RAHWAY, NJ & NUTLEY, NJ, USA I April 07, 2023 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Eisai today provided updates on two Phase 3 trials, LEAP-003 and LEAP-017 investigating KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai.
LEAP-003: Merck and Eisai are discontinuing the Phase 3 LEAP-003 trial evaluating KEYTRUDA plus LENVIMA for the first-line treatment of adults with unresectable or metastatic melanoma. This decision is based on the recommendation of an independent Data Monitoring Committee (DMC), which reviewed data from a planned interim analysis and determined KEYTRUDA plus LENVIMA did not demonstrate an improvement in overall survival (OS), one of the study’s dual primary endpoints, versus KEYTRUDA alone. Merck and Eisai are informing study investigators of the decision and advising them to reach out to patients in the study regarding treatment. At an earlier interim analysis, the trial’s other dual primary endpoint, progression-free survival (PFS), showed a statistically significant improvement in the KEYTRUDA plus LENVIMA arm versus the KEYTRUDA plus placebo arm.
LEAP-017: The Phase 3 LEAP-017 trial evaluating KEYTRUDA plus LENVIMA did not meet its primary endpoint of OS for the treatment of patients with unresectable and metastatic colorectal cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) who experienced disease progression on, or became intolerant to, prior therapy. In the final pre-specified analysis of OS, a trend toward improvement was observed with KEYTRUDA plus LENVIMA versus regorafenib or TAS-102 (trifluridine and tipiracil hydrochloride); however, these results did not meet statistical significance per the pre-specified statistical analysis plan. A trend toward improvement was also observed in key secondary endpoints of PFS, objective response rate (ORR) and duration of response (DOR) with KEYTRUDA plus LENVIMA versus regorafenib or TAS-102; however, per the pre-specified statistical analysis plan these results were not tested for statistical significance.
In both the LEAP-003 and LEAP-017 trials, the safety profile of KEYTRUDA plus LENVIMA was consistent with previously reported data on the combination. A full evaluation of the data from these studies, including pre-planned key subgroup analyses, is ongoing. The companies will work with investigators to share the results with the scientific community.
“We are grateful to all the investigators, patients and their families for their participation in these studies, and we will continue to evaluate KEYTRUDA plus LENVIMA across different types of cancer where additional treatment options are needed. We remain fully committed to building on existing treatments as part of our efforts to help as many appropriate patients with cancer as we can,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories.
“With the LEAP-003 and LEAP-017 trials, we set out to help improve outcomes for patients with two difficult-to-treat advanced cancers, melanoma and colorectal cancer,” said Corina Dutcus, M.D., Senior Vice President, Clinical Development, Oncology at Eisai Inc. “While these results are different from our initial expectation, insights from both studies will help contribute to our understanding of KEYTRUDA plus LENVIMA. We remain confident in LENVIMA as a pillar of Eisai’s oncology portfolio and will continue to evaluate its potential in ongoing trials within the LEAP program.”
KEYTRUDA plus LENVIMA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Lenvatinib is marketed as KISPLYX® for advanced RCC in the EU. Results from the LEAP-003 and LEAP-017 trials do not affect the current approved indications for the KEYTRUDA plus LENVIMA combination. Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in multiple tumor types, including but not limited to endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer and esophageal cancer, across more than 10 clinical trials.
About LEAP-003
LEAP-003 is a randomized, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03820986) evaluating KEYTRUDA plus LENVIMA versus KEYTRUDA alone for the first-line treatment of adults with unresectable or metastatic melanoma. The dual primary endpoints are OS and PFS, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Key secondary endpoints include ORR and DOR, both as assessed by RECIST v1.1, and safety. The study enrolled 674 patients who were randomized 1:1 to receive:
- KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle) plus LENVIMA (20 mg orally once daily); or
- KEYTRUDA (200 mg IV on Day 1 of each three-week cycle) plus placebo via oral capsule daily.
KEYTRUDA was administered for up to 35 cycles (approximately two years) or until protocol-specified discontinuation criteria were met. After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.
About melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of melanocytes, pigment producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer is one of the most common types of cancer diagnosed. Although melanoma accounts for only 1% of skin cancers, it accounts for a large majority of skin cancer deaths. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and approximately 8,000 deaths resulting from the disease in the U.S. in 2023. The five-year survival rates from 2012-2018 are estimated to be 71% for regional disease and 32% for distant disease.
About LEAP-017
LEAP-017 is a randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT04776148) evaluating KEYTRUDA plus LENVIMA versus regorafenib or TAS-102 for patients with unresectable and metastatic colorectal cancer that is pMMR or not MSI-H who have received and progressed on or after, or became intolerant to, prior treatment. Patients must have been previously treated for colorectal cancer and have shown disease progression as defined by RECIST v1.1 on or after, or could not tolerate, standard treatment. The standard treatment must include all of the following agents, if approved and locally available in the country where the participant is randomized:
- Fluoropyrimidine, irinotecan and oxaliplatin;
- With or without an anti-vascular endothelial growth factor monoclonal antibody (bevacizumab);
- With anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab) for RAS (KRAS/NRAS) wild-type (WT) participants; and
- BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E mutated metastatic colon cancer.
The primary endpoint is OS and key secondary endpoints include PFS, ORR and DOR, according to RECIST v1.1 per blinded independent central review (BICR). The study enrolled 480 patients randomized 1:1 to receive:
- KEYTRUDA (400 mg IV on Day 1 of each six-week cycle) plus LENVIMA (20 mg orally once daily); or
- Regorafenib (160 mg given orally once daily on Days 1 through 21 of each four-week cycle; or TAS-102 (35mg/m2 given orally twice daily on Days 1 through 5 and Days 8 through 12 of each four-week cycle).
KEYTRUDA was administered for up to 18 cycles (approximately two years), or until protocol-specified discontinuation criteria were met. After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.
About colorectal cancer
Colorectal cancer can be referred to as colon cancer or rectal cancer, depending on where the cancer starts. Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It is estimated there were more than 1,880,000 new cases of colorectal cancer globally in 2020. In the United States, it is estimated there will be approximately 107,000 new cases of colon cancer and approximately 46,000 new cases of rectal cancer, resulting in more than 52,000 deaths from colorectal cancer in 2023. The five-year relative survival rates in the U.S. for metastatic colon cancer and rectal cancer (stage IV) are estimated to be 13% and 17%, respectively.
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (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. There are currently more than 1,600 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.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
- stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is 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, as a single agent, is indicated for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.
KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-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.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
- who are not eligible for any platinum-containing chemotherapy, or
- who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
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.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based chemotherapy, or
- as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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 TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdfand Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About LENVIMA® (lenvatinib); available as 10 mg and 4 mg capsules
LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 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 (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
LENVIMA® (lenvatinib) Indications in the U.S.
- For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
- In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC)
- In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
- For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
- In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf.
About the Merck and Eisai strategic collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.
In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in multiple tumor types across more than 10 clinical trials.
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
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Eisai’s focus on cancer
Eisai acknowledges “Oncology” as one of its key strategic areas, and will continue to focus on the discovery and development of anti-cancer drugs within drug discovery domains including “microenvironment”, “proteostasis disruption”, “cell lineage and cell differentiation”, and “inflammation, hypoxia, oxidative stress and cell senescence” under the Deep Human Biology Learning (DHBL) drug discovery and development organization. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these domains, with the aim of contributing to the cure of cancers.
About Eisai
Eisai’s Corporate Concept is “to give first thought to patients and people in the daily living domain, and to increase the benefits that health care provides.” Under this Concept [also known as our human health care (hhc) Concept], we aim to effectively achieve social good in the form of relieving anxiety over health and reducing health disparities. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology.
In addition, our continued commitment to the elimination of neglected tropical diseases (NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), is demonstrated by our work on various activities together with global partners.
For more information about Eisai, please visit www.eisai.com (for global headquarters: Eisai Co., Ltd.), us.eisai.com (for U.S. headquarters: Eisai Inc.) or www.eisai.eu (for Europe, Middle East, Africa, Russia, Australia, and New Zealand headquarters: Eisai Europe Ltd.), and connect with us on Twitter (U.S. and global) and LinkedIn (for U.S. and EMEA).
SOURCE: Merck
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RAHWAY, NJ & NUTLEY, NJ, USA I April 07, 2023 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Eisai today provided updates on two Phase 3 trials, LEAP-003 and LEAP-017 investigating KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai.
LEAP-003: Merck and Eisai are discontinuing the Phase 3 LEAP-003 trial evaluating KEYTRUDA plus LENVIMA for the first-line treatment of adults with unresectable or metastatic melanoma. This decision is based on the recommendation of an independent Data Monitoring Committee (DMC), which reviewed data from a planned interim analysis and determined KEYTRUDA plus LENVIMA did not demonstrate an improvement in overall survival (OS), one of the study’s dual primary endpoints, versus KEYTRUDA alone. Merck and Eisai are informing study investigators of the decision and advising them to reach out to patients in the study regarding treatment. At an earlier interim analysis, the trial’s other dual primary endpoint, progression-free survival (PFS), showed a statistically significant improvement in the KEYTRUDA plus LENVIMA arm versus the KEYTRUDA plus placebo arm.
LEAP-017: The Phase 3 LEAP-017 trial evaluating KEYTRUDA plus LENVIMA did not meet its primary endpoint of OS for the treatment of patients with unresectable and metastatic colorectal cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) who experienced disease progression on, or became intolerant to, prior therapy. In the final pre-specified analysis of OS, a trend toward improvement was observed with KEYTRUDA plus LENVIMA versus regorafenib or TAS-102 (trifluridine and tipiracil hydrochloride); however, these results did not meet statistical significance per the pre-specified statistical analysis plan. A trend toward improvement was also observed in key secondary endpoints of PFS, objective response rate (ORR) and duration of response (DOR) with KEYTRUDA plus LENVIMA versus regorafenib or TAS-102; however, per the pre-specified statistical analysis plan these results were not tested for statistical significance.
In both the LEAP-003 and LEAP-017 trials, the safety profile of KEYTRUDA plus LENVIMA was consistent with previously reported data on the combination. A full evaluation of the data from these studies, including pre-planned key subgroup analyses, is ongoing. The companies will work with investigators to share the results with the scientific community.
“We are grateful to all the investigators, patients and their families for their participation in these studies, and we will continue to evaluate KEYTRUDA plus LENVIMA across different types of cancer where additional treatment options are needed. We remain fully committed to building on existing treatments as part of our efforts to help as many appropriate patients with cancer as we can,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories.
“With the LEAP-003 and LEAP-017 trials, we set out to help improve outcomes for patients with two difficult-to-treat advanced cancers, melanoma and colorectal cancer,” said Corina Dutcus, M.D., Senior Vice President, Clinical Development, Oncology at Eisai Inc. “While these results are different from our initial expectation, insights from both studies will help contribute to our understanding of KEYTRUDA plus LENVIMA. We remain confident in LENVIMA as a pillar of Eisai’s oncology portfolio and will continue to evaluate its potential in ongoing trials within the LEAP program.”
KEYTRUDA plus LENVIMA is approved in the U.S., the EU, Japan and other countries for the treatment of advanced renal cell carcinoma (RCC) and certain types of advanced endometrial carcinoma. Lenvatinib is marketed as KISPLYX® for advanced RCC in the EU. Results from the LEAP-003 and LEAP-017 trials do not affect the current approved indications for the KEYTRUDA plus LENVIMA combination. Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in multiple tumor types, including but not limited to endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer and esophageal cancer, across more than 10 clinical trials.
About LEAP-003
LEAP-003 is a randomized, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT03820986) evaluating KEYTRUDA plus LENVIMA versus KEYTRUDA alone for the first-line treatment of adults with unresectable or metastatic melanoma. The dual primary endpoints are OS and PFS, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Key secondary endpoints include ORR and DOR, both as assessed by RECIST v1.1, and safety. The study enrolled 674 patients who were randomized 1:1 to receive:
- KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle) plus LENVIMA (20 mg orally once daily); or
- KEYTRUDA (200 mg IV on Day 1 of each three-week cycle) plus placebo via oral capsule daily.
KEYTRUDA was administered for up to 35 cycles (approximately two years) or until protocol-specified discontinuation criteria were met. After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.
About melanoma
Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of melanocytes, pigment producing cells. The rates of melanoma have been rising over the past few decades, with nearly 325,000 new cases diagnosed worldwide in 2020. In the U.S., skin cancer is one of the most common types of cancer diagnosed. Although melanoma accounts for only 1% of skin cancers, it accounts for a large majority of skin cancer deaths. It is estimated there will be nearly 100,000 new cases of melanoma diagnosed and approximately 8,000 deaths resulting from the disease in the U.S. in 2023. The five-year survival rates from 2012-2018 are estimated to be 71% for regional disease and 32% for distant disease.
About LEAP-017
LEAP-017 is a randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT04776148) evaluating KEYTRUDA plus LENVIMA versus regorafenib or TAS-102 for patients with unresectable and metastatic colorectal cancer that is pMMR or not MSI-H who have received and progressed on or after, or became intolerant to, prior treatment. Patients must have been previously treated for colorectal cancer and have shown disease progression as defined by RECIST v1.1 on or after, or could not tolerate, standard treatment. The standard treatment must include all of the following agents, if approved and locally available in the country where the participant is randomized:
- Fluoropyrimidine, irinotecan and oxaliplatin;
- With or without an anti-vascular endothelial growth factor monoclonal antibody (bevacizumab);
- With anti-epidermal growth factor receptor monoclonal antibodies (cetuximab or panitumumab) for RAS (KRAS/NRAS) wild-type (WT) participants; and
- BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E mutated metastatic colon cancer.
The primary endpoint is OS and key secondary endpoints include PFS, ORR and DOR, according to RECIST v1.1 per blinded independent central review (BICR). The study enrolled 480 patients randomized 1:1 to receive:
- KEYTRUDA (400 mg IV on Day 1 of each six-week cycle) plus LENVIMA (20 mg orally once daily); or
- Regorafenib (160 mg given orally once daily on Days 1 through 21 of each four-week cycle; or TAS-102 (35mg/m2 given orally twice daily on Days 1 through 5 and Days 8 through 12 of each four-week cycle).
KEYTRUDA was administered for up to 18 cycles (approximately two years), or until protocol-specified discontinuation criteria were met. After completing two years of combination therapy, LENVIMA may have been administered as a single agent until protocol-specified discontinuation criteria were met.
About colorectal cancer
Colorectal cancer can be referred to as colon cancer or rectal cancer, depending on where the cancer starts. Colorectal cancer often begins with growths on the inner lining of the colon or rectum called polyps, which can change into cancer over time. Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death worldwide. It is estimated there were more than 1,880,000 new cases of colorectal cancer globally in 2020. In the United States, it is estimated there will be approximately 107,000 new cases of colon cancer and approximately 46,000 new cases of rectal cancer, resulting in more than 52,000 deaths from colorectal cancer in 2023. The five-year relative survival rates in the U.S. for metastatic colon cancer and rectal cancer (stage IV) are estimated to be 13% and 17%, respectively.
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (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. There are currently more than 1,600 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.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
- stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic.
KEYTRUDA, as a single agent, is 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, as a single agent, is indicated for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.
KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-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.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
- who are not eligible for any platinum-containing chemotherapy, or
- who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
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.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based chemotherapy, or
- as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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 TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdfand Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About LENVIMA® (lenvatinib); available as 10 mg and 4 mg capsules
LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). 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 (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
LENVIMA® (lenvatinib) Indications in the U.S.
- For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
- In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC)
- In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
- For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
- In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf.
About the Merck and Eisai strategic collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies will jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy KEYTRUDA.
In addition to ongoing clinical studies evaluating the KEYTRUDA plus LENVIMA combination across several different tumor types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in multiple tumor types across more than 10 clinical trials.
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
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Eisai’s focus on cancer
Eisai acknowledges “Oncology” as one of its key strategic areas, and will continue to focus on the discovery and development of anti-cancer drugs within drug discovery domains including “microenvironment”, “proteostasis disruption”, “cell lineage and cell differentiation”, and “inflammation, hypoxia, oxidative stress and cell senescence” under the Deep Human Biology Learning (DHBL) drug discovery and development organization. Eisai aspires to discover innovative new drugs with new targets and mechanisms of action from these domains, with the aim of contributing to the cure of cancers.
About Eisai
Eisai’s Corporate Concept is “to give first thought to patients and people in the daily living domain, and to increase the benefits that health care provides.” Under this Concept [also known as our human health care (hhc) Concept], we aim to effectively achieve social good in the form of relieving anxiety over health and reducing health disparities. With a global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to create and deliver innovative products to target diseases with high unmet medical needs, with a particular focus in our strategic areas of Neurology and Oncology.
In addition, our continued commitment to the elimination of neglected tropical diseases (NTDs), which is a target (3.3) of the United Nations Sustainable Development Goals (SDGs), is demonstrated by our work on various activities together with global partners.
For more information about Eisai, please visit www.eisai.com (for global headquarters: Eisai Co., Ltd.), us.eisai.com (for U.S. headquarters: Eisai Inc.) or www.eisai.eu (for Europe, Middle East, Africa, Russia, Australia, and New Zealand headquarters: Eisai Europe Ltd.), and connect with us on Twitter (U.S. and global) and LinkedIn (for U.S. and EMEA).
SOURCE: Merck
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