KEYTRUDA® (pembrolizumab) Plus Trastuzumab and Chemotherapy Significantly Improved Progression-Free Survival (PFS) Versus Trastuzumab and Chemotherapy in First-Line HER2-Positive Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

In the KEYNOTE-811 trial, the KEYTRUDA regimen demonstrated a statistically significant PFS improvement in advanced HER2-positive gastric or GEJ adenocarcinoma in tumors expressing PD-L1 (Combined Positive Score [CPS] ≥1) compared to trastuzumab and chemotherapy alone

RAHWAY, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the Phase 3 KEYNOTE-811 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced unresectable or metastatic 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 2023 (abstract #1511O) and are being discussed with regulatory authorities worldwide.

After a median follow-up of 28.4 months, the KEYTRUDA regimen demonstrated a statistically significant improvement in progression-free survival (PFS) in the intention-to-treat (ITT) advanced HER2-positive study population, reducing the risk of disease progression or death by 28% (HR=0.72 [95% CI, 0.60-0.87]; p=0.0002) compared to trastuzumab and chemotherapy alone. The KEYTRUDA regimen also demonstrated a clinically meaningful improvement in PFS in patients whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥1), reducing the risk of disease progression or death by 30% (HR=0.70 [95% CI, 0.58-0.85]) compared to trastuzumab and chemotherapy alone. Based on a pre-specified subgroup analysis, the improvement in PFS observed in the ITT population was limited to patients whose tumors expressed PD-L1 (CPS ≥1). In the study, more than 80% of patients’ tumors expressed PD-L1 (CPS ≥1).

At a subsequent interim analysis (median follow-up of 38.5 months), a positive trend in overall survival (OS), the trial’s other primary endpoint, was observed for the KEYTRUDA regimen versus trastuzumab and chemotherapy alone in the ITT population (HR=0.84 [95% CI, 0.70-1.01]) and the PD-L1 (CPS ≥1) subgroup (HR=0.81 [95% CI, 0.67-0.98]). Among patients whose tumors expressed PD-L1 (CPS ≥1), median OS was 20.0 months (95% CI, 17.9-22.7) for those receiving the KEYTRUDA regimen versus 15.7 months (95% CI, 13.5-18.5) for those receiving trastuzumab and chemotherapy alone. These OS results did not reach statistical significance at this interim analysis; follow-up is ongoing for a future planned OS analysis for this trial.

“The majority of patients with gastroesophageal cancer are diagnosed at an advanced stage, at which point, historically, they’ve faced extremely poor outcomes,” said Dr. Yelena Y. Janjigian, Chief Attending Physician, Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, and the global Principal Investigator for the KEYNOTE-811 trial. “The results from the KEYNOTE-811 trial further demonstrate the clinical benefit of pembrolizumab with trastuzumab and chemotherapy, which reduced the risk of disease progression or death for patients with advanced HER2-positive disease expressing PD-L1 with a CPS ≥1.”

“These progression-free survival results build on the collective body of evidence from the KEYNOTE-811 trial,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “These data emphasize the importance of KEYTRUDA, in combination with trastuzumab and chemotherapy, as a treatment option for patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 with a CPS ≥1 and reinforce our commitment to continuing to explore effective therapies for difficult-to-treat gastrointestinal cancers.”

In May 2021, KEYTRUDA was approved in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma in the U.S. This indication was approved by the U.S. Food and Drug Administration (FDA) under accelerated approval based on objective response rate (ORR) data from KEYNOTE-811, and continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. As previously announced, Merck has discussed these findings with the FDA and is working with them to update the current indication for KEYTRUDA in HER2-positive gastric and GEJ adenocarcinoma to those patients whose tumors express PD-L1 (CPS ≥1).

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 these data.

As announced, data spanning more than 15 types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the ESMO Congress 2023.

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 ORR, duration of response (DOR) 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.

At the third pre-specified interim analysis with a median follow-up of 38.5 months, the KEYTRUDA regimen continued to demonstrate an improvement in PFS, reducing the risk of disease progression or death by 27% (HR=0.73 [95% CI, 0.61-0.87]) in the ITT population, and by 29% (HR=0.71 [95% CI, 0.59-0.86]) in patients whose tumors expressed PD-L1 (CPS ≥1), compared to trastuzumab and chemotherapy alone. This pre-specified interim analysis also showed a continued improvement in ORR; for patients who received the KEYTRUDA regimen, the ORR was 73%, with a median DOR of 11.3 months, compared to trastuzumab and chemotherapy alone.

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=348) and 100% of patients receiving trastuzumab and chemotherapy alone (n=346); Grade 3-4 TRAEs occurred in 58% versus 50%, 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 36% of patients treated with the KEYTRUDA regimen and 33% of patients treated with trastuzumab and chemotherapy alone.

Immune-mediated adverse events (AEs) and infusion reactions of any grade occurred in 39% of patients receiving the KEYTRUDA regimen and 24% of patients receiving trastuzumab and chemotherapy alone; Grade 3-4 immune-mediated AEs and infusion reactions occurred in 10% versus 3%, 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 (16.6%) and hypothyroidism (10.3%). Immune-mediated AEs and infusion reactions that led to discontinuation of any study treatment occurred in 7% of patients receiving the KEYTRUDA regimen and 4% of patients receiving trastuzumab and chemotherapy alone.

About gastric cancer

Gastric (stomach) cancer tends to develop slowly over many years and rarely causes early symptoms, resulting in most patients presenting with advanced stage disease. Overall, more than 70% of patients with gastric cancer develop advanced-stage disease. Most gastric cancers are adenocarcinomas (about 90% to 95%), which develop from cells in the innermost lining of the stomach (known as the mucosa). Approximately 40-65% of patients with gastric cancer have tumors expressing PD-L1 (CPS ≥1), and approximately 10-30% of gastric cancers are HER2-positive. Gastric cancer is the fifth most diagnosed cancer and the fourth leading cause of cancer death worldwide, with approximately 1.1 million patients diagnosed and 768,000 patient deaths from the disease globally in 2020. The five-year survival rate for patients diagnosed with gastric cancer at an advanced stage is only 6%.

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.

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 Carcinoma

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy.

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 locally advanced or metastatic urothelial carcinoma (mUC):

• 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.

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 of 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 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 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) 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).

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, as a single agent, is indicated for the treatment of 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.

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.

Contacts

Media Contacts:

Julie Cunningham

(617) 519-6264

Michael McArdle

(908) 447-9453

Investor Contacts:

Peter Dannenbaum

(732) 594-1579

Damini Chokshi

(732) 594-1577

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