Approval based on results from the Phase 3 KEYNOTE-966 trial, which demonstrated significant overall survival benefit in these patients versus chemotherapy alone

Approval marks sixth gastrointestinal cancer indication for KEYTRUDA-based regimens in the US

RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC). The approval was based on results from the Phase 3 KEYNOTE-966 trial, in which KEYTRUDA plus chemotherapy demonstrated a statistically significant improvement in the study’s primary endpoint of overall survival (OS), reducing the risk of death by 17% (HR=0.83 [95% CI, 0.72-0.95]; one-sided p=0.0034) compared to chemotherapy alone at the trial’s pre-specified final analysis for OS. Median OS was 12.7 months (95% CI, 11.5-13.6) for KEYTRUDA plus chemotherapy versus 10.9 months (95% CI, 9.9-11.6) for chemotherapy alone. This approval marks the sixth indication for KEYTRUDA in gastrointestinal cancers.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

“Cancers of the biliary tract can be highly aggressive tumors, underscoring the need for additional treatment options for the growing number of patients facing this challenging disease,” said Dr. Robin Kate Kelley, professor of clinical medicine in the division of hematology/oncology, University of California, San Francisco. “Today's approval of pembrolizumab in combination with chemotherapy offers patients with locally advanced unresectable or metastatic biliary tract cancer a new immunotherapy regimen that has demonstrated the potential to help these patients live longer.”

“Many patients with biliary tract cancer are diagnosed with locally advanced or metastatic disease, at which point they are not eligible for surgery and face poor survival outcomes with limited treatment options,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “With this approval, Merck is proud to offer a new treatment option to certain patients with locally advanced unresectable or metastatic biliary tract cancer, and their healthcare providers, that has shown an overall survival benefit compared to chemotherapy alone.”

Study design and additional data supporting the approval

KEYNOTE-966 is a multicenter, double-blind, randomized, placebo-controlled Phase 3 trial (ClinicalTrials.gov, NCT04003636) evaluating KEYTRUDA in combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy in the advanced disease setting. The trial enrolled 1,069 patients.

Patients were randomized (1:1) to KEYTRUDA (200 mg) on Day 1 plus gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and Day 8 every three weeks (n=533), or placebo on Day 1 plus gemcitabine (1,000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and Day 8 every three weeks (n=536). Study medications were administered via intravenous infusion. Treatment continued until unacceptable toxicity or disease progression. For KEYTRUDA, treatment continued for a maximum of 35 cycles (or approximately 24 months). For gemcitabine, treatment could be continued beyond eight cycles, while for cisplatin, treatment could be administered for a maximum of eight cycles. Administration of KEYTRUDA with chemotherapy was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Assessment of tumor status was performed at baseline and then every six weeks through 54 weeks, followed by every 12 weeks thereafter.

The major efficacy outcome measure was OS. Additional efficacy outcome measures were progression-free survival (PFS), objective response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

At the trial’s pre-specified final analysis for PFS and ORR, KEYTRUDA plus chemotherapy reduced the risk of disease progression or death by 14% (HR=0.86 [95% CI, 0.75-1.00]) compared to chemotherapy alone. Median PFS was 6.5 months (95% CI, 5.7-6.9) for KEYTRUDA plus chemotherapy versus 5.6 months (95% CI, 5.1-6.6) for chemotherapy alone; however, this result did not reach statistical significance at this analysis. The ORR for KEYTRUDA plus chemotherapy was 29% (95% CI, 25-33), with a complete response (CR) rate of 2.1% (n=11) and a partial response (PR) rate of 27% (n=142), and the ORR for chemotherapy alone was 29% (95% CI, 25-33), with a CR rate of 1.3% (n=7) and a PR rate of 27% (n=146). At the trial’s pre-specified final analysis for OS, median DOR was 8.3 months (95% CI, 6.9-10.2) for KEYTRUDA plus chemotherapy (n=156) versus 6.8 months (95% CI, 5.7-7.1) for chemotherapy alone (n=152).

The median duration of exposure to KEYTRUDA was six months (range, 1 day to 28 months). KEYTRUDA was discontinued due to adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (≥1%) was pneumonitis (1.3%). Adverse reactions leading to interruption of KEYTRUDA occurred in 55% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (≥2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased alanine aminotransferase (ALT) (2.6%), increased aspartate aminotransferase (AST) (2.5%) and biliary obstruction (2.3%).

In the KEYTRUDA plus chemotherapy versus placebo plus chemotherapy arms, there was a difference of ≥5% incidence in adverse reactions between patients who received KEYTRUDA versus placebo for pyrexia (26% vs. 20%), rash (21% vs. 13%), pruritus (15% vs. 10%) and hypothyroidism (9% vs. 2.6%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

There was a difference of ≥5% incidence in laboratory abnormalities between patients who received KEYTRUDA plus chemotherapy versus placebo plus chemotherapy for decreased lymphocytes (69% vs. 61%). There were no clinically meaningful differences in incidence of Grade 3-4 toxicity between arms.

About biliary tract cancer

Biliary tract cancer (BTC) is a group of rare and highly aggressive cancers in the liver, gallbladder and bile ducts. Biliary tract cancer is the second most common type of primary liver cancer after hepatocellular carcinoma (HCC), accounting for approximately 15% of all liver cancers. In the U.S., there are about 20,000 patients diagnosed with BTC each year. Biliary tract cancer is most frequently diagnosed in patients between 50 and 70 years old, and approximately 70% of BTC patients are diagnosed at an advanced stage. Patients diagnosed with BTC face a very poor prognosis, with a five-year relative survival rate of 2-3% for those diagnosed with advanced disease and 9-11% for those diagnosed across all stages.

About KEYTRUDA® (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.

Biliary Tract Cancer

KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC).

See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (