KENILWORTH, N.J.---Merck (NYSE: MRK), known as MSD outside 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, as monotherapy in patients whose tumors express PD-L1 (Combined Positive Score [CPS] =1) or in combination with platinum and fluorouracil (FU), a commonly used chemotherapy regimen, for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). The approval is based on results from the pivotal Phase 3 KEYNOTE-048 trial, where KEYTRUDA demonstrated a significant improvement in overall survival (OS) compared with the EXTREME regimen (cetuximab with carboplatin or cisplatin plus FU), a standard treatment, as monotherapy in patients whose tumors expressed PD-L1 (CPS =1) (HR=0.78 [95% CI, 0.64-0.96]; p=0.0171) and in combination with chemotherapy in the total study population (HR=0.77 [95% CI, 0.63-0.93]; p=0.0067). With these new indications, KEYTRUDA is the first anti-PD-1 therapy approved in the first-line setting as monotherapy in patients whose tumors express PD-L1 (CPS =1) or in combination with chemotherapy regardless of PD-L1 expression for patients with metastatic or with unresectable, recurrent HNSCC and the first anti-PD-1 therapy to demonstrate a statistically significant improvement in OS in these patients. ?This approval is a very exciting milestone in the treatment of head and neck cancer and has the potential to transform the way we treat patients with this debilitating disease by offering important new therapeutic options,? said Dr. Barbara Burtness, professor of medicine, Yale School of Medicine and co-director, Development Therapeutics Research Program, Yale Cancer Center. ?Metastatic or recurrent head and neck cancer has been an area of significant unmet need, so it is encouraging to have immunotherapy regimens available for patients in the first-line setting.? Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or 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. ?Head and neck squamous cell carcinoma has historically presented many challenges to physicians and patients, including limited treatment options and physical and functional issues caused by the disease and its treatment,? said Dr. Jonathan Cheng, vice president, clinical research, Merck Research Laboratories. ?This approval is an important advance in the management of this devastating cancer. The results of KEYNOTE-048, which support this approval, demonstrated that KEYTRUDA monotherapy for patients whose tumors expressed PD-L1 CPS greater than or equal to one and KEYTRUDA in combination with chemotherapy regardless of PD-L1 expression significantly prolonged survival for patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma in the first-line setting.? KEYTRUDA was initially approved for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy in 2016 under the FDA?s accelerated approval process based on objective response rate data from the Phase 1b KEYNOTE-012 trial. In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-048 and has resulted in the FDA converting the accelerated approval to a full (regular) approval. Data Supporting the Approval This approval is based on data from the pre-specified interim analysis of the Phase 3 KEYNOTE-048 trial, a randomized, multi-center, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy and who were considered incurable by local therapies. Randomization was stratified by tumor PD-L1 expression (Tumor Proportion Score [TPS] =50% or <50%) according to the PD-L1 IHC 22C3 pharmDx kit, HPV status according to p16 IHC (positive or negative), and ECOG Performance Status (PS) (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:

• KEYTRUDA 200 mg intravenously every three weeks;
• KEYTRUDA 200 mg intravenously every three weeks, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m²?intravenously every three weeks and FU 1000 mg/m²/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU);
• Cetuximab 400 mg/m^2?intravenously as the initial dose then 250 mg/m²?intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every three weeks or cisplatin 100 mg/m²?intravenously every three weeks and FU 1000 mg/m²/day as a continuous intravenous infusion over 96 hours every three weeks (maximum of six cycles of platinum and FU).

Among the 882 patients, the study population characteristics were: median age of 61 years (range, 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian, and 2.4% Black; 61% had ECOG PS of 1; and 79% were former or current smokers. Twenty-two percent of patients? tumors were HPV positive; 23% had PD-L1 TPS =50%; and 95% had stage IV disease (19% were stage IVA, 6% were stage IVB, and 70% were stage IVC). Eighty-five percent of patients? tumors had PD-L1 expression of CPS =1, and 43% had CPS =20. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity or a maximum of 24 months. A retrospective re-classification of patients? tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization. The main efficacy outcome measures were OS and progression-free survival (PFS) 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) sequentially tested in the subgroup of patients with CPS =20, the subgroup of patients with CPS =1 and the overall population. Efficacy Results for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS?=1 and CPS?=20) Efficacy Results for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048 In KEYNOTE-048, the safety of KEYTRUDA, as a single agent and in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, was investigated in patients with previously untreated, recurrent or metastatic HNSCC. The median duration of exposure to KEYTRUDA 200 mg every three weeks was 3.5 months (range, 1 day to 24.2 months) in the KEYTRUDA single agent arm and was 5.8 months (range, 3 days to 24.2 months) in the combination arm. KEYTRUDA was discontinued for adverse reactions in 12% of patients in the KEYTRUDA single agent arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 31% of patients; the most common adverse reactions leading to the interruption of KEYTRUDA (=2%) were pneumonia (2.3%), pneumonitis (2.3%) and hyponatremia (2%). The most common adverse reactions (=20%) with KEYTRUDA as a single agent were fatigue (33%), constipation (20%), and rash (20%). KEYTRUDA was discontinued for adverse reactions in 16% of patients in the combination arm. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%) and septic shock (1.4%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA (=2%) were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%) and febrile neutropenia (2.9%). The most common adverse reactions (=20%) with KEYTRUDA in combination with platinum and FU were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%) and cough (22%). 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 NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) =1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic.

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, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC). KEYTRUDA, as a single agent, is indicated for the first line treatment of patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) =1] as determined by an FDA-approved test. KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. In HNSCC, the recommended dose of KEYTRUDA is 200?mg administered as an intravenous infusion over 30?minutes every 3?weeks until disease progression, unacceptable toxicity, or up to 24?months in patients without disease progression. When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate. 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 unacc