Survival Benefit Now Observed with KEYTRUDA in Combination with Chemotherapy in All Patient Populations (Regardless of PD-L1 Expression) and with KEYTRUDA Monotherapy in Patients Whose Tumors Expressed PD-L1 at CPS ≥1
KENILWORTH, NJ, USA I May 31, 2019 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of the final analysis of the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy and in combination with chemotherapy, for the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #6000). Data include the first-time presentation of certain overall survival (OS) hypotheses from the KEYTRUDA in combination with chemotherapy study arm based on PD-L1 expression and the KEYTRUDA monotherapy study arm in the total patient population. Results of an interim analysis were presented at the European Society for Medical Oncology (ESMO) 2018 Congress and demonstrated superior OS outcomes for KEYTRUDA in combination with chemotherapy in the total population and KEYTRUDA monotherapy in patients whose tumors expressed PD-L1 with Combined Positive Score (CPS) ≥20 and CPS ≥1 compared with the EXTREME regimen, the current standard of care.
“It is exciting to see the full results from this trial, which is the first study to show superior overall survival over the current standard of care known as the EXTREME regimen,” said Dr. Danny Rischin, director of the department of medical oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. “Patients with recurrent or metastatic head and neck cancer have a poor prognosis with limited treatment options. These findings underscore the potential of KEYTRUDA monotherapy and in combination with platinum-based chemotherapy to become important new treatment options.”
The new findings presented today from the final analysis showed that KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus 5-FU) reduced the risk of death by 40% in patients whose tumors expressed PD-L1 with CPS≥20, demonstrating significantly longer OS (14.7 months [95% CI, 10.3-19.3]) compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil [5-FU]), the current standard of care (11.0 months [95% CI, 9.2-13.0]) (HR=0.60 [95% CI, 0.45-0.82]; p=0.0004). For the dual primary endpoint of progression-free survival (PFS), statistical significance was not achieved for KEYTRUDA in combination with chemotherapy in the CPS≥20 population compared with the EXTREME regimen (HR=0.73 [95% CI, 0.55-.97]; p=0.0162). New findings for the CPS ≥1 population showed KEYTRUDA in combination with chemotherapy reduced the risk of death by 35% in these patients, with significantly longer OS (13.6 months [95% CI, 10.7-15.5]) compared with the EXTREME regimen (10.4 months [95% CI, 9.1-11.7]) (HR=0.65 [95% CI, 0.53-0.80]; p<0.0001). Per the sequential testing strategy, superiority for PFS was not tested in this population (HR=0.82 [95% CI, 0.67-1.00]). Results for OS with KEYTRUDA monotherapy in the total population were consistent with the previously presented interim analysis, where non-inferiority was demonstrated (HR=0.83 [95% CI, 0.70-0.99]; p=0.0199), with a median OS of 11.5 months (95% CI, 10.3-13.4) for KEYTRUDA monotherapy in the total population compared with 10.7 months (95% CI, 9.3-11.7) for the EXTREME regimen. There was no difference in PFS between KEYTRUDA monotherapy in the total population and the EXTREME regimen (HR=1.34 [95% CI, 1.13-1.59]).
“As a company, Merck is committed to advancing research in this challenging treatment setting through our expansive head and neck cancer clinical research program,” said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. “The full data from KEYNOTE-048 illustrate the impact of KEYTRUDA as monotherapy and in combination with chemotherapy as potential new first-line treatment options for patients with recurrent or metastatic head and neck squamous cell carcinoma. We would like to sincerely thank the patients and investigators for their involvement in KEYNOTE-048.”
As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA as monotherapy or in combination with platinum and 5-FU chemotherapy for the first-line treatment of patients with recurrent or metastatic HNSCC based in part on data from the second interim analysis of KEYNOTE-048. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 10, 2019.
Study Design and Additional Data from KEYNOTE-048 (Abstract #6000)
KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA in combination with chemotherapy or KEYTRUDA monotherapy, compared with the EXTREME regimen, as first-line treatment in patients with recurrent or metastatic HNSCC. The dual primary endpoints were OS and PFS. The secondary endpoints were PFS (at six months and 12 months), objective response rate (ORR) and time to deterioration in the Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of response (DOR) was evaluated as part of a pre-specified exploratory analysis. The primary and secondary endpoints, as well as exploratory DOR analysis, were evaluated in patients whose tumors expressed PD-L1 (CPS ≥20 and CPS ≥1) and in the total population, based on a fixed sequential testing strategy. Data cutoff for the final analysis was Feb. 25, 2019; data cutoff for the previously presented second interim analysis was June 13, 2018. Details of the OS benefit observed at the final analysis are below:
| |
| Summary of Overall Survival |
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| Population (number of patients with event) |
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Final Analysis Hazard Ratio (95% CI) |
| KEYTRUDA Monotherapy |
| PD-L1 CPS ≥20 (n=133) vs. EXTREME (n=122) |
|
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0.58 (0.44-0.78)b |
| PD-L1 CPS ≥1 (n=257) vs. EXTREME (n=255) |
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0.74 (0.61-0.90)b |
| Total Population (n=301) vs. EXTREME (n=300) |
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0.83 (0.70-0.99); p=0.0199c |
KEYTRUDA in Combination with
Chemotherapy |
| PD-L1 CPS ≥20 (n=126) vs. EXTREME (n=110) |
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0.60 (0.45–0.82); p=0.0004a |
| PD-L1 CPS ≥1 (n=242) vs. EXTREME (n=235) |
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0.65 (0.53–0.80); p<0.0001a |
| Total Population (n=281) vs. EXTREME (n=278) |
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0.72 (0.60-0.87)b |
| a |
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Superiority demonstrated. |
| b |
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No new statistical testing performed because population previously demonstrated superiority at interim analysis. |
| c |
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Superiority not demonstrated. |
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The secondary endpoint of ORR was 42.9% for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 38.2% for the EXTREME regimen. The ORR was 36.4% in patients whose tumors expressed PD-L1 with CPS ≥1 for KEYTRUDA in combination with chemotherapy compared with 35.7% for the EXTREME regimen. The median DOR was 7.1 months (range, 2.1+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 4.2 months (range, 1.2+ to 31.5+) for the EXTREME regimen. The median DOR was 6.7 months (range, 1.6+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥1 compared with 4.3 months (range, 1.2+ to 31.5+) for the EXTREME regimen.
In the KEYTRUDA monotherapy arm, an analysis of the total patient population showed an ORR of 16.9% compared with 36.0% for the EXTREME regimen; the median DOR was 22.6 months (range, 1.5+ to 43.0+) compared with 4.5 months (range, 1.2+ to 38.7+) for the EXTREME regimen.
As previously reported, there were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 all-cause adverse events occurred in 54.7%, 85.1% and 83.3% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Adverse events resulting in discontinuation occurred in 12.0%, 32.6% and 27.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Treatment-related deaths occurred in 1.0%, 4.0% and 2.8% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Grade 3-5 immune-mediated or infusion reactions occurred in 7.0%, 5.4% and 10.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively.
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HNSCC who were randomized to one of three regimens as first-line therapy, as follows:
- KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for up to 24 months (n=301); or
- KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV continuous from Day 1-4 Q3W (maximum six cycles), followed by additional KEYTRUDA monotherapy maintenance therapy until progression of disease, toxicity or until the patient had received a maximum of 24 months total treatment (n=281); or
- EXTREME regimen including cetuximab at a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2 IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Two substances that greatly increase the risk of developing head and neck cancer are tobacco and alcohol. It is estimated that there were more than 887,000 new cases of head and neck cancer diagnosed and over 453,000 deaths from the disease worldwide in 2018. In the U.S. alone, it is estimated that there will be more than 65,000 new cases of head and neck cancer diagnosed and over 14,000 deaths from the disease in 2019.
About KEYTRUDA® (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-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 1,000 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.
KEYTRUDA® (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. The recommended dose of KEYTRUDA in patients with unresectable or metastatic melanoma is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity.
KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. The recommended dose of KEYTRUDA for the adjuvant treatment of adult patients with melanoma is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence.
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 stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
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.
In NSCLC, the recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. 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. In adults with cHL, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
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. 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.
In adults with PMBCL, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
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 [combined positive score (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 the confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) 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, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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.
In adult patients with MSI-H cancer, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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 recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
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. The recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.
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. The recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. 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 recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma. In renal cell carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg axitinib orally twice daily until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months in patients without disease progression. When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. See also the Prescribing Information for recommended axitinib dosing information.
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 more than a century, Merck, a leading global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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Survival Benefit Now Observed with KEYTRUDA in Combination with Chemotherapy in All Patient Populations (Regardless of PD-L1 Expression) and with KEYTRUDA Monotherapy in Patients Whose Tumors Expressed PD-L1 at CPS ≥1
KENILWORTH, NJ, USA I May 31, 2019 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the presentation of the final analysis of the pivotal Phase 3 KEYNOTE-048 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy and in combination with chemotherapy, for the first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #6000). Data include the first-time presentation of certain overall survival (OS) hypotheses from the KEYTRUDA in combination with chemotherapy study arm based on PD-L1 expression and the KEYTRUDA monotherapy study arm in the total patient population. Results of an interim analysis were presented at the European Society for Medical Oncology (ESMO) 2018 Congress and demonstrated superior OS outcomes for KEYTRUDA in combination with chemotherapy in the total population and KEYTRUDA monotherapy in patients whose tumors expressed PD-L1 with Combined Positive Score (CPS) ≥20 and CPS ≥1 compared with the EXTREME regimen, the current standard of care.
“It is exciting to see the full results from this trial, which is the first study to show superior overall survival over the current standard of care known as the EXTREME regimen,” said Dr. Danny Rischin, director of the department of medical oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. “Patients with recurrent or metastatic head and neck cancer have a poor prognosis with limited treatment options. These findings underscore the potential of KEYTRUDA monotherapy and in combination with platinum-based chemotherapy to become important new treatment options.”
The new findings presented today from the final analysis showed that KEYTRUDA in combination with chemotherapy (carboplatin or cisplatin plus 5-FU) reduced the risk of death by 40% in patients whose tumors expressed PD-L1 with CPS≥20, demonstrating significantly longer OS (14.7 months [95% CI, 10.3-19.3]) compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus 5-fluorouracil [5-FU]), the current standard of care (11.0 months [95% CI, 9.2-13.0]) (HR=0.60 [95% CI, 0.45-0.82]; p=0.0004). For the dual primary endpoint of progression-free survival (PFS), statistical significance was not achieved for KEYTRUDA in combination with chemotherapy in the CPS≥20 population compared with the EXTREME regimen (HR=0.73 [95% CI, 0.55-.97]; p=0.0162). New findings for the CPS ≥1 population showed KEYTRUDA in combination with chemotherapy reduced the risk of death by 35% in these patients, with significantly longer OS (13.6 months [95% CI, 10.7-15.5]) compared with the EXTREME regimen (10.4 months [95% CI, 9.1-11.7]) (HR=0.65 [95% CI, 0.53-0.80]; p<0.0001). Per the sequential testing strategy, superiority for PFS was not tested in this population (HR=0.82 [95% CI, 0.67-1.00]). Results for OS with KEYTRUDA monotherapy in the total population were consistent with the previously presented interim analysis, where non-inferiority was demonstrated (HR=0.83 [95% CI, 0.70-0.99]; p=0.0199), with a median OS of 11.5 months (95% CI, 10.3-13.4) for KEYTRUDA monotherapy in the total population compared with 10.7 months (95% CI, 9.3-11.7) for the EXTREME regimen. There was no difference in PFS between KEYTRUDA monotherapy in the total population and the EXTREME regimen (HR=1.34 [95% CI, 1.13-1.59]).
“As a company, Merck is committed to advancing research in this challenging treatment setting through our expansive head and neck cancer clinical research program,” said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. “The full data from KEYNOTE-048 illustrate the impact of KEYTRUDA as monotherapy and in combination with chemotherapy as potential new first-line treatment options for patients with recurrent or metastatic head and neck squamous cell carcinoma. We would like to sincerely thank the patients and investigators for their involvement in KEYNOTE-048.”
As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for a new supplemental Biologics License Application (sBLA) seeking approval for KEYTRUDA as monotherapy or in combination with platinum and 5-FU chemotherapy for the first-line treatment of patients with recurrent or metastatic HNSCC based in part on data from the second interim analysis of KEYNOTE-048. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 10, 2019.
Study Design and Additional Data from KEYNOTE-048 (Abstract #6000)
KEYNOTE-048, a randomized, open-label Phase 3 trial (ClinicalTrials.gov, NCT02358031), evaluated KEYTRUDA in combination with chemotherapy or KEYTRUDA monotherapy, compared with the EXTREME regimen, as first-line treatment in patients with recurrent or metastatic HNSCC. The dual primary endpoints were OS and PFS. The secondary endpoints were PFS (at six months and 12 months), objective response rate (ORR) and time to deterioration in the Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire and Safety. Duration of response (DOR) was evaluated as part of a pre-specified exploratory analysis. The primary and secondary endpoints, as well as exploratory DOR analysis, were evaluated in patients whose tumors expressed PD-L1 (CPS ≥20 and CPS ≥1) and in the total population, based on a fixed sequential testing strategy. Data cutoff for the final analysis was Feb. 25, 2019; data cutoff for the previously presented second interim analysis was June 13, 2018. Details of the OS benefit observed at the final analysis are below:
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| Summary of Overall Survival |
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| Population (number of patients with event) |
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Final Analysis Hazard Ratio (95% CI) |
| KEYTRUDA Monotherapy |
| PD-L1 CPS ≥20 (n=133) vs. EXTREME (n=122) |
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0.58 (0.44-0.78)b |
| PD-L1 CPS ≥1 (n=257) vs. EXTREME (n=255) |
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0.74 (0.61-0.90)b |
| Total Population (n=301) vs. EXTREME (n=300) |
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0.83 (0.70-0.99); p=0.0199c |
KEYTRUDA in Combination with
Chemotherapy |
| PD-L1 CPS ≥20 (n=126) vs. EXTREME (n=110) |
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0.60 (0.45–0.82); p=0.0004a |
| PD-L1 CPS ≥1 (n=242) vs. EXTREME (n=235) |
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0.65 (0.53–0.80); p<0.0001a |
| Total Population (n=281) vs. EXTREME (n=278) |
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0.72 (0.60-0.87)b |
| a |
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Superiority demonstrated. |
| b |
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No new statistical testing performed because population previously demonstrated superiority at interim analysis. |
| c |
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Superiority not demonstrated. |
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The secondary endpoint of ORR was 42.9% for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 38.2% for the EXTREME regimen. The ORR was 36.4% in patients whose tumors expressed PD-L1 with CPS ≥1 for KEYTRUDA in combination with chemotherapy compared with 35.7% for the EXTREME regimen. The median DOR was 7.1 months (range, 2.1+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥20 compared with 4.2 months (range, 1.2+ to 31.5+) for the EXTREME regimen. The median DOR was 6.7 months (range, 1.6+ to 39.0+) for KEYTRUDA in combination with chemotherapy in patients whose tumors expressed PD-L1 with CPS ≥1 compared with 4.3 months (range, 1.2+ to 31.5+) for the EXTREME regimen.
In the KEYTRUDA monotherapy arm, an analysis of the total patient population showed an ORR of 16.9% compared with 36.0% for the EXTREME regimen; the median DOR was 22.6 months (range, 1.5+ to 43.0+) compared with 4.5 months (range, 1.2+ to 38.7+) for the EXTREME regimen.
As previously reported, there were no new safety concerns identified with the use of KEYTRUDA in KEYNOTE-048. Grade 3-5 all-cause adverse events occurred in 54.7%, 85.1% and 83.3% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Adverse events resulting in discontinuation occurred in 12.0%, 32.6% and 27.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Treatment-related deaths occurred in 1.0%, 4.0% and 2.8% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively. Grade 3-5 immune-mediated or infusion reactions occurred in 7.0%, 5.4% and 10.5% of patients in the KEYTRUDA monotherapy, KEYTRUDA in combination with chemotherapy and EXTREME regimen arms, respectively.
Additional Information About KEYNOTE-048
KEYNOTE-048 enrolled 882 patients with recurrent or metastatic HNSCC who were randomized to one of three regimens as first-line therapy, as follows:
- KEYTRUDA monotherapy (200 mg fixed dosed every three weeks [Q3W]) for up to 24 months (n=301); or
- KEYTRUDA (200 mg fixed dose Q3W) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV continuous from Day 1-4 Q3W (maximum six cycles), followed by additional KEYTRUDA monotherapy maintenance therapy until progression of disease, toxicity or until the patient had received a maximum of 24 months total treatment (n=281); or
- EXTREME regimen including cetuximab at a loading dose (400 mg/m2 IV) followed by weekly doses (250 mg/m2 IV) in combination with cisplatin (100 mg/m2 IV Q3W) or carboplatin (AUC 5 IV Q3W) plus 5-FU (1000 mg/m2/day IV) continuous from Day 1-4 Q3W (maximum six cycles), followed by additional cetuximab monotherapy maintenance therapy until progression of disease or toxicity (n=300).
About Head and Neck Cancer
Head and neck cancer describes a number of different tumors that develop in or around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas that begin in the flat, squamous cells that make up the thin surface layer of the structures in the head and neck. Two substances that greatly increase the risk of developing head and neck cancer are tobacco and alcohol. It is estimated that there were more than 887,000 new cases of head and neck cancer diagnosed and over 453,000 deaths from the disease worldwide in 2018. In the U.S. alone, it is estimated that there will be more than 65,000 new cases of head and neck cancer diagnosed and over 14,000 deaths from the disease in 2019.
About KEYTRUDA® (pembrolizumab) Injection, 100mg
KEYTRUDA is an anti-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 1,000 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.
KEYTRUDA® (pembrolizumab) Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma. The recommended dose of KEYTRUDA in patients with unresectable or metastatic melanoma is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity.
KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection. The recommended dose of KEYTRUDA for the adjuvant treatment of adult patients with melanoma is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease recurrence, unacceptable toxicity, or for up to 12 months in patients without disease recurrence.
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 stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC, and whose tumors express PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
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.
In NSCLC, the recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as appropriate.
Head and Neck Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. 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. In adults with cHL, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
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. 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.
In adults with PMBCL, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
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 [combined positive score (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 the confirmatory trials.
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
In locally advanced or metastatic urothelial carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Microsatellite Instability-High (MSI-H) 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, or
- colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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.
In adult patients with MSI-H cancer, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered as an intravenous infusion over 30 minutes at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Gastric Cancer
KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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 recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
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. The recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity or up to 24 months in patients without disease progression.
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. The recommended dose of KEYTRUDA is 200 mg as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. 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 recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma. In renal cell carcinoma, KEYTRUDA 200 mg is administered as an intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg axitinib orally twice daily until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months in patients without disease progression. When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. See also the Prescribing Information for recommended axitinib dosing information.
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 more than a century, Merck, a leading global biopharmaceutical company 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. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
SOURCE: Merck
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