CHMP Adopts Positive Opinion for BAVENCIO Plus Axitinib for First-Line Treatment of Patients with

Merck

Not intended for US, Canada and UK-based media

– Opinion based on Phase III data showing combination lowered risk of disease progression or death by 31% and improved objective response rate compared with sunitinib [1]

– Decision by the European Commission anticipated in fourth quarter of 2019

Merck and Pfizer Inc. (NYSE: PFE) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of BAVENCIO(R)(avelumab) in combination with axitinib for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). The opinion was based on positive findings from the Phase III JAVELIN Renal 101 study, which demonstrated a significant extension in median progression-free survival (PFS) and a clinically meaningful improvement in objective response rate (ORR) for the combination across all prognostic risk groups compared with sunitinib.1 The CHMP positive opinion will be reviewed by the European Commission (EC), with a decision anticipated in the fourth quarter of this year. Merck and Pfizer have a global strategic alliance to jointly develop and commercialize BAVENCIO.

“Today’s positive CHMP opinion is a significant step toward potentially transforming the treatment landscape and bringing much needed options to people living with advanced renal cell carcinoma in Europe. We believe that the combination of BAVENCIO plus axitinib has the potential to help address a significant need for patients with advanced renal cell carcinoma for first-line treatments with a benefit across all prognostic risk groups, and we look forward to a decision from the European Commission,” said Luciano Rossetti, M.D., Executive Vice President, Head of Global Research & Development at the Biopharma business of Merck.

In 2018, an estimated 136,500 new cases of kidney cancer were diagnosed in Europe, and approximately 54,700 people died from the disease.2 RCC is the most common form of kidney cancer, accounting for about 3% of all cancers in adults.2 Approximately 20% to 30% of patients are first diagnosed with RCC at the advanced stage, and 30% of patients treated for an earlier stage go on to develop metastases.3,4 About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy,5,6 for reasons that may include poor performance status or adverse events from their initial treatment.5,7,8 The five-year survival rate for patients with metastatic RCC is approximately 12%.9

“Kidney cancer represents a significant burden in Europe, where incidence rates are among the highest in the world,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. “Pfizer has been a leader in the development of kidney cancer treatments for more than a decade, and it is a privilege to continue our efforts to bring a new treatment option to this community.”

The U.S. Food and Drug Administration (FDA) approved BAVENCIO in combination with axitinib for the first-line treatment of patients with advanced RCC in May 2019.10 A supplemental application for BAVENCIO in combination with axitinib in unresectable or metastatic RCC was submitted in Japan in January 2019.

About the JAVELIN Renal 101 Study

The Phase III JAVELIN Renal 101 study is a randomized, multicenter, open-label study of BAVENCIO in combination with axitinib in 886 patients with untreated advanced or metastatic RCC. The major efficacy outcome measures were PFS as assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who have PD-L1-positive tumors (PD‑L1 expression level ≥1%). If PFS was statistically significant in patients with PD-L1-positive tumors, it was then tested in all patients irrespective of PD-L1 expression. PFS based on BICR assessment per RECIST v1.1 and OS irrespective of PD‑L1 expression, objective response, time to response (TTR), duration of response (DOR) and safety are included as secondary endpoints. The study is continuing for OS.

About the JAVELIN Clinical Development Program

The clinical development program for avelumab, known as JAVELIN, involves at least 30 clinical programs and more than 10,000 patients evaluated across more than 15 different tumor types. In addition to RCC, these tumor types include gastric/gastro-esophageal junction cancer, head and neck cancer, Merkel cell carcinoma, non-small cell lung cancer and urothelial carcinoma.

About BAVENCIO(R)(avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.11-13 BAVENCIO has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.13-15 In November 2014, Merck and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

In September 2017, the European Commission granted conditional marketing authorization for BAVENCIO(R)(avelumab) as a monotherapy for the treatment of adult patients with metastatic Merkel cell carcinoma (MCC). BAVENCIO is currently approved for patients with MCC in more than 45 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.16

In the US, BAVENCIO in combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC). Additionally, the US FDA granted accelerated approval for BAVENCIO for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.10

Avelumab Important Safety Information from the US FDA-Approved Label

The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis and hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction and other adverse reactions), infusion-related reactions, hepatotoxicity, major adverse cardiovascular events (MACE), and embryo-fetal toxicity.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions in patients occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

Axitinib Important Safety Information from the US FDA-Approved Label

In the study of advanced RCC after failure of one prior systemic therapy, the warnings and precautions for axitinib include hypertension, including hypertensive crisis, arterial and venous thrombotic events, hemorrhagic events, cardiac failure, gastrointestinal perforation and fistula, hypothyroidism, wound healing complications, reversible posterior leukoencephalopathy syndrome (RPLS), proteinuria, liver enzyme elevation, hepatic impairment and fetal harm during pregnancy.

Common adverse events (reported in at least 20% of patients) in patients receiving axitinib were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia and constipation.

About Merck-Pfizer Alliance

Immuno-oncology is a top priority for Merck and Pfizer. The global strategic alliance between Merck and Pfizer enables the companies to benefit from each other’s strengths and capabilities and further explore the therapeutic potential of BAVENCIO, an anti-PD-L1 antibody initially discovered and developed by Merck. The immuno-oncology alliance is jointly developing and commercializing BAVENCIO. The alliance is focused on developing high-priority international clinical programs to investigate BAVENCIO as a monotherapy as well as combination regimens, and is striving to find new ways to treat cancer.

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