KEYTRUDA is the first anti-PD-1/L1 therapy in combination with trastuzumab and chemotherapy to demonstrate a statistically significant improvement in OS in this patient population
Results from the final analysis of KEYNOTE-811 are being presented during a Proffered Paper Session at the European Society for Medical Oncology (ESMO) Congress 2024 and published simultaneously in the New England Journal of Medicine
In the U.S., KEYTRUDA, in combination with trastuzumab and chemotherapy, is indicated under accelerated approval for first-line treatment in the subset of this patient population whose tumors express PD-L1 (Combined Positive Score [CPS] ≥1), based on prior KEYNOTE-811 results
RAHWAY, NJ, USA I September 14, 2024 I Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced overall survival (OS) results from the final analysis of the Phase 3 KEYNOTE-811 trial evaluating KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. These data are being presented today during a proffered paper session at the European Society for Medical Oncology (ESMO) Congress 2024 (Presentation #1400O) and are also being simultaneously published in the New England Journal of Medicine.
After a median follow-up of 50.2 months (range, 31.1-64.4), the KEYTRUDA regimen demonstrated a statistically significant and clinically meaningful improvement in OS in the intention-to-treat (ITT) HER2-positive advanced gastric or GEJ study population, reducing the risk of death by 20% (HR=0.80 [95% CI, 0.67-0.94]; p=0.0040 [p-value bound 0.0201]) compared to trastuzumab and chemotherapy alone. For patients who received the KEYTRUDA regimen, median OS was 20.0 months (95% CI, 17.8-22.1) versus 16.8 months (95% CI, 14.9-18.7) for patients receiving trastuzumab plus chemotherapy alone.
The KEYTRUDA regimen also demonstrated a clinically meaningful improvement in OS in patients whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥1), reducing the risk of disease progression or death by 21% (HR=0.79 [95% CI, 0.66-0.95]) compared to trastuzumab and chemotherapy alone in these patients. Median OS was 20.1 months (95% CI, 17.9-22.9) for patients with tumors expressing PD-L1 (CPS ≥1) receiving the KEYTRUDA regimen versus 15.7 months (95% CI, 13.5-18.5) for patients receiving trastuzumab and chemotherapy alone. In the study, 85% of patients’ tumors expressed PD-L1 (CPS ≥1).
“The majority of patients with gastric and gastroesophageal cancer are diagnosed at an advanced stage, at which point the five-year survival rate is less than 10%,” said Dr. Yelena Y. Janjigian, chief attending physician, gastrointestinal oncology, Memorial Sloan Kettering Cancer Center, and global lead principal investigator for the KEYNOTE-811 trial. “These overall survival results from the KEYNOTE-811 trial are encouraging and show that adding pembrolizumab to trastuzumab and chemotherapy can extend the lives of certain patients with HER2-positive and PD-L1 positive gastric and gastroesophageal cancer.”
“With these new results, KEYNOTE-811 has met both of its primary endpoints, significantly improving progression-free and overall survival for patients with HER2-positive advanced gastric cancer, with the greatest benefit observed in patients whose tumors express PD-L1 (CPS ≥1),” said Dr. M. Catherine Pietanza, vice president, global clinical development, Merck Research Laboratories. “These new survival data add to the strong body of evidence supporting global approvals of this KEYTRUDA-based regimen and underscore the importance of providing promising new treatment options to patients.”
In the U.S., KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Since the FDA’s accelerated approval, the trial has met its dual primary endpoints of progression-free survival (PFS) and OS. These results have been shared with regulatory authorities worldwide.
In August 2023, the European Commission (EC) approved KEYTRUDA in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in adults whose tumors express PD-L1 (CPS ≥1) based on PFS results from KEYNOTE-811.
Merck has an extensive clinical development program evaluating KEYTRUDA in gastrointestinal cancers and is continuing to study KEYTRUDA for multiple uses in gastric, hepatobiliary, esophageal, pancreatic and colorectal cancers.
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-811
KEYNOTE-811 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT03615326) evaluating KEYTRUDA in combination with trastuzumab and chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. The dual primary endpoints are PFS per RECIST v1.1 as assessed by blinded independent central review and OS. Secondary endpoints include objective response rate (ORR), duration of response and safety. The trial enrolled 698 patients who were randomized to receive KEYTRUDA (200 mg every three weeks) in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy (investigator’s choice of 5-fluorouracil plus cisplatin or capecitabine plus oxaliplatin), or placebo in combination with trastuzumab and chemotherapy.
As previously announced, KEYNOTE-811 met the dual primary endpoint of PFS at an earlier interim analysis, results of which were presented at the ESMO Congress 2023. At this final analysis, in the ITT patient population, the PFS benefit observed in the previous interim analyses was maintained and the KEYTRUDA regimen reduced the risk of disease progression or death by 27% (HR=0.73 [95% CI, 0.61-0.87]), with a median PFS of 10.0 months (95% CI, 8.6-12.2) versus 8.1 months (95% CI, 7.0-8.5) for trastuzumab and chemotherapy alone. In patients with tumors expressing PD-L1 (CPS ≥1), the KEYTRUDA regimen reduced the risk of disease progression or death by 28% (HR=0.72 [95% CI, 0.60-0.87]), with a median PFS of 10.9 months (95% CI, 8.5-12.5) in the KEYTRUDA arm versus 7.3 months (95% CI, 6.8-8.4) for trastuzumab and chemotherapy alone. Based on a pre-specified subgroup analysis, the greatest benefit in PFS was observed in patients whose tumors express PD-L1 (CPS ≥1).
The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Treatment related adverse events (TRAEs) occurred in 99% of patients receiving the KEYTRUDA regimen (n=350) and 100% of patients receiving trastuzumab and chemotherapy alone (n=346); Grade 3-4 TRAEs occurred in 58% (n=202) versus 50% (n=173), respectively; Grade 5 TRAEs occurred in 1.0% of patients receiving the KEYTRUDA regimen (n=4) versus 1.0% of patients receiving trastuzumab and chemotherapy alone (n=3). Treatment-related adverse events led to discontinuation of any study treatment in 37% of patients treated with the KEYTRUDA regimen (n=130) and 34% of patients treated with trastuzumab and chemotherapy alone (n=117).
Immune-mediated adverse events (AEs) and infusion reactions of any grade occurred in 40% of patients receiving the KEYTRUDA regimen (n=140) and 25% of patients receiving trastuzumab and chemotherapy alone (n=86); Grade 3-4 immune-mediated AEs and infusion reactions occurred in 11% (n=38) versus 3% (n=11), respectively; Grade 5 immune-mediated AEs and infusion reactions occurred in 1.0% of patients receiving the KEYTRUDA regimen (n=3) versus less than 1.0% of patients (n=1) who received trastuzumab and chemotherapy alone. The most common of these events (occurring in ≥10% of patients) were infusion reactions and hypothyroidism. Immune-mediated AEs and infusion reactions that led to discontinuation of any study treatment occurred in 8% of patients receiving the KEYTRUDA regimen (n=27) and 4% of patients receiving trastuzumab and chemotherapy alone (n=14).
About gastric cancer
Gastric (stomach) cancer tends to develop slowly over many years and rarely causes early symptoms, resulting in most cases going undetected until an advanced stage.More than 70% of patients with gastric cancer develop advanced-stage disease. Most gastric cancers are adenocarcinomas (about 90-95%), which develop from cells in the innermost lining of the stomach (known as the mucosa). Gastric cancer is the fifth most diagnosed cancer and the fifth leading cause of cancer death worldwide, with approximately 969,000 patients diagnosed and 660,000 deaths from the disease globally in 2022.In the U.S., it is estimated there will be approximately 26,890 patients diagnosed with gastric cancer and 10,880 deaths from the disease in 2024. The five-year survival rate for patients diagnosed with gastric cancer at an advanced stage is only 7%.
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 Indications in the U.S.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection.
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:
- Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
- metastatic.
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 is indicated for the treatment of patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
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.
Head and Neck Squamous Cell Cancer
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 tumors 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.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Urothelial Cancer
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:
- who are not eligible for any platinum-containing chemotherapy, or
- who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
- in combination with platinum- and fluoropyrimidine-based chemotherapy, or
- as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
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.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.
Biliary Tract Cancer
KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Endometrial Carcinoma
KEYTRUDA, in combination with carboplatin and paclitaxel, followed by KEYTRUDA as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.
KEYTRUDA, as a single agent, is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
Merck’s focus on cancer
Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
