Try our mobile app
RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today provided updates on two Phase 3 trials, KEYNOTE-641 and KEYNOTE-789. Merck is discontinuing the Phase 3 KEYNOTE-641 trial evaluating KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with enzalutamide and androgen deprivation therapy (ADT) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) based on the recommendation of an independent Data Monitoring Committee. At an interim analysis, KEYTRUDA in combination with enzalutamide and ADT did not demonstrate an improvement in radiographic progression-free survival (rPFS) or overall survival (OS), the trial’s dual primary endpoints, compared to placebo plus enzalutamide and ADT, and crossed a pre-specified futility boundary for OS. Merck is informing study investigators of the decision and advises patients in the study to speak to their physician regarding treatment.
Merck also announced that the Phase 3 KEYNOTE-789 trial evaluating KEYTRUDA in combination with pemetrexed plus platinum-based chemotherapy did not meet its dual primary endpoint of OS for the treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with epidermal growth factor receptor (EGFR)-genomic tumor mutations, who have previously progressed on a tyrosine kinase inhibitor (TKI), including osimertinib. At the final analysis of the study, there was an improvement in OS for patients who received KEYTRUDA plus pemetrexed with platinum-based chemotherapy compared to pemetrexed with platinum-based chemotherapy; however, these results did not meet statistical significance per the pre-specified statistical plan. At an earlier interim analysis, the trial’s other dual primary endpoint, progression-free survival (PFS) was tested and showed an improvement in the KEYTRUDA arm compared to chemotherapy alone, but these results did not reach statistical significance.
In KEYNOTE-641 and KEYNOTE-789, the safety profile of KEYTRUDA was consistent with that observed in previously reported studies and no new safety signals were identified. In KEYNOTE-641, the combination was associated with a higher incidence of Grade 3-5 adverse events and serious adverse events compared to the control arm. Results will be shared at future scientific congresses.
“Throughout the clinical development of KEYTRUDA, we have asked the tough questions in an effort to fully explore the potential of this breakthrough immunotherapy and determine how we could help as many patients as possible,” said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Science is rarely a straight line, and while we are disappointed in these study results, our research to investigate KEYTRUDA in many difficult-to-treat types of cancer continues in earnest. We are extremely grateful to all the investigators and patients for their participation in these studies.”
About KEYNOTE-641
KEYNOTE-641 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT03834493) evaluating KEYTRUDA in combination with enzalutamide and ADT versus placebo in combination with enzalutamide and ADT in patients with mCRPC who have not received chemotherapy for mCRPC, are abiraterone-naïve or are intolerant to or progressed on abiraterone acetate. The primary endpoints are OS and rPFS per Prostate Cancer Working Group-modified RECIST v1.1 as assessed by blinded independent central review. Secondary endpoints include objective response rate (ORR), duration of response (DOR) and safety. The trial enrolled an estimated 1,240 patients who were randomized to receive KEYTRUDA (200 mg intravenously every three weeks for up to two years) plus enzalutamide (160 mg daily) or placebo plus enzalutamide.
About metastatic castration-resistant prostate cancer
Prostate cancer is the second most common cancer in male patients globally and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body, despite the use of ADT to block the action of male sex hormones. Approximately 10-20% of patients with prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.
About KEYNOTE-789
KEYNOTE-789 (ClinicalTrials.gov, NCT03515837) is a randomized, double-blind Phase 3 trial investigating KEYTRUDA with pemetrexed plus platinum-based chemotherapy compared with pemetrexed plus platinum-based chemotherapy for the treatment of patients with TKI-resistant, EGFR-mutated metastatic, nonsquamous NSCLC. These patients experienced disease progression per RECIST v1.1 criteria following treatment with TKI therapy and either had: a) T790M-negative mutation tumors; b) T790M-positive mutation tumors with prior exposure to osimertinib; or c) first-line osimertinib failure regardless of T790M mutation status. The primary endpoints are OS and PFS. Secondary endpoints include ORR, DOR and safety. The study enrolled 492 patients who were randomized to receive either:
About lung cancer
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, accounting for about 81% of all cases. Among people with nonsquamous NSCLC, approximately 10-15% have EGFR mutations in the U.S. and Europe and up to 40-50% in Asia. In the U.S., 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 U.S. who are eligible were screened for lung cancer in 2021.
About Merck’s research in lung cancer
Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In NSCLC, KEYTRUDA has five approved U.S. indications (see indications below) and is approved for advanced disease in more than 95 countries. Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA.
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.
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:
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 as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.
See additional selected indications for KEYTRUDA 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 41 (7%) patients, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. In adult patients who received adjuvant therapy for NSCLC, 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 (
