KEYTRUDA® (Pembrolizumab) Plus LENVIMA® (Lenvatinib) Combination Treatment for Patients with Certain Types of Endometrial Carcinoma.” Merck, 17 Sept

Page Indication Date Approved Date Updated

2 Endometrial Carcinoma Sept 17, 2019 Sept 19, 2019 Squamous Cell Carcinoma of the 3 July 30, 2019 July 31, 2019 Esophagus 4 Small-Cell Lung Cancer June 17, 2019 June 18, 2019

5 Metastatic Renal Cell Carcinoma April 19, 2019 May 9, 2019

6 Melanoma Feb 15, 2019 May 9, 2019

7 Merkel Cell Carcinoma Dec 19, 2018 Feb 1, 2019

8 Hepatocellular Carcinoma Nov 9, 2018 Feb 1, 2019

9 Primary Mediastinal B-Cell Lymphoma June 13, 2018 Feb 1, 2019

10 Cervical Cancer June 12, 2018 Feb 1, 2019 Adenocarcinoma Of The Gastroesophageal 11 Sept 22, 2017 Feb 1, 2019 Junction 12 Microsatellite Instability-High Cancer May 23, 2017 Feb 1, 2019 Metastatic Transitional (Urothelial) Tract 13 May 18, 2017 Feb 1, 2019 Cancer Hodgkin Lymphoma (B-Cell Hodgkin 14 March 14, 2017 Feb 1, 2019 Lymphoma) Recurrent Head and Neck Squamous Cell June 10, 2019 15 June 11, 2019 Carcinoma Aug 5, 2016 April 11, 2019 Oct 2, 2015 16 Non-Small Cell Lung Cancer May 9, 2019 Oct 24, 2016 May 10, 2017 17 Metastatic Melanoma Sept 4, 2014 Feb 1, 2019

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval N/A Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 9/17/2019 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 7/31/2018 Administration: Intravenous Designation Priority Review Designation: N/A Indication Details Sales Forecast Indication Incidence Incidence Type Endometrial U.S. 61,880 * Carcinoma Global N/A

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Sep 19, 2019. Comments Section

On September 17, 2019, FDA approved Keytruda (pembrolizumab), in combination with lenvatinib, for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation.

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.

Endometrial Cancer Prevalence (US, 2016): 772,245 *

Sources: “FDA Approves KEYTRUDA® (Pembrolizumab) plus LENVIMA® (Lenvatinib) Combination Treatment for Patients with Certain Types of Endometrial Carcinoma.” Merck, 17 Sept. 2019, investors.merck.com/news/press-release-details/2019/FDA-Approves-KEYTRUDA-pembrolizumab-plus-LENVIMA- lenvatinib-Combination-Treatment-for-Patients-with-Certain-Types-of-Endometrial-Carcinoma/default.aspx. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com, Accessed: September 19, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2019. * SEER Cancer Stat Facts: Uterine Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/corp.html. Accessed: September 19, 2019. “Simultaneous Review Decisions for Pembrolizumab plus Lenvatinib in Australia, Canada and US.” U.S. Food & Drug Administration, 17 Sept. 2019, www.fda.gov/drugs/resources-information-approved-drugs/simultaneous-review-decisions-pembrolizumab-plus-lenvatinib-australia-canada-and-us.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Original Anticipated Approval Drug Brand N/A Keytruda (PDUFA): Name: Regulatory Status: Approved

Drug Generic Regulatory Status Date: 7/30/2019 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: 6/15/2017 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Breakthrough Therapy Route of N/A Intravenous Designation Administration: Priority Review Designation: N/A Indication Details Sales Forecast Indication Incidence Incidence Type Squamous Cell U.S. 17,650* Carcinoma of the Esophagus Global 329,762 (ESCC)

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

On July 30, 2019, FDA approved Keytruda (pembrolizumab) for the treatment of patients with recurrent, locally advanced or metastatic squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10], as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Esophageal Cancer Prevalence: There were an estimated 46,477 people living with esophageal cancer in the United States in 2016.*

Sources: “FDA Approves New Monotherapy Indication for Merck’s KEYTRUDA® (Pembrolizumab).” Merck, 31 July 2019, www.mrknewsroom.com/news- release/prescription-medicine-news/fda-approves-new-monotherapy-indication-mercks-keytruda-pemb. “FDA Approves Pembrolizumab for Advanced Esophageal Squamous Cell Cancer.” U.S. Food and Drug Administration, 31 July 2019, www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-esophageal-squamous-cell-cancer. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: July 31, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2019. * SEER Cancer Stat Facts: Esophageal Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/esoph.html. Accessed: July 31, 2019.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 6/17/2019 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 6/17/2019 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: 10/3/2017 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 2/20/2019 Indication Details Sales Forecast Indication Prevalence Prevalence Type Small-Cell U.S. 16,845 Lung Cancer Global 278,821

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

On February 20, 2019, FDA accepted and granted priority review for a new Supplemental BLA for Keytruda, as monotherapy for the treatment of patients with advanced small cell lung cancer (SCLC) whose disease has progressed after two or more lines of prior therapy.

UPDATE: On June 17, 2019, FDA approved Keytruda (pembrolizumab) for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

Sources: “FDA Approves Pembrolizumab for Metastatic Small Cell Lung Cancer.” U.S. Food and Drug Administration, 18 June 2019, www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-metastatic-small-cell-lung-cancer. “FDA Grants Priority Review to Merck's Supplemental Biologics License Application for KEYTRUDA® (Pembrolizumab) Monotherapy for Third-Line Treatment of Patients with Advanced Small Cell Lung Cancer (SCLC).” Merck - Investors, 20 Feb. 2019, investors.merck.com/news/press-release- details/2019/FDA-Grants-Priority-Review-to-Mercks-Supplemental-Biologics-License-Application-for-KEYTRUDA-pembrolizumab-Monotherapy-for-Third- Line-Treatment-of-Patients-with-Advanced-Small-Cell-Lung-Cancer-SCLC/default.aspx. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: June 18, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2019.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 6/20/2019 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 4/19/2019 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 1/9/2018 Administration: Intravenous Designation Priority Review Designation: 2/15/2019 Indication Details Sales Forecast Indication Incidence Incidence Type Metastatic Renal U.S. 10.9 / 100,000 Cell Carcinoma Global > 400,000

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

On April 19, 2019, FDA approved Keytruda (pembrolizumab) in combination with axitinib (Inlyta) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Renal Cell Carcinoma Prevalence (U.S., 2019): 248,722 Renal Cell Carcinoma Prevalence (Global, 2019): 997,049 It is estimated that up to 30% of patients with renal cell carcinoma have metastatic disease at the time of diagnosis.

Sources: Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424. https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21492. “FDA Approves Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma.” U.S. Food and Drug Administration, 22 Apr. 2019, www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-plus-axitinib-advanced-renal-cell-carcinoma. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. “Kidney Cancer Statistics.” World Cancer Research Fund, 12 Sept. 2018, www.wcrf.org/dietandcancer/cancer-trends/kidney-cancer-statistics. Protzel C, Maruschke M, Hakenberg OW. Epidemiology, Aetiology, and Pathogenesis of Renal Cell Carcinoma. European Urology Supplements. 2012 Aug; 11(3):52-59. https://www.sciencedirect.com/science/article/abs/pii/S1569905612000309?via%3Dihub.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 2/16/2019 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 2/15/2019 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: N/A Indication Details Sales Forecast Indication Incidence Incidence Type Melanoma U.S. 94,494 Global 228,275

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

On February 15, 2019, FDA approved Keytruda (pembrolizumab) for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

The U.S. prevalence of melanoma was estimated to be 1,222,023 cases in 2015.

Sources: “Cancer Stat Facts: Melanoma of the Skin.” NIH: National Cancer Institute - Surveillance, Epidemiology, and End Results Program (SEER), seer.cancer.gov/statfacts/html/melan.html. Accessed: January 28, 2019. “FDA Approves Pembrolizumab for Adjuvant Treatment of Melanoma.” U.S. Food and Drug Administration, 18 Mar. 2019, www.fda.gov/drugs/drug- approvals-and-databases/fda-approves-pembrolizumab-adjuvant-treatment-melanoma. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 12/28/2018 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 12/19/2018 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: 12/28/2016 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 7/1/2018 Administration: Intravenous Designation Priority Review Designation: 9/4/2018 Indication Details Sales Forecast Indication Incidence Incidence Type Merkel Cell U.S. 2,000 / yr Carcinoma 0.6 / 100,000 Global / yr

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 28, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel Cell Carcinoma (MCC). FDA approved this indication under accelerated approval based on tumor response rate and durability of response results from the KEYNOTE-017 trial (NCT02267603). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Sources: “FDA Approves Pembrolizumab for Merkel Cell Carcinoma.” U.S. Food and Drug Administration, 19 Dec. 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628867.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 28, 2019. Hughes MP, Hardee ME, Cornelius LA, Hutchins LF, Becker JC, Gao L. Merkel Cell Carcinoma: Epidemiology, Target, and Therapy. Curr Dermatol Rep. 2014; 3(1): 46–53. “Key Statistics for Merkel Cell Carcinoma.” American Cancer Society, 9 Oct. 2018, www.cancer.org/cancer/merkel-cell-skin-cancer/about/key- statistics.html. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 11/9/2018 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 11/9/2018 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: 6/12/2017 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 7/11/2018 Indication Details Sales Forecast Indication Prevalence Prevalence Type Hepatocellular U.S. 39,720 Carcinoma Global 497,282

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 28, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of patients with Hepatocellular Carcinoma (HCC) who have been previously treated with sorafenib. On November 9, 2018, FDA granted priority review and accelerated approval for this indication. As a condition of accelerated approval, further studies are required.

Sources: “FDA Grants Accelerated Approval to Pembrolizumab for Hepatocellular Carcinoma.” U.S. Food and Drug Administration, 17 Dec. 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm625705.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 28, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 7/3/2018 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 6/13/2018 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: 1/14/2016 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 12/11/2017 Indication Details Sales Forecast Indication Incidence Incidence Type Primary 0.4 / 1,000,000 U.S. Mediastinal / yr B-Cell Global N/A Lymphoma

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 31, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed 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. Limitations of Use: Keytruda is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

On June 13, 2018, this indication was approved by FDA under accelerated approval based on tumor response rate and durability of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

PMBCL represents approximately 2-4% of all non-Hodgkin lymphomas (NHLs) and 6-10% of diffuse large B-cell lymphomas (DLBCLs).

Sources: Dabrowska-Iwanicka A, Walewski JA. Primary Mediastinal Large B-cell Lymphoma. Curr Hematol Malig Rep. 2014; 9(3): 273–283. “FDA Approves Pembrolizumab for Treatment of Relapsed or Refractory PMBCL.” U.S. Food and Drug Administration, 13 June 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610670.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 31, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. Penfold, Terri. “Primary Mediastinal Large B-Cell Lymphoma: Incidence, Survival, Immunophenotype, and Molecular Characteristics.” Lymphoma Hub, 2 Feb. 2017, lymphomahub.com/medical-information/primary-mediastinal-large-b-cell-lymphoma-incidence-survival-immunophenotype-and-molecular- characteristics.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 6/28/2018 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 6/12/2018 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 3/13/2018 Indication Details Sales Forecast Indication Incidence Incidence Type Cervical 7.4 / 100,000 U.S. Cancer / yr Global 500,000

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 30, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS >1) as determined by an FDA- approved test.

FDA granted Keytruda priority review. Its cervical cancer indication was approved under accelerated approval on June 12, 2018 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.

Sources: “Cervical Cancer Statistics.” World Cancer Research Fund, www.wcrf.org/dietandcancer/cancer-trends/cervical-cancer-statistics. Accessed: January 30, 2019. “FDA Approves Pembrolizumab for Advanced Cervical Cancer with Disease Progression during or after Chemotherapy.” U.S. Food and Drug Administration, 13 June, 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610572.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 30, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. SEER Cancer Stat Facts: Cervical Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/cervix.html

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 9/22/2017 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 9/22/2017 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: 6/16/2015 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 5/23/2017 Indication Details Sales Forecast Indication Prevalence Prevalence Type Adenocarcinoma U.S. 45,147 Of The Gastroesophageal Global 1,040,557 Junction

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 30, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum- containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

On September 22, 2017, this indication was approved by FDA 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.

Sources: “FDA Grants Accelerated Approval to Pembrolizumab for Advanced Gastric Cancer.” U.S. Food and Drug Administration, 22 Sept. 2017, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577093.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 30, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval N/A Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 5/23/2017 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: N/A Indication Details Sales Forecast Indication Incidence Incidence Type Microsatellite U.S. N/A Instability-High Cancer Global N/A

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 31, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient: • 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 a fluoropyrimidine, oxaliplatin, and irinotecan. Limitations of Use: The safety and effectiveness of Keytruda in pediatric patients with MSI-H central nervous system cancers have not been established.

On May 23, 2017, FDA granted accelerated approval for this indication based on tumor response rate and durability of response. Further studies are required to confirm clinical benefit of pembrolizumab for this indication. This is FDA’s first tissue/site-agnostic approval.

Microsatellite instability (MSI) has been identified in approximately 15-17% of Colorectal Cancers (CRCs).

Sources: Ashktorab H, Ahuja S, Kannan L, Llor X, Ellis NA, et al. A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget. 2016 Jun 7; 7(23): 34546–34557. “FDA Grants Accelerated Approval to Pembrolizumab for First Tissue/Site Agnostic Indication.” U.S. Food and Drug Administration, 30 May 2017, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 31, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. Scarpa A, Cataldo I, Salvatore L. “Microsatellite Instability - Defective DNA Mismatch Repair: ESMO Biomarker Factsheet.” Oncology PRO, 19 Oct. 2016, oncologypro.esmo.org/Education-Library/Factsheets-on-Biomarkers/Microsatellite-Instability-Defective-DNA-Mismatch-Repair#eztoc1701983_0_0_5.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 6/14/2017 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 5/18/2017 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 2/3/2017 Indication Details Sales Forecast Indication Incidence Incidence Type Metastatic U.S. 81,190 Transitional (Urothelial) Global 456,819 Tract Cancer

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 30, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of patients with: • Locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. • 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.

On May 18, 2017, this indication was approved by FDA under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

On May 18, 2018, FDA issued a safety alert concerning decreased survival associated with the use of Keytruda (pembrolizumab) as monotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the protein programmed death ligand 1 (PD-L1). The drug’s labeling has since been revised to reflect the new restricted indications, as listed above. See the full FDA alert: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm608253.htm

Sources: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 30, 2019. “Keytruda (Pembrolizumab) or Tecentriq (Atezolizumab): FDA Alerts Health Care Professionals and Investigators: FDA Statement - Decreased Survival in Some Patients in Clinical Trials Associated with Monotherapy.” U.S. Food and Drug Administration, 18 May 2018, www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm608253.htm. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. SEER Cancer Stat Facts: Bladder Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/urinb.html

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 3/15/2017 Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: 3/14/2017 Drug Generic pembrolizumab Name: Regulatory Status Reason: See Comments Section below regarding FDA’s requirements for continued approval Orphan Drug Designation: 12/30/2015 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 4/18/2016 Administration: Intravenous Designation Priority Review Designation: 12/1/2016 Indication Details Sales Forecast Indication Prevalence Prevalence Type Hodgkin U.S. 50,051 Lymphoma (B-Cell Hodgkin Global 110,588 Lymphoma)

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Jan 31, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed 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.

On March 14, 2017, this indication was approved by FDA under accelerated approval. Further studies are required to confirm clinical benefit of pembrolizumab for this indication.

Sources: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 31, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. “Pembrolizumab (KEYTRUDA) for Classical Hodgkin Lymphoma.” U.S. Food and Drug Administration, 15 Mar. 2017, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546893.htm.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated 8/9/2016, 6/10/2019 Name: Keytruda Approval (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 8/5/2016, 6/10/2019 pembrolizumab Name: Regulatory Status Reason: See Comments Section below Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy N/A Administration: Intravenous Designation Priority Review Designation: 4/13/2016, 2/11/2019 Indication Details Sales Forecast Indication Prevalence Prevalence Type Recurrent U.S. 203,787 Head and Neck Squamous Cell Global 1,422,973 Carcinoma

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

On August 5, 2016, FDA approved Keytruda (pembrolizumab) for the treatment of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC) with disease progression on or after platinum-containing chemotherapy.

UPDATE: On June 10, 2019, FDA approved Keytruda (pembrolizumab) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC). Keytruda was approved for use in combination with platinum and fluorouracil (FU) for all patients and as a single agent for patients whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 1) as determined by an FDA-approved test.

About 10-20% of patients with early-stage HNSCC show recurrent disease during follow-up. Among patients with locally advanced disease, the recurrence rate is approximately 50%. Approximately 61,760 new cases of HNSCC were estimated in the U.S. in 2016.

Sources: “FDA Approves Pembrolizumab for First-Line Treatment of Head and Neck Squamous Cell Carcinoma.” U.S. Food and Drug Administration, 11 June 2019, www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-first-line-treatment-head-and-neck-squamous-cell-carcinoma. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: June 11, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. “Pembrolizumab (KEYTRUDA).” U.S. Food and Drug Administration, 9 Aug. 2016, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm515627.htm. Saleh K, Eid R, Haddad FGH, Khalife-Saleh N, Kourie HR. New developments in the management of head and neck cancer – impact of pembrolizumab. Ther Clin Risk Manag. 2018; 14: 295–303.

Drug Information Regulatory Information Manufacturer: Merck Application Type: Supplemental BLA Drug Brand Original Anticipated Approval 10/2/2015, 12/24/2016, 5/10/2017, Name: Keytruda (PDUFA): 4/11/2019 Regulatory Status: Approved Regulatory Status Date: 10/2/2015, 10/24/2016, 5/10/2017, Drug Generic 4/11/2019 pembrolizumab Name: Regulatory Status Reason: See Comments Section below for timeline of FDA approvals for NSCLC Orphan Drug Designation: N/A Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 10/27/2014, 9/7/2016 Administration: Intravenous Designation Priority Review Designation: 2/27/2014, 9/7/2016, 1/10/2017, 9/12/2018 Indication Details Sales Forecast Indication Prevalence Prevalence Type Non-Small Cell U.S. 314,777 Lung Cancer (NSCLC) Global 1,589,206

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Comments Section

Keytruda (pembrolizumab) is approved by FDA: • 10/2/2015 – As a single agent 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. • 10/24/2016 – As a single agent for the first-line treatment of patients with metastatic 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. • 5/10/2017 (modified 8/20/2018) – In combination with pemetrexed and platinum chemotherapy, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK genomic tumor aberrations. • 10/30/2018 – In combination with carboplatin and either paclitaxel or nab-paclitaxel, as first-line treatment of patients with metastatic squamous NSCLC. • 4/11/2019 – For first-line treatment of patients with stage III NSCLC who are not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (TPS ≥ 1%) as determined by an FDA- approved test.

Sources: “FDA Approves Pembrolizumab in Combination with Chemotherapy for First-Line Treatment of Metastatic Squamous NSCLC.” U.S. Food and Drug Administration, 17 Dec. 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm624659.htm. “FDA Expands Pembrolizumab Indication for First-Line Treatment of NSCLC (TPS ≥1%).” U.S. Food and Drug Administration, 11 Apr. 2019, www.fda.gov/drugs/fda-expands- pembrolizumab-indication-first-line-treatment-nsclc-tps-1. “FDA Grants Regular Approval for Pembrolizumab in Combination with Chemotherapy for First-Line Treatment of Metastatic Nonsquamous NSCLC.” U.S. Food and Drug Administration, 20 16

Aug. 2018, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617471.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: May 9, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018. “Pembrolizumab (Keytruda) 5-10-2017.” U.S. Food and Drug Administration, 11 May 2017, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm558048.htm. “Pembrolizumab (KEYTRUDA) Checkpoint Inhibitor.” U.S. Food and Drug Administration, 25 Oct. 2016, www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm.

Drug Information Regulatory Information Manufacturer: Merck Application Type: BLA Drug Brand Original Anticipated Approval N/A Name: Keytruda (PDUFA): Regulatory Status: Approved Regulatory Status Date: Drug Generic 9/4/2014 pembrolizumab Name: Regulatory Status Reason: N/A Orphan Drug Designation: 11/19/2012 Drug Type: Monoclonal Antibody FDA Fast Track Designation: N/A Route of Breakthrough Therapy 1/17/13 Administration: Intravenous Designation Priority Review Designation: N/A Indication Details Sales Forecast Indication Incidence Incidence Type Metastatic U.S. 94,494 Melanoma Global 228,275

Source: GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: Feb 15, 2019. Comments Section

Keytruda (pembrolizumab) is currently marketed for the treatment of patients with unresectable or metastatic melanoma.

Keytruda (pembrolizumab) was approved under accelerated approval for its original BLA on September 4, 2014. It was originally approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

Sources: “Approved Drugs - Pembrolizumab.” U.S. Food and Drug Administration, 1 Sept. 2015, wayback.archive- it.org/7993/20170111231652/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm412861.htm. GlobalData, Pharma Intelligence Center. https://pharma.globaldata.com , Accessed: January 31, 2019. Keytruda (pembrolizumab) [Package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2018.