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RAHWAY, N.J. & NUTLEY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Eisai today provided an update on the Phase 3 LEAP-010 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor (TKI) discovered by Eisai, as a first-line treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1. The primary endpoints of the study were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).
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Two planned interim analyses were conducted by an independent Data Monitoring Committee (DMC) over an 11-month period. In the first analysis, KEYTRUDA plus LENVIMA showed a statistically significant improvement in PFS and ORR versus KEYTRUDA plus placebo. At the second analysis, KEYTRUDA plus LENVIMA did not demonstrate an improvement in OS compared to KEYTRUDA plus placebo, and the likelihood of reaching the protocol-specified threshold for statistical significance for OS was evaluated by Merck and Eisai and deemed to be low. Accordingly, the study will be closed, and the companies are informing investigators of this decision. The safety profile of KEYTRUDA plus LENVIMA was consistent with previously reported data on the combination. A full evaluation of the data from this study, including pre-planned subgroup analyses, is ongoing. The companies will work with investigators to share the results with the scientific community.
“With the LEAP-010 trial, we aimed to explore whether this combination could improve upon options already available with KEYTRUDA-based regimens for appropriate patients with metastatic or with unresectable, recurrent HNSCC,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories. “Although the progression-free survival results from this study were encouraging, unfortunately, the combination did not result in an overall survival benefit for patients. We will apply lessons from this trial to help continue advancing research of this combination.”
“While we were initially encouraged to see that KEYTRUDA plus LENVIMA met two of its three primary endpoints at an earlier interim analysis, unfortunately the combination did not meet the threshold for the third primary endpoint of overall survival,” said Corina Dutcus, M.D., Senior Vice President, Global Clinical Development, Oncology at Eisai Inc. “Our clinical program is designed to help accelerate our efforts to tackle difficult-to-treat, advanced cancers, and while the outcome may not always be what we anticipate, we know that this is part of clinical development, and we remain committed to scientific exploration in pursuit of improving care for patients.”
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. Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in various tumor types, including but not limited to endometrial carcinoma, hepatocellular carcinoma, non-small cell lung cancer, RCC, head and neck cancer, gastric cancer and esophageal cancer across multiple clinical trials. KEYTRUDA is currently approved as monotherapy and in combination regimens for appropriate patients with metastatic or with unresectable, recurrent HNSCC in the U.S., Europe, China, Japan and other countries around the world.
Results from the LEAP-010 trial do not affect the current approved indications for KEYTRUDA plus LENVIMA or other ongoing trials from the LEAP clinical program, including the ongoing LEAP-009 trial, evaluating KEYTRUDA in combination with LENVIMA versus chemotherapy in people living with recurrent or metastatic HNSCC who progressed after platinum therapy and immunotherapy.
About LEAP-010
LEAP-010 is a randomized, placebo-controlled, double-blinded, Phase 3 trial (ClinicalTrials.gov, NCT04199104) evaluating KEYTRUDA plus LENVIMA versus KEYTRUDA monotherapy as a first-line treatment for patients with recurrent or metastatic HNSCC whose tumors express PD-L1. The trial’s three primary endpoints are OS, PFS and ORR. PFS and ORR were assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version (RECIST) v1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The study enrolled an estimated 511 patients who were randomized 1:1 to receive:
In both arms, 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 head and neck cancer
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Two substances that increase the risk of developing head and neck cancer are tobacco and alcohol. Worldwide, it is estimated there were more than 930,000 new cases of head and neck cancer diagnosed and over 465,000 deaths from the disease in 2020. In the U.S., it is estimated there will be more than 66,000 new cases of head and neck cancer diagnosed and more than 15,000 deaths from the disease in 2023.
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.
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.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (
