Longer Term Follow-Up Data With Merck & Co.’S KEYTRUDA (Pembrolizumab) In Combination With Pemetrexed And Carboplatin In First-Line Nonsquamous Metastatic Non-Small Cell Lung Cancer (NSCLC) To Be Presented At 2017 ASCO Annual Meeting
KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced updated results from KEYNOTE-021, Cohort G1, which studied KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in combination with pemetrexed and carboplatin (pem/carbo) in the first-line treatment of patients with advanced nonsquamous non-small cell lung cancer (NSCLC), irrespective of PD-L1 expression. Data – which are based on an additional five months of follow-up – demonstrated continued benefit with KEYTRUDA plus pem/carbo, including an overall response rate (ORR) of 56.7 percent compared to 30.2 percent with pem/carbo alone (95% CI, 8.9%-42.3%; P = 0.0016). Progression-free survival (PFS) was longer in the KEYTRUDA combination group, with the median not reached (95% CI, 8.5 months-not reached) compared to 8.9 months in the pem/carbo group (95% CI, 6.2-10.3) (HR 0.50 [95% CI, 0.29-0.84, P = 0.0038]). Though statistical significance was not met, an updated overall survival (OS) analysis for the combination with KEYTRUDA plus pem/carbo showed a trend towards improvement compared to patients treated with pem/carbo alone (HR, 0.69 [95% CI, 0.36-1.31, P = 0.13]). The findings are being presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #9094).
“With an additional five months of follow-up, we are seeing continued benefits in overall response rate and progression-free survival with KEYTRUDA plus pemetrexed/carboplatin,” said Dr. Vassiliki Papadimitrakopoulou, section chief thoracic medical oncology, UT MD Anderson Cancer Center. “These data support the use of this combination regimen for patients with nonsquamous metastatic non-small cell lung cancer, irrespective of PD-L1 expression.”
Merck has one of the world’s most robust clinical development programs in immuno-oncology. The program includes extensive research in lung cancer with multiple registration-enabling studies for KEYTRUDA (pembrolizumab) currently underway. The KEYTRUDA clinical development program encompasses more than 30 tumor types in more than 500 clinical trials, including more than 300 trials that combine KEYTRUDA with other cancer treatments.
“A significant unmet need in lung cancer has existed for decades, and we are now seeing that KEYTRUDA combined with pemetrexed and carboplatin shows a continued benefit for patients with metastatic nonsquamous non-small cell lung cancer in the first-line treatment of this disease,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “We are encouraged by these additional data and look forward to continuing to study this combination through our ongoing clinical research program.”
KEYNOTE-021, Cohort G1: Data in First-Line Patients Irrespective of PD-L1 Expression (Abstract #9094)
Cohort G1 of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of KEYTRUDA in combination with pemetrexed and carboplatin (KEYTRUDA + pem/carbo combination group) compared with pemetrexed and carboplatin (pem/carbo group) in 123 patients with metastatic, nonsquamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. The KEYNOTE-021G1 trial was conducted in collaboration with Eli Lilly and Company, the maker of pemetrexed. Patients were randomized to receive KEYTRUDA + pem/carbo (n=60) or pem/carbo alone (n=63). Patients in the KEYTRUDA + pem/carbo combination group received KEYTRUDA (200 mg), pemetrexed (500 mg/m2) and carboplatin (AUC 5 mg/mL/min) every three weeks for four cycles followed by KEYTRUDA every three weeks. In the pem/carbo group, patients received pemetrexed (500 mg/m2) and carboplatin (AUC 5 mg/mL/min) alone for four cycles. At the investigator’s discretion, maintenance pemetrexed (500 mg/m2) every three weeks was permitted in both treatment groups. The major efficacy outcome measure was overall response rate (ORR) as assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Additional efficacy outcome measures were PFS as assessed by BICR using RECIST 1.1, duration of response and OS.
Data to be presented at ASCO include a median follow-up of 14.5 months (range: 0.8-24.0). In this analysis, the KEYTRUDA + pem/carbo combination demonstrated improvement over pem/carbo alone in response rate, duration of response and PFS. ORR was 56.7 percent in the KEYTRUDA + pem/carbo combination group compared to 30.2 percent in the pem/carbo group (95% CI, 8.9%-42.3%; P = 0.0016). The median duration of response had not been reached in the KEYTRUDA + pem/carbo combination group (range: 1.4+ to 18.6+) and was 16.2 months (range: 2.8 to 20.7+) in the pem/carbo group.
Findings also included an analysis based on PD-L1 expression. In patients whose tumors did not express PD-L1 (TPS of less than 1%), ORR was 62 percent (95% CI, 38-82) with KEYTRUDA (pembrolizumab) + pem/carbo compared to 13 percent (95% CI, 3-34) with pem/carbo alone. In patients whose tumors expressed PD-L1 (TPS of 1% or more), ORR was 54 percent (95% CI, 37-70) with KEYTRUDA+ pem/carbo compared to 40 percent (95% CI, 25-57) with pem/carbo alone. Among these patients, those with high levels of PD-L1 (TPS of 50% or more) were most likely to respond, with an ORR of 80 percent (95% CI, 56-94) with KEYTRUDA + pem/carbo compared to 41 percent (95% CI, 18-67) with pem/carbo alone. In patients with lower levels of PD-L1 expression (TPS of one to 49%), ORR was 26 percent (95% CI, 9-51) with KEYTRUDA + pem/carbo compared to 39 percent (95% CI, 20-61) with pem/carbo alone.
PFS was longer in the KEYTRUDA combination group, with the median not reached (95% CI, 8.5 months-not reached) compared to 8.9 months in the pem/carbo group (95% CI, 6.2-10.3) (HR 0.50 [95% CI, 0.29-0.84, P = 0.0038]). At nine and 12 months, PFS was 63.2 percent and 56.4 percent, respectively, in the KEYTRUDA + pem/carbo combination group compared to 48.1 percent and 33.9 percent in the pem/carbo group.
Seventy-five percent (n=36/48) of patients in the pem/carbo group received subsequent anti-PD-1 or PD-L1 therapy, including 22 who received KEYTRUDA as part of study crossover.
Though statistical significance was not met in an analysis of OS, the KEYTRUDA + pem/carbo combination was associated with a 31 percent (HR, 0.69 [95% CI, 0.36-1.31, P = 0.13]) reduction in the risk of death. Median OS was not reached in either group; at nine and 12 months, the estimated OS rate was 84.6 percent and 76.0 percent, respectively, in the KEYTRUDA + pem/carbo combination group compared to 82.3 percent and 69.3 percent in the pem/carbo group.
The safety findings were consistent with what has been seen in previous trials among patients treated with KEYTRUDA. Grade 3-5 treatment-related adverse events occurring in the KEYTRUDA + pem/carbo group were anemia (11.9%), neutrophil count decreased (6.8%), fatigue (3.4%), nausea (1.7%), rash (1.7%), vomiting (1.7%), aspartate aminotransferase increased (1.7%) and alanine aminotransferase increased (1.7%). The most common immune-mediated adverse events of any grade in patients receiving KEYTRUDA + pem/carbo were hypothyroidism (11.9%), hyperthyroidism (8.5%), pneumonitis (6.8%), infusion reactions (3.4%), severe skin toxicity (1.7%) and colitis (1.7%). There was one treatment-related death in a patient receiving KEYTRUDA + pem/carbo and two in patients receiving pem/carbo alone.
About Lung Cancer
Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be two percent.
About KEYTRUDA® (pembrolizumab) Injection
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.
Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.
KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.
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, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (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 also 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 (pembrolizumab).
KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg 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 pemetrexed and carboplatin.
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 at a fixed dose 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 three 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 at a fixed dose 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 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 (pembrolizumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. 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 also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma 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 at a fixed dose 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.
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 is administered at a fixed dose 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 MSI-H cancer, KEYTRUDA is administered 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.
Selected Important Safety Information for KEYTRUDA® (pembrolizumab)
KEYTRUDA (pembrolizumab) can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.
KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.
KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
KEYTRUDA (pembrolizumab) can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.
KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.
Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA. Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.