Merck�s KEYTRUDA� (pembrolizumab) Receives Four New Approvals in Japan, Including in High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)

KEYTRUDA now approved for 23 uses in 13 different types of cancer in Japan

RAHWAY, N.J.–(BUSINESS WIRE)–$MRK #MRK–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that KEYTRUDA, Merck�s anti-PD-1 therapy, received four new approvals from Japan’s Ministry of Health, Labor and Welfare (MHLW):

• KEYTRUDA in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery for patients with hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-negative breast cancer at high risk of recurrence, based on data from the KEYNOTE-522 trial;
• KEYTRUDA as monotherapy for the adjuvant treatment of certain patients with renal cell carcinoma (RCC) at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions, based on data from the KEYNOTE-564 trial;
• KEYTRUDA in combination with chemotherapy, with or without bevacizumab, for the treatment of patients with advanced or recurrent cervical cancer with no prior chemotherapy who are not amenable to curative treatment, based on data from the KEYNOTE-826 trial, and;
• KEYTRUDA as monotherapy for the adjuvant treatment of patients with stage IIB or IIC melanoma after complete resection, based on data from the KEYNOTE-716 trial.

“Based on compelling data from our clinical trial program, KEYTRUDA has become an important treatment option in Japan and now has 23 approved uses across 13 different types of cancer,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “These four new approvals provide certain patients with advanced or recurrent cervical cancer, high-risk early-stage triple-negative breast cancer, renal cell carcinoma and completely resected stage IIB and IIC melanoma the opportunity to be treated with KEYTRUDA.”

“In Japan, the cancer mortality rate continues to rise annually, and patients are in need of new treatment options – particularly those with breast cancer, which is the most prevalent cancer among women in the country,” said Kyle Tattle, Representative Director and President, MSD Japan. “These new approvals for KEYTRUDA are the result of strong collaboration with the MHLW and provide additional treatment options for appropriate patients with difficult-to-treat cancers.”

Approval as neoadjuvant and adjuvant treatment regimen for triple-negative breast cancer

The approval of KEYTRUDA plus chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery for patients with hormone receptor-negative and HER2-negative breast cancer at high risk of recurrence is based on results from the Phase 3 KEYNOTE-522 trial, in which KEYTRUDA in combination with chemotherapy before surgery and continued as a single agent after surgery resulted in a statistically significant and clinically meaningful improvement in event-free survival (EFS), reducing the risk of disease progression that precludes curative surgery, local or distant recurrence, second primary malignancy or death by 37% (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031) compared to neoadjuvant placebo in combination with chemotherapy and adjuvant placebo alone after surgery in these patients.

The Japanese package insert states that in KEYNOTE-522, adverse reactions were observed in 774 patients (98.9%) out of the safety analysis set of 783 patients (including 45/45 Japanese patients) receiving KEYTRUDA at a dose of 200 mg every three weeks in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery. The most common adverse reactions (?20%) were nausea (63.2%), alopecia (60.2%), anemia (54.8%), neutropenia (46.9%), fatigue (42.1%), diarrhea (30.4%), elevated alanine aminotransferase (26.1%), vomiting (25.5%), asthenia (25.3%), rash (25.0%), constipation (24.0%), decreased neutrophil count (23.6%) and elevated aspartate aminotransferase (20.1%).

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which has the highest risk of recurrence within the first five years after diagnosis and is associated with worse outcomes compared to other forms of breast cancer. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of HER2, TNBC tests negative for all three. Triple-negative breast cancer is known to be prevalent in Japan, as approximately 15% of patients with breast cancer in Japan are diagnosed with TNBC. Breast cancer is the most commonly diagnosed cancer in women in Japan, with more than 94,000 people diagnosed in 2020.

Approval in renal cell carcinoma

The approval of KEYTRUDA for the adjuvant treatment of certain patients with RCC at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions is based on results from the Phase 3 KEYNOTE-564 trial, in which KEYTRUDA as adjuvant treatment demonstrated a statistically significant improvement in disease-free survival, reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared to placebo.

The Japanese package insert states that in KEYNOTE-564, adverse reactions were observed in 386 patients (79.1%) out of the safety analysis set of 488 patients receiving KEYTRUDA at a dose of 200 mg every three weeks or 400 mg every six weeks for up to 12 months. The most common adverse reactions (?10%) were fatigue (20.3%), pruritus (18.6%), hypothyroidism (17.6%), diarrhea (15.8%), rash (15.0%) and hyperthyroidism (10.2%).

Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. In Japan, it is estimated there were more than 25,000 new cases of kidney cancer diagnosed and more than 8,000 deaths from the disease in 2020.

Approval in advanced cervical cancer

The approval for KEYTRUDA plus chemotherapy, with or without bevacizumab, for the treatment of patients with advanced or recurrent cervical cancer with no prior chemotherapy who are not amenable to curative treatment is based on results from the Phase 3 KEYNOTE-826 trial, in which KEYTRUDA plus chemotherapy, with or without bevacizumab, demonstrated a statistically significant improvement in overall survival, reducing the risk of death by 33% (HR=0.67 [95% CI, 0.54-0.84]; p=0.0003), and progression-free survival, reducing the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.53-0.79]; p<0.0001), compared to chemotherapy with or without bevacizumab in these patients.

The Japanese package insert states that in KEYNOTE-826, adverse reactions were observed in 298 patients (97.1%) out of the safety analysis set of 307 patients (including 35/35 Japanese patients) receiving KEYTRUDA at a dose of 200 mg every three weeks in combination with investigator’s choice of anti-cancer regimens. The most common adverse reactions (?20%) were alopecia (55.7%), anemia (48.5%), nausea (33.9%), diarrhea (24.8%), peripheral neuropathy (24.4%), fatigue (22.8%), peripheral sensory neuropathy (22.5%), neutropenia (22.1%) and vomiting (20.5%).

Cervical cancer forms in the lower part of the uterus and in the cells lining the cervix. All women are at risk for cervical cancer, and the disease is most frequently diagnosed between the ages of 35 to 44. In Japan, it is estimated there were more than 12,700 new cases of cervical cancer diagnosed and nearly 4,200 deaths from the disease in 2020.

Expanded indication in the adjuvant treatment of melanoma

The expanded indication for KEYTRUDA as monotherapy for the adjuvant treatment of patients with stage IIB or IIC melanoma after complete resection is based on results of the Phase 3 KEYNOTE-716 trial, in which KEYTRUDA as adjuvant treatment significantly prolonged recurrence-free survival, reducing the risk of disease recurrence or death by 35% (HR=0.65 [95% CI, 0.46-0.92]; p=0.00658) compared to placebo in these patients. With this expansion, Keytruda is now approved for the adjuvant treatment of resected stage IIB, IIC and stage III melanoma.

The Japanese package insert states that in KEYNOTE-716, adverse reactions were observed in 400 patients (82.8%) out of the safety analysis set of 483 patients (including 2/2 Japanese patients) receiving KEYTRUDA at a dose of 200 mg every three weeks. The most common adverse reactions (?10%) were pruritus (24.2%), fatigue (21.1%), diarrhea (18.6%), arthralgia (16.1%), rash (15.7%) and hypothyroidism (15.5%).

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. In Japan, the rates of skin cancer have been rapidly increasing, and it is estimated there were more than 1,500 new cases of melanoma diagnosed and nearly 700 deaths from the disease in Japan 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 1,600 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.

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.

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 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.

Non-muscle Invasive Bladder Cancer

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, 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 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 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). 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 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] 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 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.

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.

Contacts

Media Contacts:

Melissa Moody

(215) 407-3536

John Infanti

(609) 500-4714

Investor Contacts:

Peter Dannenbaum

(908) 740-1037

Damini Chokshi

(908) 740-1807

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