This KEYTRUDA Combination Is the First Immunotherapy Regimen Approved for High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)
KEYTRUDA Is Now Approved in the US for 30 Indications
KENILWORTH, NJ, USA I July 27, 2021 I Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. 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, U.S. 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. For more information, see “Selected Important Safety Information” below.
“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the U.S. 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.
Data Supporting the Approval
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.
Efficacy results showed:
| Endpoint |
KEYTRUDA With
Chemotherapy/KEYTRUDA
n=784
|
Placebo With
Chemotherapy/Placebo
n=390
|
| pCR (ypT0/Tis ypN0) * |
|
|
| Number of patients with pCR |
494 |
217 |
| pCR rate (%), (95% CI) |
63.0 (59.5, 66.4) |
55.6 (50.6, 60.6) |
| Treatment difference (%) estimate (95% CI)†‡ |
7.5 (1.6, 13.4) |
| EFS |
|
|
| Number of patients with event (%) |
123 (16%) |
93 (24%) |
| Hazard ratio (95% CI)§ |
0.63 (0.48, 0.82) |
| p-Value ¶,# |
0.00031 |
|
* Based on entire intent-to-treat population (n=1,174 patients)
† Based on a pre-specified pCR interim analysis in n=602 patients, the pCR rate difference was statistically significant (p=0.00055 compared to a significance level of 0.003).
‡ Based on Miettinen and Nurminen method stratified by nodal status, tumor size, and choice of carboplatin
§ Based on stratified Cox regression model
¶ Based on a pre-specified EFS interim analysis (compared to a significance level of 0.0052)
# Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin
|
At the protocol’s pre-specified interim analysis of OS (interim analysis four), OS data were not mature, with 45% of the required events for the final analysis.
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%).
About Triple-Negative Breast Cancer
Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some people with breast cancer may test positive for estrogen receptors, progesterone receptors, or overexpression of human epidermal growth factor receptor 2 (HER2), people with TNBC test negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American, or who have a BRCA1 mutation.
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 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 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.
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 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.
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) 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 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.
About the Merck Access Program for KEYTRUDA
At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com.
About Merck’s Patient Support Program for KEYTRUDA
Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For 130 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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This KEYTRUDA Combination Is the First Immunotherapy Regimen Approved for High-Risk Early-Stage Triple-Negative Breast Cancer (TNBC)
KEYTRUDA Is Now Approved in the US for 30 Indications
KENILWORTH, NJ, USA I July 27, 2021 I Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. 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, U.S. 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. For more information, see “Selected Important Safety Information” below.
“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the U.S. 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.
Data Supporting the Approval
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.
Efficacy results showed:
| Endpoint |
KEYTRUDA With
Chemotherapy/KEYTRUDA
n=784
|
Placebo With
Chemotherapy/Placebo
n=390
|
| pCR (ypT0/Tis ypN0) * |
|
|
| Number of patients with pCR |
494 |
217 |
| pCR rate (%), (95% CI) |
63.0 (59.5, 66.4) |
55.6 (50.6, 60.6) |
| Treatment difference (%) estimate (95% CI)†‡ |
7.5 (1.6, 13.4) |
| EFS |
|
|
| Number of patients with event (%) |
123 (16%) |
93 (24%) |
| Hazard ratio (95% CI)§ |
0.63 (0.48, 0.82) |
| p-Value ¶,# |
0.00031 |
|
* Based on entire intent-to-treat population (n=1,174 patients)
† Based on a pre-specified pCR interim analysis in n=602 patients, the pCR rate difference was statistically significant (p=0.00055 compared to a significance level of 0.003).
‡ Based on Miettinen and Nurminen method stratified by nodal status, tumor size, and choice of carboplatin
§ Based on stratified Cox regression model
¶ Based on a pre-specified EFS interim analysis (compared to a significance level of 0.0052)
# Based on log-rank test stratified by nodal status, tumor size, and choice of carboplatin
|
At the protocol’s pre-specified interim analysis of OS (interim analysis four), OS data were not mature, with 45% of the required events for the final analysis.
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%).
About Triple-Negative Breast Cancer
Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some people with breast cancer may test positive for estrogen receptors, progesterone receptors, or overexpression of human epidermal growth factor receptor 2 (HER2), people with TNBC test negative for all three. Approximately 10-15% of patients with breast cancer are diagnosed with TNBC. TNBC tends to be more common in people who are younger than 40 years of age, who are African American, or who have a BRCA1 mutation.
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 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 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.
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 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.
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) 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 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.
About the Merck Access Program for KEYTRUDA
At Merck, we are committed to supporting accessibility to our cancer medicines. Merck provides multiple programs to help appropriate patients who are prescribed KEYTRUDA have access to our anti-PD-1 therapy. The Merck Access Program provides reimbursement support for patients receiving KEYTRUDA, including information to help with out-of-pocket costs and co-pay assistance for eligible patients. More information is available by calling 855-257-3932 or visiting www.merckaccessprogram-keytruda.com.
About Merck’s Patient Support Program for KEYTRUDA
Merck is committed to helping provide patients and their caregivers support throughout their treatment with KEYTRUDA. The KEY+YOU Patient Support Program provides a range of resources and support. For further information and to sign up, eligible patients may call 85-KEYTRUDA (855-398-7832) or visit www.keytruda.com.
Merck’s Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
About Merck
For 130 years, Merck, known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases in pursuit of our mission to save and improve lives. We demonstrate our commitment to patients and population health by increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to prevent and treat diseases that threaten people and animals – including cancer, infectious diseases such as HIV and Ebola, and emerging animal diseases – as we aspire to be the premier research-intensive biopharmaceutical company in the world. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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