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KEYNOTE-A18 is the first Phase 3 study of an immunotherapy in combination with CRT to demonstrate a statistically significant and clinically meaningful improvement in overall survival versus CRT alone in these patients
Resultswere selected for the official press briefing and presentation during a Presidential Symposium session at the European Society for Medical Oncology Congress 2024 and published simultaneously in The Lancet
RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the first presentation of overall survival (OS) results from the pivotal Phase 3 KEYNOTE-A18 trial, also known as ENGOT-cx11/GOG-3047, investigating KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with concurrent chemoradiotherapy (CRT) for newly diagnosed patients with high-risk (stage IB2-IIB with lymph node-positive disease and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer. At a median follow-up of 29.9 months (range, 12.8-43.0), KEYTRUDA in combination with concurrent CRT reduced the risk of death by 33% (HR=0.67 [95% CI, 0.50-0.90]; p=0.0040) versus concurrent CRT alone for these patients. These data were selected for the official Press Briefing and are being presented for the first time today during a Presidential Symposium session at the European Society for Medical Oncology (ESMO) Congress 2024 (Presentation #709O) and published simultaneously in The Lancet.
For patients who received the KEYTRUDA-based regimen, the 36-month OS rate was 82.6% versus 74.8% for those who received concurrent CRT alone. Median OS was not reached in either group. The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies; no new safety signals were identified.
“Cervical cancer is one of the leading causes of cancer-related deaths for women across the globe, but treatment advances in recent years have not demonstrated a significant survival benefit for patients with high-risk, locally advanced forms of the disease,” said Dr. Domenica Lorusso, the study’s overall principal investigator, lead investigator for ENGOT and professor of Obstetrics and Gynecology at Humanitas University. “These are the first positive overall survival results for an immunotherapy-based regimen for newly diagnosed patients with high-risk locally advanced cervical cancer and have the potential to change the treatment paradigm for these patients.”
KEYNOTE-A18 is one of four Phase 3 studies of a KEYTRUDA-based regimen in an earlier stage of cancer to demonstrate an OS benefit, in addition to KEYNOTE-522 in newly diagnosed, high-risk early-stage triple-negative breast cancer and KEYNOTE-671 in resectable stage II, IIIA or IIIB non-small cell lung cancer (in both studies, as treatment with chemotherapy before surgery and then as a single agent after surgery, compared to pre-operative chemotherapy), as well as KEYNOTE-564 in renal cell carcinoma for patients at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions (compared to placebo).
“Merck is committed to advancing research for people impacted by women’s cancers, including in earlier stages of disease, where there is a greater chance for better outcomes,” said Dr. Gursel Aktan, vice president, global clinical development, Merck Research Laboratories. “These findings showed this KEYTRUDA-based regimen can reduce the risk of death by one-third compared to CRT alone, demonstrating the potential of this regimen to benefit appropriate patients with high-risk locally advanced cervical cancer.”
These results are being discussed with regulatory authorities worldwide. As previously reported, KEYNOTE-A18 met its other primary endpoint of progression-free survival (PFS) in 2023. These PFS data were presented at the ESMO Congress 2023 and supported the U.S. Food and Drug Administration’s (FDA) approval of KEYTRUDA in combination with CRT for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer in January 2024.
In the U.S., KEYTRUDA has two additional approved indications in cervical cancer: in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test; and as a single agent, for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
As announced, data spanning more than 20 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2024.
Study design and additional data from KEYNOTE-A18/ENGOT-cx11/GOG-3047 KEYNOTE-A18, also known as ENGOT-cx11/GOG-3047, is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT04221945) sponsored by Merck and conducted in collaboration with the European Network for Gynaecological Oncology Trial (ENGOT) groups and the GOG Foundation, Inc. (GOG) investigating KEYTRUDA in combination with CRT (cisplatin and external beam radiotherapy [EBRT] followed by brachytherapy [BT]) compared to placebo plus concurrent CRT for the treatment of newly diagnosed high-risk (stage IB2-IIB with lymph node-positive disease, and stage III-IVA with and without lymph node-positive disease) locally advanced cervical cancer where patients are treated with definitive intent. The primary endpoints are PFS and OS, and secondary endpoints include complete response rate, objective response rate and safety. The trial enrolled 1,060 patients who were randomized 1:1 to receive:
The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 69.1% of patients receiving KEYTRUDA plus concurrent CRT versus 61.3% of patients receiving placebo plus concurrent CRT. No new safety concerns were identified.
Immune-mediated adverse events (AEs) of any grade occurred in 39% of patients receiving the KEYTRUDA regimen and 17% of patients receiving the placebo regimen. Grade 3-5 immune-mediated AEs occurred in 4.7% versus 1.3%, respectively. The most common of these all-grade immune-mediated AEs (occurring in more than two patients) was hypothyroidism (22.5%) in patients receiving the KEYTRUDA regimen. Immune-mediated AEs led to one death among patients receiving the KEYTRUDA regimen.
About cervical cancer Cervical cancer forms in the cells lining the cervix, which is the lower part of the uterus. All women are at risk for cervical cancer, and it is most frequently diagnosed between the ages of 35 and 44. While screenings and prevention have resulted in declining cervical cancer rates, the disease continues to affect many people in the U.S. and around the world. Cervical cancer is the fourth most common cancer in women globally. In the U.S., it is estimated there will be approximately 13,820 new patients diagnosed with invasive cervical cancer and about 4,360 deaths from the disease in 2024.
About Merck’s research in breast and gynecologic cancers Merck is advancing research aimed at expanding treatment options for certain breast and gynecologic (ovarian, cervical and endometrial) cancers, with a goal of improving outcomes for more patients affected by these diseases. Breast cancer and gynecological cancers are the first and second most commonly occurring cancer types among women worldwide, respectively, and Merck aims to give patients facing these devastating diseases options. With more than 20 clinical trials in more than 18,000 patients around the world, Merck is driving innovative research to purposefully advance standards of care in women’s cancers. Merck’s research efforts include trials focused on evaluating its medicines in earlier stages, as well as identifying novel mechanisms and new combinations with these treatments. Merck is working to develop a portfolio and pipeline to address the impact of women’s cancers on patients, their families and communities globally.
About Merck’s early-stage cancer clinical program Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer.
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.Cervical Cancer KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer.
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (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 cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
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 programmed death receptor-1 (PD-1) or the programmed death ligand 1 (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 (
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