Merck known as MSD outside of the United States and Canada, 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.
