Merck, Eisai provide updates on two phase 3 trials evaluating Keytruda plus Lenvima in patients with certain types of metastatic NSCLC

Merck, Eisai provide updates on two phase 3 trials evaluating Keytruda plus Lenvima in patients with certain types of metastatic NSCLC

Merck, known as MSD outside of the United States and Canada, and Eisai provided updates on two phase 3 trials, LEAP-006 and LEAP-008, evaluating Keytruda, Merck’s anti-PD-1 therapy, plus Lenvima, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, in patients with certain types of metastatic non-small cell lung cancer.

LEAP-006: The phase 3 LEAP-006 trial evaluating Keytruda plus Lenvima in combination with pemetrexed (Alimta) and platinum-containing chemotherapy versus Keytruda with pemetrexed and platinum-containing chemotherapy, a current standard of care option in this disease setting, as a first-line treatment for adult patients with metastatic, nonsquamous non-small cell lung cancer (NSCLC) who have confirmation that epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1)-directed therapies are not indicated, did not meet its dual primary endpoints of overall survival (OS) and progression free survival (PFS). At the study’s final analysis, there was not an improvement in OS for patients treated with Keytruda plus Lenvima with chemotherapy compared to Keytruda with chemotherapy. Earlier interim analyses did not demonstrate a statistically significant improvement in PFS or objective response rate (ORR), a key secondary endpoint.

LEAP-008: The phase 3 LEAP-008 trial evaluating Keytruda plus Lenvima versus docetaxel, a current second line standard of care option, as a treatment for patients with metastatic NSCLC who progressed on or after platinum-containing chemotherapy and one prior anti-PD-1/-L1 immunotherapy, and have confirmation that EGFR-, ALK- or ROS1-directed therapies are not indicated, did not meet its dual primary endpoints of OS and PFS. At the final analysis of the study, there was not an improvement in OS for patients who received Keytruda plus Lenvima compared to docetaxel. Earlier interim analyses did not demonstrate a statistically significant improvement in PFS or ORR, a key secondary endpoint.

In both the LEAP-006 and LEAP-008 trials, the safety profiles of the Keytruda plus Lenvima-based treatment regimens were consistent with that observed in previously reported studies evaluating the combination. A full evaluation of the data from these studies is ongoing. The companies will work with investigators to share the results with the scientific community.

“As a leader in lung cancer research, we continue to try to advance science for our patients by building upon the standard we set several years ago with Keytruda,” said Dr. Gregory Lubiniecki, vice president, global clinical development, Merck Research Laboratories. “While these results are not what we hoped for, we are proud of the foundational role that Keytruda has established in the treatment of certain types of lung cancer, and we are committed to continuing to research how we can further improve responses to our medicines for patients with difficult-to-treat forms of the disease.”

“Despite great progress in recent years, unmet needs still remain in the treatment of patients with metastatic non-small cell lung cancer, particularly for those without targetable biomarkers,” said Dr. Corina Dutcus, senior vice president, global clinical development, oncology at Eisai Inc. “Keytruda plus Lenvima has demonstrated survival benefit in advanced renal cell carcinoma and advanced endometrial carcinoma, and while we are disappointed that the final analyses of these non-small cell lung cancer studies did not show the same benefit, we remain committed to applying learnings from these studies and furthering research in oncology for people with unmet needs. We thank all the patients, their families and the investigators involved.”

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 programme in various tumour types, including but not limited to endometrial carcinoma, hepatocellular carcinoma, RCC, head and neck cancer, gastric cancer and esophageal cancer across multiple clinical trials.

Results from the LEAP-006 and LEAP-008 trials do not affect the current approved indications for the Keytruda plus Lenvima combination or other ongoing trials from the LEAP clinical programme.

LEAP-006 is a randomized, placebo-controlled phase 3 trial (ClinicalTrials.gov, NCT03829319) evaluating Keytruda plus Lenvima with pemetrexed and platinum-containing chemotherapy versus Keytruda plus placebo with pemetrexed and platinum- containing chemotherapy for the first-line treatment of adult patients with metastatic, nonsquamous NSCLC who have confirmation that EGFR-, ALK- or ROS1-directed therapies are not indicated. The dual primary endpoints are PFS, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1 (RESIST v1.1) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Secondary endpoints include ORR and duration of response (DOR), as assessed by BICR per RECIST v1.1, quality of life, and safety. The study enrolled an estimated 748 patients who were randomized 1:1 to receive:

Keytruda (200 mg intravenously [IV] on Day 1 of each three-week cycle [Q3W]) plus Lenvima (8 mg orally once daily) with pemetrexed 500 mg/m2 IV Q3W and carboplatin Area Under Curve 5 mg/mL/min (AUC5) or cisplatin 75 mg/m2 Q3W IV; or Keytruda (200 mg IV Q3W) plus placebo (oral capsule once daily) with pemetrexed 500 mg/m2 IV Q3W and carboplatin AUC5 or cisplatin 75 mg/m2 Q3W IV.

All study drugs were continued until protocol-specified discontinuation criteria. Keytruda was administered for up to 35 cycles (approximately two years). After completing two years of combination therapy, Lenvima may have been administered as a single agent until protocol-specified discontinuation criteria were met. Carboplatin or cisplatin was administered for up to four cycles. The LEAP-006 study was conducted in collaboration with Eli Lilly and Company, the makers of Alimta (pemetrexed).

LEAP-008 is a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT03976375) evaluating Keytruda plus Lenvima versus docetaxel for the treatment of patients with metastatic NSCLC who progressed on or after platinum-containing chemotherapy and one prior anti-PD-1/-L1 therapy, and have confirmation that EGFR-, ALK- or ROS1-directed therapies are not indicated. The trial’s dual primary endpoints are PFS, as assessed by BICR per RECIST v1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and OS. Secondary endpoints include ORR and DOR as assessed by BICR per RECIST v1.1, quality of life and safety. The study enrolled an estimated 422 patients who were randomized 4:4:1 to receive:

Keytruda (200 mg IV every three weeks) plus Lenvima (20 mg orally once daily); or
Docetaxel (75 mg/m2 IV every three weeks); or Lenvima (24 mg orally once 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.

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer in the US, accounting for about 81% of all cases. In the US, the overall five-year survival rate for patients diagnosed with lung cancer is 25%, which is a 21% improvement over the last five years. Improved survival rates are due, in part, to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. Only 5.8% of people in the US who are eligible were screened for lung cancer in 2021.

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.

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, tumour 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 (PDGFRa), KIT, and RET. In syngeneic mouse tumour models, Lenvima decreased tumour-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.

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 various tumour types across multiple clinical trials.

Merck’s 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 its focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programmes in the industry across more than 30 tumour types.

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