KEYTRUDA (pembrolizumab) in Combination with Inlyta (axitinib) Reduced Risk of Death by Nearly Half Compared to Sunitinib as First-Line Treatment for Advanced Renal Cell Carcinoma (RCC)
Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced presentation of the full results from the pivotal Phase 3 KEYNOTE-426 trial investigating KEYTRUDA, Merck?s anti-PD-1 therapy, in combination with Inlyta (axitinib), a tyrosine kinase inhibitor, for the first-line treatment of advanced renal cell carcinoma (RCC) at the 2019 Genitourinary Cancers Symposium (ASCO GU) (Abstract #543). These data were also simultaneously published in the?New England Journal of Medicine. This is the first combination regimen to significantly improve overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) compared to sunitinib. Results were consistent across all IMDC subgroups, including favorable, intermediate and poor risk groups, and regardless of PD-L1 expression.
As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for a supplemental Biologics License Application (sBLA) for KEYTRUDA in combination with axitinib for the first-line treatment of patients with advanced RCC based on the results of KEYNOTE-426, and has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 20, 2019.
?Historically, patients with advanced RCC have faced five-year survival rates of less than 10 percent. Given the aggressive nature of this disease and the poor long-term prognosis, these new survival data with KEYTRUDA in combination with axitinib from KEYNOTE-426 offer the potential of a new treatment option for patients with advanced renal cell carcinoma,? said Dr. Thomas Powles, lead investigator for KEYNOTE-426, professor of genitourinary oncology, lead for Solid Tumor Research at Barts Cancer Institute, director of Barts Cancer Centre.
Findings from the first interim analysis showed KEYTRUDA in combination with axitinib reduced the risk of death by 47 percent ? significantly improving OS compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). For the dual primary endpoint of PFS, the KEYTRUDA combination showed a reduction in the risk of progression of disease or death of 31 percent compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). In the study, the ORR was 59.3 percent for patients who received KEYTRUDA in combination with axitinib (95% CI, 54.5-63.9) and 35.7 percent for those who received sunitinib (95% CI, 31.1-40.4) (p<0.0001), with a complete response rate of 5.8 percent (n=25) and 1.9 percent (n=8) and a partial response rate of 53.5 percent (n=231) and 33.8 percent (n=145), for patients receiving the KEYTRUDA combination or sunitinib, respectively. Median duration of response was not reached in the KEYTRUDA combination arm (range, 1.4+ to 18.2+ months) and was 15.2 months (range, 1.1+ to 15.4+) in the sunitinib arm. The results for OS, PFS and ORR were consistent across all IMDC risk groups and seen regardless of PD-L1 expression. The observed adverse event profile was as expected based on the known profiles of KEYTRUDA and axitinib. There was a higher incidence of grade 3 or 4 liver enzyme elevation with KEYTRUDA plus axitinib than previously observed with each agent as monotherapy.
?With a reduction in the risk of death by nearly half, these findings are particularly impressive considering the benefit was not limited to one subgroup of patients ? we observed an overall survival improvement across all IMDC risk groups and regardless of PD-L1 expression,? said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. ?We are pleased that these findings have been accepted for priority review by the FDA, and hopeful that they will be viewed positively by regulatory authorities worldwide. In the meantime, we are grateful to the investigators and patients for their involvement in this important study.?
"These data build on the single-agent activity of pembrolizumab and axitinib, and represent the first time a kidney cancer regimen has improved overall survival, progression-free survival and objective response rate versus sunitinib. More importantly, they offer patients with this aggressive form of kidney cancer a potential new first-line treatment option,? said Dr. Brian Rini, lead author for the?New England Journal of Medicine?publication of KEYNOTE-426,medical oncologist at Cleveland Clinic Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. As reported by the Cleveland Clinic, Dr. Rini reports consulting and research funding from Merck.
Merck has filed these data with regulatory authorities worldwide. Merck has an extensive clinical development program in RCC and is advancing multiple potential registration-enabling studies with KEYTRUDA, as monotherapy and in combination with other treatments, including KEYNOTE-564 and KEYNOTE-581.
Study Design and Additional Data from KEYNOTE-426
KEYNOTE-426 is a randomized, double-arm, Phase 3 trial (ClinicalTrials.gov, NCT02853331) evaluating the safety and efficacy of KEYTRUDA in combination with axitinib as first-line treatment for advanced or metastatic RCC compared to sunitinib monotherapy. The dual primary endpoints of the study were OS and PFS; key secondary endpoints include ORR, safety, duration of response, PFS at 12, 18 and 24 months and OS at 12, 18 and 24 months. The primary outcome measures were further evaluated based on PD-L1 tumor expression (combined positive score [CPS] <1 [n=325] and =1 [n=497]). In the trial, 861 patients determined to be favorable-, intermediate- or poor-risk by IMDC criteria (n=269, n=484, n=108, respectively) were randomly assigned to receive KEYTRUDA 200 mg intravenously every three weeks plus axitinib 5 mg orally twice daily for up to 24 months (n=432), or sunitinib 50 mg orally once daily for four weeks followed by no treatment for two weeks (n=429).
At the first interim analysis, after a median follow-up of 12.8 months, overall survival was significantly longer in the KEYTRUDA combination arm than in the sunitinib arm (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). Estimated 12-month survival rates were 89.9 percent (95% CI, 86.4-92.4) in the KEYTRUDA combination arm compared to 78.3 percent (95% CI, 73.8-82.1) in the sunitinib arm; the 18-month survival estimates were 82.3 percent (95% CI, 77.2-86.3) and 72.1 percent (95% CI, 66.3-77.0), respectively. Median survival was not reached in either group. Progression-free survival was also significantly longer in the KEYTRUDA combination arm than in the sunitinib arm (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The 12-month PFS rate was 59.6 percent in the KEYTRUDA combination arm and 46.2 percent in the sunitinib arm; the 18-month PFS rate was 41.1 percent in the KEYTRUDA combination arm and 32.9 percent in the sunitinib arm. Median PFS was 15.1 months (95% CI, 12.6-17.7) in the KEYTRUDA combination arm compared to 11.1 months (95% CI, 8.7-12.5) in the sunitinib arm.
Analysis of the OS endpoint based on patient subgroups showed consistent results across each of the IMDC risk categories (favorable, intermediate and poor) (HR=0.64 [95% CI, 0.24-1.68]; HR=0.53 [95% CI, 0.35-0.82]; and HR=0.43 [95% CI, 0.23-0.81], respectively), and regardless of PD-L1 expression (PD-L1 combined positive score [CPS <1 [HR=0.59 (95% CI, 0.34-1.03)] and PD-L1 CPS =1 [HR=0.54 (95% CI, 0.35-0.84]). Results were also consistent for PFS across these same IMDC risk categories (HR=0.81 [95% CI, 0.53-1.24]; HR=0.70 [95% CI, 0.54-0.91]; and HR=0.58 [95% CI, 0.35-0.94], respectively), as well as for tumors with PD-L1 CPS <1 (HR=0.87 [95% CI, 0.62-1.23]) and PD-L1 CPS =1 (HR=0.62 [95% CI, 0.47-0.80]). Subgroup analyses were not controlled for multiplicity.
Grade 3-5 treatment-related adverse events (TRAEs) occurred in 62.9 percent of the 429 treated patients in the KEYTRUDA combination arm and 58.1 percent of the 425 treated patients in the sunitinib arm. TRAEs resulting in discontinuation of any treatment occurred in 25.9 percent of patients in the KEYTRUDA combination arm and 10.1 percent of patients in the sunitinib arm; 8.2 percent of patients discontinued both KEYTRUDA and axitinib. The most common grade 3-5 TRAEs (occurring in =10% of patients) were hypertension (22.1%) and increased alanine aminotransferase (ALT) (13.3%) in the KEYTRUDA combination arm and hypertension (19.3%) in the sunitinib arm.
Immune-mediated adverse events and infusion reactions of any grade occurred in 51.3 percent of patients in the KEYTRUDA combination arm and 36.2 percent of patients in the sunitinib arm. The most common immune-mediated adverse events (occurring in =10% of patients) were hypothyroidism (35.4%) and hyperthyroidism (12.8%) in the KEYTRUDA combination arm and hypothyroidism (31.5%) in the sunitinib arm. Treatment-related deaths occurred in four patients in the KEYTRUDA combination arm (myasthenia gravis, myocarditis, necrotizing fasciitis, pneumonitis [n=1 each]), and seven patients in the sunitinib arm (acute myocardial infarction, cardiac arrest, fulminant hepatitis, gastrointestinal hemorrhage, intracranial hemorrhage, malignant neoplasm progression, pneumonia [n=1 each]).
About Renal Cell Carcinoma (RCC)
Renal cell carcinoma is by far the most common type of kidney cancer; about 9 out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. There were approximately 403,000 cases of kidney cancer diagnosed worldwide in 2018 and about 175,000 deaths from the disease. In the U.S. alone, there will be an estimated 74,000 new cases of kidney cancer diagnosed in 2019 and about 15,000 people will die from the disease.
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 900 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 at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
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 nab-paclitaxel, 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 metastatic NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) =50%] 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 metastatic 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 is administered as an intravenous infusion over 30 minutes of 200 mg 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 is administered as an intravenous infusion over 30 minutes of 200 mg 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 is administered as an intravenous infusion over 30 minutes of 200 mg 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 is administered as an intravenous infusion over 30 minutes of 200 mg 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.
Share this article on WhatsApp, LinkedIn and Twitter
X
Incisive News in 3 Shots.
Contact Us
- First Floor, B-66, Sector 63 Noida, Uttar Pradesh, INDIA - 201301
- +91-120 428 0707
- connect@pharmashots.com
- Newsletter
Our Information
Copyright © 2024 PharmaShots - All Rights Reserved.
Modal title
Modal body text goes here.