US FDA approves Merck’s Keytruda in combo with chemotherapy to treat high-risk early-stage TNBC
Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, 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, based on the phase 3 KEYNOTE-522 trial.
TNBC is an aggressive type of breast cancer with an increased risk for disease recurrence. KEYNOTE-522 showed that Keytruda in combination with chemotherapy (carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide) before surgery and continued as a single agent after surgery significantly prolonged event-free survival (EFS) versus the same neoadjuvant chemotherapy regimens alone in patients with previously untreated stage II or stage III TNBC – there was a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031). With this approval, Keytruda is now approved in the U.S. for 30 indications.
“Even when TNBC is diagnosed early, 30-40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Dr. Joyce O’Shaughnessy, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.
“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the US in younger women and in Black women,” said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with Keytruda is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”
Additionally, the FDA converted the accelerated approval of Keytruda in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] =10) as determined by an FDA-approved test to a full (regular) approval based on confirmatory data from KEYNOTE-522. This approval was originally granted in November 2020 based on results from the phase 3 KEYNOTE-355 trial.
Merck is rapidly advancing a broad portfolio in gynecologic and breast cancers with an extensive clinical development program for Keytruda and several other investigational and approved medicines across these areas.
The approval was based on data from KEYNOTE-522 (ClinicalTrials.gov, NCT03036488), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 1,174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 centimeter [cm] but =2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor programmed death ligand 1 (PD-L1) expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4) and choice of carboplatin (dosed every three weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study mediations were administered intravenously:
Arm 1: Four cycles of preoperative Keytruda 200 mg every three weeks on Day 1 of Cycles 1-4 of treatment regimen in combination with carboplatin Area Under Curve (AUC) 5 mg/mL/min every three weeks on Day 1 of Cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen plus paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen; Followed by four additional cycles of preoperative Keytruda 200 mg every three weeks on Day 1 of Cycles 5-8 of treatment regimen in combination with either doxorubicin 60 mg/m2or epirubicin 90 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen plus cyclophosphamide 600 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen; Following surgery, nine cycles of Keytruda 200 mg every three weeks were administered.
Arm 2: Four cycles of preoperative placebo every three weeks on Day 1 of Cycles 1-4 of treatment regimen in combination with carboplatin AUC 5 mg/mL/min every three weeks on Day 1 of Cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen plus paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen; Followed by four cycles of preoperative placebo every three weeks on Day 1 of Cycles 5-8 of treatment regimen in combination with either doxorubicin 60 mg/m2or epirubicin 90 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen plus cyclophosphamide 600 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen; Following surgery, nine cycles of placebo every three weeks were administered.
The main efficacy outcomes were pathological complete response (pCR) rate and EFS. Pathological complete response rate was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. Event-free survival was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, secondary primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS).
The study population characteristics were: median age of 49 years (range, 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, and 13% ECOG PS of 1; 56% were pre-menopausal, and 44% were post-menopausal; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall stage II, and 25% were stage III.
In the study, the median duration of exposure to Keytruda was 13.3 months (range, 1 day to 21.9 months). Fatal adverse reactions occurred in 0.9% of patients receiving Keytruda, including one each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving Keytruda. Serious adverse reactions in =2% of patients who received Keytruda included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). Keytruda was discontinued due to adverse reactions in 20% of patients. The most common adverse reactions (=1%) resulting in permanent discontinuation of Keytruda were increased alanine aminotransferase (ALT) (2.7%), increased aspartate aminotransferase (AST) (1.5%), and rash (1%). Adverse reactions leading to the interruption of Keytruda occurred in 57% of patients. The most common adverse reactions leading to interruption of Keytruda (=2%) were neutropenia (26%), thrombocytopenia and increased ALT (6% each), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia and leukopenia (2.8% each), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). The most common adverse reactions (all grades =20%) were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
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 programme 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.
Source:http://www.pharmabiz.com/NewsDetails.aspx?aid=140330&sid=2
TNBC is an aggressive type of breast cancer with an increased risk for disease recurrence. KEYNOTE-522 showed that Keytruda in combination with chemotherapy (carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide) before surgery and continued as a single agent after surgery significantly prolonged event-free survival (EFS) versus the same neoadjuvant chemotherapy regimens alone in patients with previously untreated stage II or stage III TNBC – there was a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR=0.63 [95% CI, 0.48-0.82]; p=0.00031). With this approval, Keytruda is now approved in the U.S. for 30 indications.
“Even when TNBC is diagnosed early, 30-40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Dr. Joyce O’Shaughnessy, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, Texas. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.
“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the US in younger women and in Black women,” said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with Keytruda is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”
Additionally, the FDA converted the accelerated approval of Keytruda in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] =10) as determined by an FDA-approved test to a full (regular) approval based on confirmatory data from KEYNOTE-522. This approval was originally granted in November 2020 based on results from the phase 3 KEYNOTE-355 trial.
Merck is rapidly advancing a broad portfolio in gynecologic and breast cancers with an extensive clinical development program for Keytruda and several other investigational and approved medicines across these areas.
The approval was based on data from KEYNOTE-522 (ClinicalTrials.gov, NCT03036488), a randomized, multicenter, double-blind, placebo-controlled trial conducted in 1,174 patients with newly diagnosed previously untreated high-risk early-stage TNBC (tumor size >1 centimeter [cm] but =2 cm in diameter with nodal involvement or tumor size >2 cm in diameter regardless of nodal involvement). Patients were enrolled regardless of tumor programmed death ligand 1 (PD-L1) expression. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by nodal status (positive vs. negative), tumor size (T1/T2 vs. T3/T4) and choice of carboplatin (dosed every three weeks vs. weekly). Patients were randomized (2:1) to one of the following two treatment arms; all study mediations were administered intravenously:
Arm 1: Four cycles of preoperative Keytruda 200 mg every three weeks on Day 1 of Cycles 1-4 of treatment regimen in combination with carboplatin Area Under Curve (AUC) 5 mg/mL/min every three weeks on Day 1 of Cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen plus paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen; Followed by four additional cycles of preoperative Keytruda 200 mg every three weeks on Day 1 of Cycles 5-8 of treatment regimen in combination with either doxorubicin 60 mg/m2or epirubicin 90 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen plus cyclophosphamide 600 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen; Following surgery, nine cycles of Keytruda 200 mg every three weeks were administered.
Arm 2: Four cycles of preoperative placebo every three weeks on Day 1 of Cycles 1-4 of treatment regimen in combination with carboplatin AUC 5 mg/mL/min every three weeks on Day 1 of Cycles 1-4 of treatment regimen or AUC 1.5 mg/mL/min every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen plus paclitaxel 80 mg/m2 every week on Days 1, 8, and 15 of Cycles 1-4 of treatment regimen; Followed by four cycles of preoperative placebo every three weeks on Day 1 of Cycles 5-8 of treatment regimen in combination with either doxorubicin 60 mg/m2or epirubicin 90 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen plus cyclophosphamide 600 mg/m2 every three weeks on Day 1 of Cycles 5-8 of treatment regimen; Following surgery, nine cycles of placebo every three weeks were administered.
The main efficacy outcomes were pathological complete response (pCR) rate and EFS. Pathological complete response rate was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0) and was assessed by the blinded local pathologist at the time of definitive surgery. Event-free survival was defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes definitive surgery, local or distant recurrence, secondary primary malignancy, or death due to any cause. An additional efficacy outcome was overall survival (OS).
The study population characteristics were: median age of 49 years (range, 22 to 80), 11% age 65 or older; 99.9% female; 64% White, 20% Asian, 4.5% Black, and 1.8% American Indian or Alaska Native; 87% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, and 13% ECOG PS of 1; 56% were pre-menopausal, and 44% were post-menopausal; 7% were primary Tumor 1 (T1), 68% T2, 19% T3, and 7% T4; 49% were nodal involvement 0 (N0), 40% N1, 11% N2, and 0.2% N3; 75% of patients were overall stage II, and 25% were stage III.
In the study, the median duration of exposure to Keytruda was 13.3 months (range, 1 day to 21.9 months). Fatal adverse reactions occurred in 0.9% of patients receiving Keytruda, including one each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving Keytruda. Serious adverse reactions in =2% of patients who received Keytruda included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). Keytruda was discontinued due to adverse reactions in 20% of patients. The most common adverse reactions (=1%) resulting in permanent discontinuation of Keytruda were increased alanine aminotransferase (ALT) (2.7%), increased aspartate aminotransferase (AST) (1.5%), and rash (1%). Adverse reactions leading to the interruption of Keytruda occurred in 57% of patients. The most common adverse reactions leading to interruption of Keytruda (=2%) were neutropenia (26%), thrombocytopenia and increased ALT (6% each), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia and leukopenia (2.8% each), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%). The most common adverse reactions (all grades =20%) were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
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 programme 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.
Source:http://www.pharmabiz.com/NewsDetails.aspx?aid=140330&sid=2
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