Merck to discontinue phase 3 KEYLYNK-008 trial of Keytruda plus Lynparza to treat metastatic squamous NSCLC

Merck, known as MSD outside of the United States and Canada, announced that it will stop the phase 3 KEYLYNK-008 trial evaluating Keytruda, Merck’s anti-PD-1 therapy, in combination with maintenance Lynparza, a PARP inhibitor, for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC). Merck is discontinuing the study based on the recommendation of an independent Data Monitoring Committee (DMC), which reviewed data from a planned interim analysis (IA3). At the interim analysis 3, Keytruda in combination with chemotherapy followed by Keytruda plus Lynparza did not demonstrate an improvement in overall survival (OS), one of the study’s dual primary endpoints, compared to Keytruda in combination with chemotherapy followed by Keytruda plus placebo.

The study’s other dual primary endpoint, progression-free survival (PFS), was not statistically significant at the second interim analysis, but there was a numerical improvement compared to the control arm. The safety profile in this trial was consistent with that observed in previously reported studies for the individual therapies and no new safety signals were identified. Merck will inform study investigators of the recommendation from the DMC and advise patients in the study to speak to their physician regarding treatment. Data from this study will be presented at an upcoming scientific congress.

“While there have been significant scientific advancements in lung cancer research in recent years, unmet needs remain for patients with advanced non-small cell lung cancer,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “We sincerely thank the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate Keytruda-based combinations and novel candidates for patients with lung cancer.”

Merck has an extensive clinical development programme in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies evaluating Keytruda-based combinations in NSCLC include KEYLYNK-006, KEYLYNK-012, KEYVIBE-003, KEYVIBE-006 and KEYVIBE-007.

KEYLYNK-008 is a randomized, triple-blind, phase 3 trial (ClinicalTrials.gov, NCT03976362) evaluating Keytruda in combination with chemotherapy (carboplatin plus paclitaxel or nab-paclitaxel) followed by Keytruda plus maintenance Lynparza for the first-line treatment of metastatic squamous NSCLC. The dual primary endpoints are PFS per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR) and OS. The secondary endpoints include safety and health-related quality of life assessments. The trial enrolled an estimated 857 patients. In the Induction Phase, patients received Keytruda (200 mg intravenously [IV] every three weeks for four cycles) in combination with carboplatin plus either paclitaxel or nab-paclitaxel every three weeks. In the Maintenance Phase, patients with a partial or complete response or with stable disease after completing four cycles of induction therapy were randomized to receive Keytruda (200 mg IV every three weeks for up to 31 cycles) plus maintenance Lynparza (300 mg orally twice daily) or maintenance placebo until progressive disease, physician decision or intolerable toxicity.

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 26.2%, which is a 22% 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 4.5% of people in the US who are eligible were screened for lung cancer in 2022.

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 tumour 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.

Lynparzais a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of tumour types with defects and dependencies in the DDR.

Lynparza, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

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