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14.2 pembrolizumab

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of product in accordance with the protocol and any applicable laws and regulations. 14.2.1 Source Commercially available pembrolizumab will be supplied under a CTA with the manufacturer, Merck. 14.2.2 Clinical Supplies Disclosure This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.
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14.2.3 toxicity

The most frequently reported adverse events that were considered by the investigator to be "possibly," "probably," or "definitely" related to pembrolizumab are displayed below in Table 7. The 5 most frequently reported AEs considered drug related by the investigator were fatigue (24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), and nausea (10.9%).  
| Pembrolizumab                                                                                           | Reference Safety Dataset for Pembrolizumab   |        |
|---------------------------------------------------------------------------------------------------------|----------------------------------------------|--------|
| Preferred Term                                                                                          | a                                            |        |
| N                                                                                                       | (%)                                          |        |
| Subjects in population                                                                                  | 2799                                         |        |
| Fatigue                                                                                                 | 678                                          | (24.2) |
| Pruritus                                                                                                | 467                                          | (16.7) |
| Rash                                                                                                    | 386                                          | (13.8) |
| Diarrhea                                                                                                | 343                                          | (12.3) |
| Nausea                                                                                                  | 304                                          | (10.9) |
| Arthralgia                                                                                              | 281                                          | (10.0) |
| Decreased appetite                                                                                      | 255                                          | (9.1)  |
| Asthenia                                                                                                | 218                                          | (7.8)  |
| Hypothyroidism                                                                                          | 213                                          | (7.6)  |
| Vitiligo                                                                                                | 159                                          | (5.7)  |
| Myalgia                                                                                                 | 146                                          | (5.2)  |
| Every subject is counted a single time for each applicable row and column. MedDRA version used is 18.1. |                                              |        |  
a. Includes all subjects who received at least one dose of MK-3475 in KN001 Part B1, B2, B3, D,  
| Reference Safety Dataset for Pembrolizumab               |     |
|----------------------------------------------------------|-----|
| Preferred Term                                           | a   |
| N                                                        | (%) |
| C, F1, F2, F3; KN002 (original phase), KN006, and KN010. |     |  
| Table 8: Serious Adverse Reactions Considered Expected for Pembrolizumab System/Category Adverse Reaction  (MedDRA Preferred  Terms) NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Anemia (NSCLC Combo  Tx, UC) Hemolytic anemia Blood and  lymphatic  system disorders Autoimmune myocarditis Myocarditis Cardiac  failure (MEL) Cardiac Adrenal insufficiency   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                   | Adverse Reaction                                            |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                             |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Adrenocortical  insufficiency acute Autoimmune thyroiditis Hyperthyroidism Hypophysitis Hypopituitarism Hypothyroidism Lymphocytic  hypophysitis Secondary adrenocortical  insufficiency Thyroid disorder Thyroiditis Autoimmune uveitis Iridocyclitis |                                                             |
| Eye disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Ocular myasthenia Iritis Uveitis Abdominal discomfort  (UC) |
| Gastrointestinal                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Abdominal pain (MEL,                                        |
| disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                | UC) Abdominal pain lower  (UC)                              |  
Version Date: *02/16/21*  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | Adverse Reaction   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                    |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Abdominal pain upper  (UC) Autoimmune pancreatitis Colitis Colitis microscopic Constipation (MEL,  NSCLC, NSCLC Combo  Tx, UC) Diarrhea Enterocolitis Enterocolitis hemorrhagic Frequent bowel  movements (UC) Gastroenteritis (cHL,  UC) Nausea (MEL, NSCLC,  NSCLC Combo Tx, cHL,  UC) Pancreatitis Oral lichen  planus Pancreatitis acute |                    |  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                                                                        | Adverse Reaction                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                   |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Vomiting (MEL,  NSCLC, NSCLC Combo  Tx, HNSCC, cHL,  UC)Pancreatitis  necrotizing Asthenia (MEL, NSCLC,  cHL, UC) Face edema (HNSCC) Fatigue (MEL, NSCLC,  NSCLC Combo Tx,  HNSCC, cHL, UC) |                                                                                                                                   |
| General  disorders and  administration  site conditions                                                                                                                                                                                                                                                                                                                                                       | Generalized edema  (MEL) Generalized physical  health deterioration  (MEL) Pyrexia Autoimmune hepatitis Drug-induced liver injury |
| Hepatobiliary  disorders                                                                                                                                                                                                                                                                                                                                                                                      | Hepatitis Hepatic pain  (UC) Hepatitis acute                                                                                      |  
Version Date: *02/16/21*  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                                       | Adverse Reaction                                                                                                                      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                       |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Hepatitis fulminant Hepatitis toxic (UC) Hyperbilirubinemia (UC) Liver injury (UC) Anaphylactic reaction Anaphylactoid reaction Cytokine release  syndrome |                                                                                                                                       |
| Immune system  disorders                                                                                                                                                                                                                                                                                                                                                     | Drug hypersensitivity Graft versus host disease  (cHL) Hypersensitivity Serum sickness Gastroenteritis (cHL,  UC) Herpes zoster (cHL) |
| Infections and  infestations                                                                                                                                                                                                                                                                                                                                                 | Pneumonia (NSCLC,  HNSCC, cHL, UC) Rash pustular                                                                                      |  
Version Date: *02/16/21*  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                  | Adverse Reaction                                                              |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                               |                                                                               |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Septic shock (cHL) Sepsis (UC) Upper respiratory tract  infection (NSCLC  Combo Tx, cHL) Urinary tract infection  (UC) Urosepsis (UC) |                                                                               |
| Injury, poisoning  and procedural  complications                                                                                                                                                                                                                                                                                                        | Infusion related reaction Alanine  aminotransferase  increased (UC) Aspartate |
| Investigations                                                                                                                                                                                                                                                                                                                                          | aminotransferase  increased (UC) Blood bilirubin  increased (UC)              |  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Adverse Reaction                                                                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                             |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Blood creatinine  increased(UC)Hepatic  enzyme increased  (NSCLC, UC)Liver  function test increased  (UC)Neutrophil count  decreased (NSCLC  Combo  Tx)Transaminases  increased (UC)Weight  decreased (UC) Decreased appetite  (MEL, NSCLC,  NSCLC Combo Tx  HNSCC, UC) Diabetic ketoacidosis |                                                                                             |
| Metabolism and  nutritional  disorders                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Fulminant type 1  diabetes mellitus Hyponatremia (UC) Latent autoimmune  diabetes in adults |  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                                                        | Adverse Reaction                                                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                   |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Type 1 diabetes  mellitus Arthralgia (MEL,  NSCLC, NSCLC  Combo Tx, cHL, UC) Arthritis Back pain (MEL,  NSCLC, cHL, UC) Bone pain (cHL, UC) |                                                                                                                                                                   |
| Musculoskeletal  and connective  tissue disorders                                                                                                                                                                                                                                                                                                             | Flank pain (UC) Musculoskeletal chest  pain (cHL,  UC)Immune-mediated  necrotizing myopathy Musculoskeletal  discomfort (cHL, UC) Musculoskeletal pain  (cHL, UC) |
| Neoplasms  benign,  malignant and  unspecified (incl  cysts and  polyps)                                                                                                                                                                                                                                                                                      | Tumor pain (UC) Axonal neuropathy                                                                                                                                 |
| Nervous system  disorders                                                                                                                                                                                                                                                                                                                                     | Demyelinating  polyneuropathy                                                                                                                                     |  
| System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Adverse Reaction   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                    |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Dizziness (NSCLC  Combo Tx)Diabetic  ketoacidotic  hyperglycemic coma Dysgeusia (NSCLC  Combo Tx) Dysesthesia (cHL) Guillain-Barre  syndrome Headache (MEL,  NSCLC Combo Tx,  cHL)Hypoesthesia  (cHL) Lethargy (UC) Miller Fisher syndrome Myasathenia  gravisMyasthenia  gravis crisis Myasthenic syndrome Myelitis Neuropathy peripheral  (MEL, cHL) |                    |  
Version Date: *02/16/21*  
| Version Date: 02/16/21 System/Category                                                                                                                                                                                                                                                                                         | Adverse Reaction                                                                                                                                              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                      |                                                                                                                                                               |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Paresthesia  (cHL)Peripheral  sensory neuropathy  (cHL)Polyneuropathy  (MEL, cHL) Confusional state  (HNSCC) |                                                                                                                                                               |
| Psychiatric                                                                                                                                                                                                                                                                                                                    | Insomnia (NSCLC  Combo Tx) Acute kidney injury  (NSCLC Combo Tx,  UC) Autoimmune nephritis Chromaturia (UC) Glomerulonephritis Glomerulonephritis  membranous |
| Renal and  urinary disorders                                                                                                                                                                                                                                                                                                   | Hematuria (UC) Nephritis Nephrotic syndrome Tubulointerstitial  nephritis                                                                                     |  
| Version Date: 02/16/21 System/Category                                                                                                                                                                            | Adverse Reaction                                                                                                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                         |                                                                                                                                     |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. |                                                                                                                                     |
| Reproductive  system and                                                                                                                                                                                          | Pelvic pain (UC)                                                                                                                    |
| breast disorders                                                                                                                                                                                                  | Cough (MEL, NSCLC,  NCSLC Combo Tx,  cHL, UC) Dyspnea (MEL,  NSCLC, NSCLC  Combo Tx, HNSCC,  cHL, UC) Dyspnea exertional  (cHL, UC) |
| Respiratory,  thoracic and  mediastinal  disorders                                                                                                                                                                | Interstitial lung disease Pneumonitis Productive cough  (cHL, UC) Respiratory failure  (HNSCC) Wheezing (cHL, UC) Acute febrile     |
| Skin and                                                                                                                                                                                                          | neutrophilic dermatosis                                                                                                             |
| subcutaneous                                                                                                                                                                                                      |                                                                                                                                     |  
Version Date: *02/16/21*  
| Version Date: 02/16/21 System/Category                                                                                                                                                                            | Adverse Reaction                                                                                                                                                                                                                                                                               |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. |                                                                                                                                                                                                                                                                                                |
| tissue disorders                                                                                                                                                                                                  | Dermatitis Dermatitis acneiform  (cHL, UC) Dermatitis bullous Dermatitis exfoliative  Dermatitis contact  (cHL, UC) Dermatitis psoriasiform  (cHL) Drug eruptionDrug  reaction with  eosinophilia and  systemic symptoms Eczema Eczema asteatotic  (cHL, UC) Erythema (UC) Erythema multiforme |  
| System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Adverse Reaction   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                    |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Lichen planus Lichenoid keratosis  (UC)Palmar-plantar  erythrodysesthesia  syndrome Pemphigoid Pruritus Perivascular  dermatitis Psoriasis Rash Rash erythematous Rash generalized Rash macular Rash maculo-papular Rash papular Rash  morbilliform Rash pruritic Skin disorder |                    |  
| System/Category                                                                                                                                                                                                                                                                                                                                                                                                              | Adverse Reaction   |      |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                    |                    |      |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted. Skin hypopigmentation  (MEL) Skin necrosis Skin reaction (UC) Skin toxicity Stasis dermatitis Stevens-Johnson  syndrome Subacute cutaneous  lupus erythematosus Toxic epidermal  necrolysis Vitiligo (MEL) |                    |      |
| Vascular  disorders                                                                                                                                                                                                                                                                                                                                                                                                          | Vasculitis         | rare |  
| System/Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Adverse Reaction   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|
| (MedDRA Preferred  Terms)                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                    |
| NOTE: Adverse reaction  term is considered  expected for all  indications unless  otherwise noted. Those  terms followed by  parentheses with  notations afterward, are  expected only in the  indications noted.                                                                                                                                                                                                                                                                         |                    |
| cHL = Classical Hodgkin Lymphoma;  MEL = Melanoma; HNSCC = Head and  Neck Squamous Cell Carcinoma; NSCLC  = Non-Small Cell Lung Cancer; NSCLC  Combo Tx = Non-Small Cell Lung Cancer  participants receiving KEYTRUDA in  combination with chemotherapy  (pemetrexed and carboplatin); and UC =  Urothelial Carcinoma For the purpose of  safety reporting in clinical trials only  serious adverse reactions are considered  expected *Term also considered expected with fatal  outcome |                    |
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14.2.4 formulation and preparation

| Product Name & Potency    | Dosage Form            |
|---------------------------|------------------------|
| Pembrolizumab 100 mg/ 4mL | Solution for Injection |  
14.2.5 Stability and Storage Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 14.2.6 Administration procedures Please refer to section 3.2.2. 14.2.7 Incompatibilities None
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14.2.8 returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the participants and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the Investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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Higano C, Bubley GJ, Dreicer R *et al*: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008, 26(7):1148-1159.  
39. Rustin GJ, Quinn M, Thigpen T, du Bois A, Pujade-Lauraine E, Jakobsen A, Eisenhauer E, Sagae S, Greven K, Vergote I *et al*: **Re: New guidelines to evaluate the response to** treatment in solid tumors (ovarian cancer). *Journal of the National Cancer Institute* 2004, 96(6):487-488.  
40. Bubley GJ, Carducci M, Dahut W, Dawson N, Daliani D, Eisenberger M, Figg WD,
Freidlin B, Halabi S, Hudes G *et al*: Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. *Journal of clinical oncology : official* journal of the American Society of Clinical Oncology 1999, 17(11):3461-3467.  
41. Vergote I, Rustin GJ, Eisenhauer EA, Kristensen GB, Pujade-Lauraine E, Parmar MK,
Friedlander M, Jakobsen A, Vermorken JB: **Re: new guidelines to evaluate the** response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. *Journal of the National Cancer Institute* 2000, 92(18):1534-1535.  
42. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A *et al*: iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. *Lancet Oncol* 2017, 18(3):e143-e152.  
43. Simon R: **Optimal two-stage designs for phase II clinical trials**. *Control Clin Trials* 1989, 10(1):1-10.  
44. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I:
Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 2007, 13(17):5144-5149.
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16 appendices

| 16.1                                                                                                   | APPENDIX A: PERFORMANCE STATUS CRITERIA ECOG Performance Status Scale                                   | Karnofsky Performance Scale                     |                                                              |           |                                 |                                   |                                 |
|--------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|-------------------------------------------------|--------------------------------------------------------------|-----------|---------------------------------|-----------------------------------|---------------------------------|
| Grade                                                                                                  | Descriptions                                                                                            | Percent                                         | Description                                                  |           |                                 |                                   |                                 |
| 100                                                                                                    | Normal,                                                                                                 | no                                              | complaints,                                                  | no        |                                 |                                   |                                 |
| evidence of disease.                                                                                   |                                                                                                         |                                                 |                                                              |           |                                 |                                   |                                 |
| Normal activity. Fully active, able                                                                    |                                                                                                         |                                                 |                                                              |           |                                 |                                   |                                 |
| 0                                                                                                      | to                                                                                                      | carry                                           | on                                                           | all       | pre-disease                     | Able to carry on normal activity; |                                 |
| performance without restriction.                                                                       | 90                                                                                                      | minor                                           | signs                                                        | or        | symptoms                        | of                                |                                 |
| disease. Normal                                                                                        | activity                                                                                                | with                                            | effort;                                                      |           |                                 |                                   |                                 |
| 80                                                                                                     | some                                                                                                    | signs                                           | or                                                           | symptoms  | of                              |                                   |                                 |
| disease.                                                                                               |                                                                                                         |                                                 |                                                              |           |                                 |                                   |                                 |
| 1                                                                                                      | Symptoms,                                                                                               | but                                             | ambulatory.                                                  |           |                                 |                                   |                                 |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or | Cares for self, unable to carry on                                                                      |                                                 |                                                              |           |                                 |                                   |                                 |
| sedentary                                                                                              | nature                                                                                                  | (e.g.,                                          | light                                                        | 70        | normal activity or to do active |                                   |                                 |
| housework, office work).                                                                               | work. Requires occasional assistance,                                                                   |                                                 |                                                              |           |                                 |                                   |                                 |
| In                                                                                                     | bed                                                                                                     | <50%                                            | of                                                           | the       | time.                           | 60                                | but is able to care for most of |
| Ambulatory and capable of all                                                                          | his/her needs.                                                                                          |                                                 |                                                              |           |                                 |                                   |                                 |
| 2                                                                                                      | self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.   | 50                                              | Requires considerable assistance  and frequent medical care. |           |                                 |                                   |                                 |
| 40                                                                                                     | Disabled, requires special care  and assistance.                                                        |                                                 |                                                              |           |                                 |                                   |                                 |
| 3                                                                                                      | In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of | Severely                                        | disabled,                                                    |           |                                 |                                   |                                 |
| waking hours.                                                                                          | 30                                                                                                      | hospitalization indicated. Death  not imminent. |                                                              |           |                                 |                                   |                                 |
| 20                                                                                                     | Very                                                                                                    | sick,                                           | hospitalization                                              |           |                                 |                                   |                                 |
| indicated. Death not imminent.                                                                         |                                                                                                         |                                                 |                                                              |           |                                 |                                   |                                 |
| 4                                                                                                      | 100%                                                                                                    | bedridden.                                      | Completely                                                   |           |                                 |                                   |                                 |
| disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                           | 10                                                                                                      | Moribund,                                       | fatal                                                        | processes |                                 |                                   |                                 |
| progressing rapidly.                                                                                   |                                                                                                         |                                                 |                                                              |           |                                 |                                   |                                 |
| 5                                                                                                      | Dead.                                                                                                   | 0                                               | Dead.                                                        |           |                                 |                                   |                                 |
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16.2 appendix b contraception requirements

A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile (see below) Women in the following categories are not considered WOCBP:
Premenarchal Premenopausal female with 1 of the following:  
o Documented hysterectomy o Documented bilateral salpingectomy o Documented bilateral oophorectomy
Note: Documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview.  
Postmenopausal female o A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.  
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required.  
o Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
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male participants

Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the protocol defined time frame in section 2.1.1.10:  
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as described in Table 9 when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant.
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female participants

Female participants of childbearing potential are eligible to participate if they agree to use a highly effective method of contraception consistently and correctly as described in Table 9 during the protocol-defined time frame in Section 2.1.1.10.
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table 9 highly effective contraception

Highly Effective Contraceptive Methods That Are User Dependent a Failure rate of < 1% per year when used consistently and correctly.  
- Combined (estrogen- and progestogen- containing) hormonal contraception
- Oral - Intravaginal - Transdermal - Injectable
- Progestogen-only hormonal contraception
- Oral - Injectable Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly.  
- Progestogen- only contraceptive implant - Intrauterine hormone-releasing system (IUS) - Intrauterine device (IUD) - Bilateral tubal occlusion - **Vasectomized partner**
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.
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- sexual abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.)
Notes: Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies.  
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and correctly).  
| PROGRESSIVE DISEASE ON PEMBROLIZUMAB Clinically Stable                                                                                                                                                                                                                                                            | Clinically Unstable                                                                                      |                                                                                                                                   |                                                                                      |                       |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|-----------------------|
| Imaging                                                                                                                                                                                                                                                                                                           | Treatment                                                                                                | Imaging                                                                                                                           | Treatment                                                                            |                       |
| First                                                                                                                                                                                                                                                                                                             | radiologic                                                                                               |                                                                                                                                   |                                                                                      |                       |
| evidence of PD by  RECIST 1.1 or  mRECIST                                                                                                                                                                                                                                                                         | Repeat imaging at  4 to 8 weeks to  confirm PD.                                                          | May continue study  treatment at the  Investigator's  discretion while  awaiting confirmatory  tumor imaging by site  by iRECIST. | Repeat imaging at  4 to 8 weeks to  confirm PD per  Investigator's  discretion only. | Discontinue treatment |
| Repeat                                                                                                                                                                                                                                                                                                            | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                                                                                                                           | confirms                                                                                                 |                                                                                                                                   |                                                                                      |                       |
| PD                                                                                                                                                                                                                                                                                                                | (iCPD)                                                                                                   | by                                                                                                                                |                                                                                      |                       |
| iRECIST                                                                                                                                                                                                                                                                                                           | per                                                                                                      |                                                                                                                                   |                                                                                      |                       |
| Investigator  assessment                                                                                                                                                                                                                                                                                          | No                                                                                                       | additional                                                                                                                        | Discontinue treatment                                                                |                       |
| imaging required.                                                                                                                                                                                                                                                                                                 | (exception is possible  upon consultation  with Sponsor).                                                | No                                                                                                                                | additional                                                                           | Not applicable        |
| imaging required.                                                                                                                                                                                                                                                                                                 |                                                                                                          |                                                                                                                                   |                                                                                      |                       |
| Repeat                                                                                                                                                                                                                                                                                                            | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                                                                                                                           | shows                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| iUPD by iRECIST  per Investigator  assessment                                                                                                                                                                                                                                                                     | Repeat imaging at  4 to 8 weeks to  confirm PD. May  occur at next  regularly  scheduled  imaging visit. | Continue                                                                                                                          | study                                                                                |                       |
| treatment                                                                                                                                                                                                                                                                                                         | at                                                                                                       | the                                                                                                                               |                                                                                      |                       |
| Investigator's  discretion.                                                                                                                                                                                                                                                                                       | Repeat imaging at  4 to 8 weeks to  confirm PD per  Investigator's  discretion only.                     | Discontinue treatment                                                                                                             |                                                                                      |                       |
| Repeat                                                                                                                                                                                                                                                                                                            | tumor                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| imaging                                                                                                                                                                                                                                                                                                           | shows                                                                                                    |                                                                                                                                   |                                                                                      |                       |
| iSD, iPR, or iCR  by iRECIST per  Investigator  assessment.                                                                                                                                                                                                                                                       | Continue  regularly  scheduled  imaging  assessments.                                                    | Continue                                                                                                                          | study                                                                                |                       |
| treatment                                                                                                                                                                                                                                                                                                         | at                                                                                                       | the                                                                                                                               |                                                                                      |                       |
| Investigator's  discretion.                                                                                                                                                                                                                                                                                       | Continue  regularly  scheduled  imaging  assessments.                                                    | May                                                                                                                               | restart                                                                              | study                 |
| treatment if condition  has improved and/or  clinically stable per  Investigator's  discretion. Next tumor  image should occur  according to the regular  imaging schedule.                                                                                                                                       |                                                                                                          |                                                                                                                                   |                                                                                      |                       |
| iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified  Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease;  iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response |                                                                                                          |                                                                                                                                   |                                                                                      |                       |  
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1., mRECIST = Modified RECIST Criteria for malignant pleural mesothelioma
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16.4 appendix d second course

Tumor imaging must be performed within 28 days prior to restarting treatment with pembrolizumab. Investigator assessment with site radiology reading will be used to determine eligibility. The first on-study imaging assessment should be performed at 2 cycles ±7 days) after the restart of treatment. Subsequent tumor imaging should be performed every 2 cycles ±7 days or more frequently, if clinically indicated. Per RECIST 1.1, if tumor imaging shows initial PD, tumor assessment should be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing treatment while awaiting radiologic confirmation of progression. Participants who obtain confirmatory imaging do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until the next scheduled imaging time point, if clinically stable. Imaging should continue to be performed until disease progression, the start of a new anticancer treatment, withdrawal of consent, death, or investigator discretion, whichever occurs first. Disease progression may be confirmed 4 to 8 weeks after the first tumor imaging indicating PD, by the Investigator using iRECIST, in clinically stable participants. In participants who discontinue study treatment, tumor imaging should be performed at the time of treatment discontinuation (±4-week window). If previous imaging was obtained within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory. In participants who discontinue study treatment due to documented disease progression, this is the final required tumor imaging. In participants who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imaging every 6 weeks ±7 days until either the start of a new anticancer treatment, disease progression, death, or the end of the study, whichever occurs first.