KEYNOTE-010 Published in The Lancet and to be Presented at the European Society for Medical Oncology (ESMO) Asia 2015 Congress
Merck, known as MSD outside the United States and Canada, today announced results from the pivotal KEYNOTE-010 study, the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC). In the Phase 2/3 study, KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy, significantly improved overall survival (OS) compared to chemotherapy in patients with any level of PD-L1 expression, as defined by a tumor proportion score (TPS) of 1 percent or more. The results were published in The Lancet and will be presented at the European Society for Medical Oncology (ESMO) Asia 2015 Congress.
“Because lung cancer remains one of the most common and most challenging cancers to treat, understanding the role that KEYTRUDA can play in helping patients was essential to our development program. In this study in patients with PD-L1 expression of one percent or greater, KEYTRUDA demonstrably improved overall survival compared to chemotherapy in previously-treated patients with non-small cell lung cancer, including both squamous and non-squamous histologies,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.
Merck plans to submit a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration for KEYTRUDA based on findings from KEYNOTE-010 by the end of 2015. The Company plans to submit a Marketing Authorization Application to the European Medicines Agency in early 2016.
Overall Survival Findings from KEYNOTE-010
The Phase 2/3 KEYNOTE-010 study included 1,034 patients with advanced NSCLC with PD-L1 expression (TPS of 1% or more). Similar findings were shown in patients who received the FDA-approved dose of KEYTRUDA (pembrolizumab) (2 mg/kg every three weeks) (n=345) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks) (n=346). Both groups of patients who received KEYTRUDA were compared to patients who received docetaxel (n=343). PD-L1 expression was assessed by the immunohistochemistry companion diagnostic test PD-L1 IHC 22C3 PharmDx, made by Dako North America, Inc., an Agilent Technologies Company. The findings from KEYNOTE-010 are based on the final study analysis. The median follow-up was 13.1 months (IQR, 8.6-17.7).
In the total study population (all levels of PD-L1 expression), both doses of KEYTRUDA studied significantly improved OS compared with docetaxel. Specifically, KEYTRUDA resulted in a 29 percent improvement in OS for the 2 mg/kg dose (HR 0.71, P=0.0008; 95% CI, 0.58-0.88) and a 39 percent improvement in OS for the 10 mg/kg dose (HR 0.61, P<0.0001; 95% CI, 0.49-0.75), compared to docetaxel. The estimated 1-year OS rates for KEYTRUDA were 43.2 percent and 52.3 percent, respectively, compared to 34.6 percent for docetaxel. Median OS for KEYTRUDA were 10.4 months (95% CI, 9.4-11.9) and 12.7 months (95% CI, 10.0-17.3), respectively, compared to 8.5 months for docetaxel (95% CI, 7.5-9.8).
Among patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater), OS was superior for both KEYTRUDA doses compared with docetaxel. Specifically, KEYTRUDA improved OS by 46 percent for the 2 mg/kg dose (HR 0.54, P=0.0002; 95% CI, 0.38-0.77) and by 50 percent for the 10 mg/kg dose (HR 0.50, P<0.0001; 95% CI, 0.36-0.70), compared to docetaxel. Median OS for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) was 14.9 months (95% CI, 10.4 to not reached) and 17.3 months (95% CI, 11.8 to not reached), compared to 8.2 months for docetaxel (95% CI, 6.4-10.7).
“This is an exciting time, and studies such as KEYNOTE-010 with KEYTRUDA are paving the way to a better understanding of how to identify the right medicine for each patient,” said Dr. Roy Herbst, Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. “These study findings show KEYTRUDA provided superior overall survival in patients with advanced lung cancer who had positive PD-L1 expression, and support its potential in the treatment of this disease.”
Additional Findings from KEYNOTE-010
In the total study population, KEYTRUDA (pembrolizumab) prolonged progression-free survival (PFS) at both doses, though statistical significance was not met (HR 0.88 [95% CI, 0.74-1.05], P=0.07 for 2 mg/kg; HR 0.79 [95% CI, 0.66-0.94], P=0.004 for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 3.9 months (95% CI, 3.1-4.1) and 4.0 months (95% CI, 2.7-4.3), compared to 4.0 months for docetaxel (95% CI, 3.1-4.2).
Patients with higher levels of PD-L1 expression (a TPS score of 50 percent or greater) who were treated with KEYTRUDA had significantly prolonged PFS compared to docetaxel (HR 0.59 [95% CI, 0.44-0.78, P=0.0001] for 2 mg/kg; HR 0.59 [95% CI, 0.45-0.78, P<0.0001] for 10 mg/kg). Among patients treated with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), median PFS was 5.0 months (95% CI, 4.0-6.5) and 5.2 months (95% CI, 4.1-8.1), compared to 4.1 months for docetaxel (95% CI, 3.6-4.3).
Additionally, the safety of KEYTRUDA was consistent with what has been seen in previous trials among advanced lung cancer patients. Grade 3-5 treatment-related adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: decreased appetite (n=3, n=1), fatigue (n=4, n=6), nausea (n=1, n=2), rash (n=1, n=1), diarrhea (n=2, n=0), asthenia (n=1, n=2), stomatitis (n=0, n=1), and anemia (n=3, n=1). The most common immune-mediated adverse events for KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) included: hypothyroidism (8% [n=28], 8% [n=28]), hyperthyroidism (4% [n=12], 6% [n=20]), and pneumonitis (5% [n=16], 4% [n=15]). There were three treatment-related deaths among patients receiving KEYTRUDA at the 2 mg/kg dose (pneumonitis [n=2], pneumonia [n=1]) and three treatment-related deaths among patients receiving KEYTRUDA at the 10 mg/kg dose (myocardial infarction [n=1], pneumonia [n=1], and pneumonitis [n=1]).
About KEYNOTE-010 and the KEYTRUDA Development Program
KEYNOTE-010 is a global, open-label, randomized, pivotal Phase 2/3 study (ClinicalTrials.gov, NCT01905657) evaluating two doses of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to docetaxel (75 mg/m^2 every three weeks) in 1,034 patients with squamous and non-squamous NSCLC who experienced disease progression after platinum-containing systemic therapy and whose tumors expressed PD-L1. The primary endpoints were OS and PFS. Tumor response was assessed at week 9, then every 9 weeks thereafter per RECIST 1.1 criteria by independent, central, blinded, radiographic review and investigator-assessed, immune-related response criteria.
The KEYTRUDA program currently addresses more than 30 tumor types in more than 160 clinical trials, including more than 80 combinations of KEYTRUDA with other cancer treatments. In lung cancer, KEYTRUDA is being studied across lines of therapy, both as a monotherapy and in combination with chemotherapy. Registration-enabling trials of KEYTRUDA (pembrolizumab) are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, esophageal cancer, breast cancer, Hodgkin lymphoma, multiple myeloma and other tumors, with further trials in planning for other cancers.
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 relative survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be four percent.
About KEYTRUDA (pembrolizumab) Injection 100 mg
KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA 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.
KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is also indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 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. The NSCLC indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Selected Important Safety Information for KEYTRUDA (pembrolizumab)
Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) 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.
Immune-mediate hepatitis occurred in patients receiving KEYTRUDA. 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.
Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. 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.
Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%). Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%). Thyroid disorders can occur at any time during treatment. 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 Grade 4 hyperthyroidism.
Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.
Immune-mediated nephritis occurred in patients receiving KEYTRUDA. 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.
Other clinically important immune-mediated adverse reactions can occur. 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 steroid taper. Permanently discontinue KEYTRUDA (pembrolizumab) 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% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.
Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 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.
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%)
No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.
Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.