was the same. Objective responses were seen regardless of tumor MSI status. Confirmed objective responses were seen in patients with MSS tumors (16/45 [ORR 35.6%]; 95% CI: 21.9-51.2) and MSI-H tumors (2/4 [ORR 50.0%]; 95% CI: 6.8-93.2). Secondary analysis of tumor efficacy by independent radiology review (IRR) showed an ORR at week 24 of 45.3% (95% CI: 31.6-59.6) and an overall ORR of 47.2% (95% CI: 33.3-61.4) with 22 partial responses and three complete responses. Of responding patients, 83.0% (95% CI: 55.9-94.2) had a response duration of six months or more and 64.5% (95% CI: 32.8-84.2) had a response duration of 12 months or more per investigator assessment, and median duration of response had not yet been reached (95% CI: 7.4-NE). When assessed by IRR, among responding patients, 79.3% (95% CI: 48.5-92.9) had a response duration of 12 months or more, and median duration of response was also not yet reached (95% CI: 5.8-NE). Median PFS was 7.4 months (95% CI: 5.0-not estimable [NE]) per investigator assessment. Most patients showed a decrease in the mean maximum percentage change from baseline in the sum of the diameters of target lesions, regardless of MSI or PD-L1 expression status. Grade 3 treatment-related adverse events (TRAEs) occurred in 37 patients (70%); there were no Grade 4 TRAEs. Five patients (9%) discontinued treatment due to TRAEs. The most common TRAEs (any grade) were hypertension (59%), fatigue (55%), diarrhea (51%), hypothyroidism (47%), decreased appetite (40%), nausea (38%) and stomatitis (34%). A randomized, international, 2-arm, Phase 3 study in recurrent endometrial carcinoma is underway (Study 309/KEYNOTE-775; NCT03517449; please visit clinicaltrials.gov for more information).
- Biomarker results and preclinical rationale for combination of lenvatinib and pembrolizumab in advanced endometrial carcinoma (Abstract #5597)
In an exploratory analysis, 41 candidate serum biomarkers were assessed in immunoassay panels of serum samples collected at baseline, on cycle one, day 15 (C1D15); and cycle two, day one (C2D1) from 37 patients with EC receiving the LENVIMA plus KEYTRUDA combination. In patients with advanced EC, treatment with the combination was associated with changes in several serum biomarkers, including interferon (IFN)-γ and IFN-γ-regulated chemokines, some of which may be associated with tumor response. In addition to the exploratory analysis from Study 111/KEYNOTE-526, preclinical studies on the immunomodulatory and antitumor activity of LENVIMA when combined with PD-1/PD-L1 blockade were presented to more clearly define the basis of combination LENVIMA plus KEYTRUDA. The in vivo preclinical models suggest that LENVIMA monotherapy may decrease the population of tumor-associated macrophage in the tumor microenvironment and the combination therapy may act via a mechanism that includes the interferon signaling pathways to enhance antitumor activity over each monotherapy. Overall, these findings provide rationale for the antitumor activity of LENVIMA plus KEYTRUDA in combination.
About LENVIMA® (lenvatinib) capsules 4 mg and 10 mg
LENVIMA® (lenvatinib) is a kinase inhibitor that is indicated for:
- Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
- Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.
Lenvatinib, discovered and developed by Eisai, is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET.
About KEYTRUDA® (pembrolizumab) Injection 100 mg
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.
Merck has the industry’s largest immuno-oncology clinical research program, which currently involves more than 750 trials studying KEYTRUDA across a wide 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 benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
KEYTRUDA (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, as a single agent, is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)
- solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.
In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
About the Eisai and Merck Strategic Collaboration
In March 2018, Eisai and Merck, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will develop and commercialize LENVIMA jointly, both as monotherapy and in combination with Merck’s anti-PD-1 therapy. In addition to ongoing clinical studies of the combination, the companies will jointly initiate new clinical studies evaluating the combination to support 11 potential indications in six types of cancer (bladder cancer, endometrial cancer, head and neck cancer, hepatocellular carcinoma, melanoma, and non-small cell lung cancer), as well as a basket trial targeting six additional cancer types. The combination is not approved in any cancer types today.
About Eisai Inc.
At Eisai Inc., human health care (hhc) is our goal. We give our first thoughts to patients and their families, and helping to increase the benefits health care provides. As the U.S. pharmaceutical subsidiary of Tokyo-based Eisai Co., Ltd., we have a passionate commitment to patient care that is the driving force behind our efforts to discover and develop innovative therapies to help address unmet medical needs.
Eisai is a fully integrated pharmaceutical business that operates in two global business groups: oncology and neurology (dementia-related diseases and neurodegenerative diseases). Each group functions as an end-to-end global business with discovery, development, manufacturing and marketing capabilities. Our U.S. headquarters, commercial and clinical development organizations are located in New Jersey; our discovery labs are in Massachusetts and Pennsylvania; and our global demand chain organization resides in Maryland and North Carolina. To learn more about Eisai Inc., please visit us at eisai.com/us.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment.
As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.
For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Eisai
