Merck, Eisai provide update on phase 3 LEAP-010 trial evaluating Keytruda plus Lenvima in patients with certain types of recurrent or metastatic HNSCC

Merck, known as MSD outside of the United States and Canada, and Eisai 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 tumours express PD-L1. The primary endpoints of the study were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

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 US, 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 tumour 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 US, 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.

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 tumours 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 Tumours 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: 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 (orally once daily).

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.

Head and neck cancer describes a number of different tumours 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 US, 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.

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 tumour 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 tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research programme. There are currently more than 1,600 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical programme 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, 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 tumours 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. 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 tumour types, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in various tumour types across multiple clinical trials.

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