European Commission Approves Merck’s KEYTRUDA® (pembrolizumab) Plus Chemotherapy for Certain Patients With Esophageal Cancer or HER2-Negative Gastroesophageal Junction (GEJ) Adenocarcinoma
KEYTRUDA is Now Approved in Combination With Platinum- and Fluoropyrimidine-Based Chemotherapy As First-Line Treatment for Certain Patients With Locally Advanced Unresectable or Metastatic Esophageal Carcinoma or HER2-Negative GEJ Adenocarcinoma Whose Tumors Express PD-L1 (CPS ≥10)
KEYTRUDA is First Anti-PD-1 Therapy Approved in Europe in Combination With Chemotherapy for First-Line Treatment of Advanced Esophageal or GEJ Cancer, Regardless of Histology
KENILWORTH, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the European Commission (EC) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the esophagus or human epidermal growth factor receptor 2 (HER2)-negative gastroesophageal junction (GEJ) adenocarcinoma in adults whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10).
This approval is based on results from the Phase 3 KEYNOTE-590 trial, in which KEYTRUDA plus 5-fluorouracil (5-FU) and cisplatin demonstrated statistically significant improvements in overall survival (OS) and progression-free survival (PFS) compared with 5-FU and cisplatin alone in all pre-specified study populations. KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001) and reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.55-0.76]; p<0.0001) versus 5-FU and cisplatin alone. In a pre-specified analysis of patients whose tumors expressed PD-L1 (CPS ≥10) (n=383/749), KEYTRUDA plus 5-FU and cisplatin reduced the risk of death by 38% (HR=0.62 [95% CI, 0.49-0.78]; p<0.0001) and reduced the risk of disease progression or death by 49% (HR=0.51 [95% CI, 0.41-0.65]; p<0.0001) versus 5-FU and cisplatin alone. For patients treated with KEYTRUDA plus 5-FU and cisplatin, the objective response rate (ORR) was 51.1% (95% CI, 43.7-58.5), with a complete response (CR) rate of 5.9% and a partial response (PR) rate of 45.2%, versus 26.9% (95% CI, 20.8-33.7), with a CR rate of 2.5% and a PR rate of 24.4%, for patients treated with 5-FU and cisplatin alone (p<0.0001).
“We have seen few advances over the last three decades that have improved historically poor survival outcomes for patients with esophageal cancer,” said Professor Antoine Adenis, Department of Medical Oncology, Montpellier Cancer Institute, France. “The European Commission’s approval of KEYTRUDA plus chemotherapy for the treatment of certain patients with esophageal and HER2-negative GEJ cancer provides a new option in the first-line setting that has shown significant improvements in progression-free and overall survival.”
“KEYTRUDA plus chemotherapy is the first anti-PD1 therapy approved in Europe in this first-line setting, allowing these patients to be treated with immunotherapy earlier in the course of their treatment,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories.
This approval allows marketing of the KEYTRUDA combination in all 27 European Union member states plus Iceland, Lichtenstein, Norway and Northern Ireland.
Merck is continuing to study KEYTRUDA across multiple settings and stages of gastrointestinal cancer through its broad clinical program, including studies in esophageal, gastric, hepatobiliary, pancreatic, colorectal and anal cancers.
Data Supporting the European Approval
The approval was based on data from KEYNOTE-590 (NCT03189719), a multicenter, randomized, double-blind placebo-controlled trial that enrolled 749 patients with locally advanced unresectable or metastatic esophageal or GEJ carcinoma (Siewert Type I) who were not candidates for surgical resection or definitive chemoradiation. Patients were randomized (1:1) to receive either KEYTRUDA (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with cisplatin (80 mg/m2 on Day 1 every three weeks for up to six cycles) plus 5-FU (800 mg/m2 per day on Days 1 to 5 every three weeks, or per local standard for 5-FU administration, for up to 24 months); all study medications were administered via intravenous infusion.
Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1).
Treatment with KEYTRUDA or chemotherapy continued until unacceptable toxicity or disease progression or a maximum of 24 months. Patients could be treated with KEYTRUDA for up to 24 months in the absence of disease progression. Patients randomized to KEYTRUDA were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least four weeks later with repeat imaging. Assessment of tumor status was performed every nine weeks.
The primary efficacy outcome measures were OS and PFS, as assessed by the investigator according to RECIST v1.1 in squamous cell histology, PD-L1 expression (CPS ≥10), and in all patients. Secondary efficacy outcome measures were ORR and duration of response (DOR), as assessed by the investigator according to RECIST v1.1.
In a pre-specified analysis of KEYNOTE-590 in patients whose tumors expressed PD-L1 (CPS ≥10) (n=383), performed at a median follow-up time of 13.5 months (range, 0.5 to 32.7), KEYTRUDA plus 5-FU and cisplatin showed a median OS of 13.5 months (95% CI, 11.1-15.6) versus 9.4 months (95% CI, 8.0-10.7) for patients treated with 5-FU and cisplatin alone. Additionally, KEYTRUDA plus 5-FU and cisplatin showed a median PFS of 7.5 months (95% CI, 6.2-8.2) versus 5.5 months (95% CI, 4.3-6.0) for patients treated with 5-FU and cisplatin alone. Median DOR was 10.4 months (range, 1.9 to 28.9+) with KEYTRUDA plus 5-FU and cisplatin versus 5.6 months (range, 1.5+ to 25+) with 5-FU and cisplatin alone.
The safety of KEYTRUDA in combination with chemotherapy has been evaluated in 1,437 patients with non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC) or esophageal carcinoma receiving 200 mg, 2 mg/kg bodyweight (bw) or 10 mg/kg bw KEYTRUDA every 3 weeks, in clinical studies. In this patient population, the most frequent adverse reactions were nausea (55%), anemia (51%), fatigue (39%), constipation (37%), diarrhea (33%), neutropenia (29%) and vomiting (28%). Incidences of Grades 3-5 adverse reactions in patients with NSCLC were 67% for KEYTRUDA combination therapy and 66% for chemotherapy alone; in patients with HNSCC were 85% for KEYTRUDA combination therapy and 84% for chemotherapy plus cetuximab; and in patients with esophageal carcinoma were 86% for KEYTRUDA combination therapy and 83% for chemotherapy alone.
About Esophageal Cancer in Europe
Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. In Europe, it is estimated there were more than 52,000 new cases of esophageal cancer diagnosed and approximately 45,000 deaths resulting from the disease in 2020.
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 1,500 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.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) 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 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.
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, 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 (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 Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or mUC who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ 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 that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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 MSI-H central nervous system cancers have not been established.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. 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.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or 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 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. 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.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma.
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] 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) that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
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. 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.
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 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA with Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%.
Contacts
Media:
Melissa Moody
(215) 407-3536
Andrea Park
(929) 481-2599
Investors:
Peter Dannenbaum
(908) 740-1037
Courtney Ronaldo
(908) 740-6132