KEYTRUDA, Pembrolizumab Form

Pembrolizumab (Keytruda®) is a programmed death receptor-1 (PD-1)-blocking antibody. Pediatrics X X X X
X X (excludes CNS tumor) FDA Approved Indication(s) Indication Melanoma Non-small cell lung cancer Head and neck squamous cell carcinoma Classical Hodgkin lymphoma Primary mediastinal large B-cell lymphoma Urothelial carcinoma Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer
(First-line treatment for colorectal cancer limited to adults.) Gastric cancer Esophageal cancer Cervical cancer Hepatocellular carcinoma Biliary tract cancer
Merkel cell carcinoma Renal cell carcinoma Endometrial carcinoma Tumor mutational burden-high (TMB-H) cancer Cutaneous squamous cell carcinoma Triple-negative breast cancer (TNBC) Off-label uses Mycosis fungoides Sezary syndrome Anal carcinoma Gestational trophoblastic neoplasia Extranodal NK/T-cell lymphoma Vulvar carcinoma Adrenocortical carcinoma Alveolar soft part sarcoma Thymic carcinoma Anaplastic large cell lymphoma Adults X X X X X X X X X X X X X X X X X X X X X X X X X X X X Page 1 of 29

CLINICAL POLICY
Pembrolizumab Indication Small cell lung cancer Kaposi sarcoma
Glioma
*If a solid tumor is characterized as MSI-H/dMMR or TMB-H, see criteria at Sections I.G or I.N respectively Adults X X Pediatrics X Keytruda is indicated: • Melanoma
o For the treatment of patients with unresectable or metastatic melanoma. o For the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection. • Non-small cell lung cancer (NSCLC)
o 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. o In combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as first- line treatment of patients with metastatic squamous NSCLC. o As a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) ≥ 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:  Stage III where patients are not candidates for surgical resection or definitive chemoradiation, or  Metastatic. o 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. o For the treatment of patients with resectable (tumors ≥ 4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. o As a single agent for the adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC.
• Head and neck squamous cell cancer (HNSCC) o In combination with platinum and fluorouracil (FU) for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC. o As a single agent for the first line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 1] as determined by an FDA-approved test. o As a single agent for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum containing chemotherapy. • Classical Hodgkin lymphoma (cHL) o For the treatment of adult patients with relapsed or refractory cHL. o For the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy. Page 2 of 29

CLINICAL POLICY
Pembrolizumab • Primary mediastinal large B-cell lymphoma (PMBCL) o For the treatment of adult and pediatric patients with refractory PMBCL, or who have relapsed after 2 or more prior lines of therapy.
o Limitations of use: Keytruda is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. • Urothelial carcinoma o In combination with enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.
o As a single agent for the treatment of patients with locally advanced or metastatic urothelial carcinoma:  who are not eligible for any platinum-containing chemotherapy, or  who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. o As a single agent for the treatment of patients with Bacillus Calmette-Guerin (BCG)- unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy. • Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) cancer o For the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. • Microsatellite instability-high or mismatch repair deficient colorectal cancer (CRC) o For the treatment of patients with unresectable or metastatic MSI-H or dMMR CRC as determined by an FDA-approved test. • Gastric cancer
o In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test.* o In combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2- negative gastric or GEJ adenocarcinoma. • Esophageal cancer
o For the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
• In combination with platinum- and fluoropyrimidine-based chemotherapy, or • As a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥ 10) as determined by an FDA approved test. • Cervical cancer o In combination with chemoradiotherapy (CRT) for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer. Page 3 of 29

CLINICAL POLICY
Pembrolizumab o In combination with chemotherapy, with or without bevacizumab, for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥ 1) as determined by an FDA-approved test. o As a single agent 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. • Hepatocellular carcinoma (HCC) o For the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.
• Biliary tract cancer (BTC) o In combination with gemcitabine and cisplatin for the treatment of patients with locally advanced unresectable or metastatic BTC.
• Merkel cell carcinoma (MCC) o For the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC. • Renal cell carcinoma (RCC) o In combination with axitinib, for the first-line treatment of adult patients with advanced RCC. o In combination with lenvatinib, for the first-line treatment of adult patients with advanced RCC. • o For the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Endometrial carcinoma o In combination with lenvatinib, for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA- approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. o As a single agent for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. • Tumor mutational burden-high (TMB-H) cancer o For the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.* o Limitations of use: The safety and effectiveness of Keytruda in pediatric patients with TMB-H central nervous system cancers have not been established. • Cutaneous squamous cell carcinoma (cSCC) o For the treatment of patients with recurrent or metastatic cSCC or locally advanced cSCC that is not curable by surgery or radiation. • Triple-negative breast cancer (TNBC) o For the treatment of patients with high-risk early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. Page 4 of 29

CLINICAL POLICY
Pembrolizumab o In combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10) as determined by an FDA approved test. • Adult cHL and adult PMBCL o For use at an additional recommended dosage of 400 mg every 6 weeks for cHL and PMBCL in adults.** _

• 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. ** This indication is approved under accelerated approval based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. Continued approval for this dosing may be contingent upon verification and description of clinical benefit in the confirmatory trials. Contents: I. Initial Approval Criteria A. Melanoma
  B. Non-Small Cell Lung Cancer
  C. Head And Neck Squamous Cell Cancer D. Classical Hodgkin Lymphoma E. Primary Mediastinal Large B-Cell Lymphoma F. Urothelial Carcinoma G. Microsatellite Instability-High Cancer H. Gastric Cancer, Esophageal Cancer, or Gastroesophageal Junction Cancer
  I. Cervical Cancer J. Hepatocellular Carcinoma K. Biliary Tract Cancer
  L. Merkel Cell Carcinoma M. Renal Cell Carcinoma N. Endometrial Carcinoma O. Tumor Mutational Burden-High Cancer P. Cutaneous Squamous Cell Carcinoma Q. Triple Negative Breast Cancer R. Glioma (off-label) S. Adult NCCN Recommended Uses (off-label) II. Continued Therapy III. Diagnoses/Indications for which coverage is NOT authorized IV. Appendices/General Information V. Dosage and Administration VI. Product Availability VII. References Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
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  CLINICAL POLICY
  Pembrolizumab It is the policy of health plans affiliated with Centene Corporation® that Keytruda is medically necessary when the following criteria are met:
  I. Initial Approval Criteria
  A. Melanoma (must meet all):

  1. Diagnosis of melanoma;
  2. Prescribed by or in consultation with an oncologist;
  3. Age ≥ 12 years;
  4. Disease is Stage IIB, IIC, III, recurrent, unresectable, or metastatic;
  5. Prescribed as one of the following (a, b, or c):
     a. A single agent; b. In combination with Lenvima® or Yervoy®; c. In combination with Mekinist® and Trafinlar® for disease with BRAF V600 activating mutation;
  6. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks (for a maximum of 12 months if adjuvant treatment); b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Non-Small Cell Lung Cancer (must meet all):
  7. Diagnosis of NSCLC;
  8. Prescribed by or in consultation with an oncologist;
  9. Age ≥ 18 years;
  10. One of the following (a or b):
      a. Disease is resectable or resected;
      b. Disease is recurrent, advanced, or metastatic, and request meets one of the following (i, ii, iii, iv, v, or vi): i. Disease mutation status is negative for actionable biomarkers (EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, and ERBB2 [HER2]); ii. Disease mutation status is positive for EGFR S768I, L861Q, and/or G719X, and member has received prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib; iii. Disease mutation status is positive for EGFR exon 19 deletion or L858R, and member has received prior erlotinib ± (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib; iv. Disease mutation status is positive for ROS1 rearrangement, and member has received prior crizotinib, entrectinib, or ceritinib; v. Disease mutation status is positive for ALK rearrangement, and member has received prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib; Page 6 of 29

  CLINICAL POLICY
  Pembrolizumab vi. Disease mutation status is positive for EGFR exon 20, KRAS G12C, NRTK1/2/3, BRAF V600E, MET exon 14 skipping, RET rearrangement, or ERBB2 (HER2); *Prior authorization may be required

  5. Keytruda is prescribed in one of the following ways (a, b, c, d, or e): a. For PD-L1 positive disease (TPS ≥ 1%); b. In combination with a chemotherapy regimen (see Appendix B); c. In combination with a chemotherapy regimen (see Appendix B) as neoadjuvant treatment, followed by single-agent adjuvant treatment after surgery for patients with resectable (tumors ≥ 4 cm or node positive) disease;
     d. As single-agent continuation maintenance therapy if previously given first line as part of a chemotherapy regimen; e. As single-agent adjuvant treatment following resection and platinum-based chemotherapy (e.g., cisplatin, carboplatin) for adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA disease;
  6. Member does not have contraindications to PD-1/PD-L1 inhibitor therapy (e.g., Opdivo®, Yervoy, Tecentriq®, Imfinzi®) (see Appendix F);
  7. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum duration of one of the following (i, ii, or iii):
     i. 24 months;
     ii. 12 months if adjuvant treatment; iii. 12 weeks if neoadjuvant treatment, followed by 39 weeks of adjuvant treatment; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer C. Head and Neck Squamous Cell Carcinoma (must meet all):
  8. Diagnosis of HNSCC (locations include paranasal sinuses, larynx, pharynx, lip, oral cavity, salivary glands; may be occult primary – i.e., primary source unknown);
  9. Prescribed by or in consultation with an oncologist;
  10. Age ≥ 18 years;
  11. Disease is unresectable, recurrent, or metastatic;
  12. Keytruda is prescribed in one of the following ways (a, b, or c): a. In combination with platinum-containing chemotherapy and either FU, docetaxel, or gemcitabine; b. As a first-line single agent and the tumor expresses PD-L1 with a CPS of ≥ 1; c. As a single agent for disease that has progressed on or after platinum-containing chemotherapy (e.g., cisplatin, carboplatin);
  13. Request meets one of the following (a or b):* a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; Page 7 of 29

  CLINICAL POLICY
  Pembrolizumab b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
  Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer D. Classical Hodgkin Lymphoma (must meet all):

  1. Diagnosis of cHL;
  2. Prescribed by or in consultation with an oncologist or hematologist;
  3. Age ≥ 6 months;
  4. Keytruda is prescribed as single-agent therapy (adults or pediatrics) or in combination with GVD (gemcitabine, vinorelbine, liposomal doxorubicin) (adults only) in one of the following ways (a, b, c, or d): a. After hematopoietic stem cell transplant;
     b. For disease that is refractory to ≥ 1 line of systemic therapy (see Appendix B);
     c. Age ≥ 18 years: For disease that has relapsed after ≥ 1 line of systemic therapy (see Appendix B);
     d. Age ≥ 6 months to < 18 years: For disease that has relapsed after ≥ 2 lines of systemic therapy (see Appendix B);
  5. Request meets one of the following (a, b, or c): a. Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer E. Primary Mediastinal Large B-Cell Lymphoma (must meet all):
  6. Diagnosis of PMBCL;
  7. Prescribed by or in consultation with an oncologist or hematologist;
  8. Age ≥ 6 months;
  9. Disease is refractory to or has relapsed after ≥ 1 line of systemic therapy (see Appendix B);
  10. Prescribed in one of the following ways (a or b):
      a. As a single agent; b. For age ≥ 6 months to < 18 years only, in combination with Adcetris®;
  11. Request meets one of the following (a, b, or c):* a. Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; Page 8 of 29

  CLINICAL POLICY
  Pembrolizumab c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
  Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer F. Urothelial Carcinoma (must meet all):

  1. Diagnosis of urothelial carcinoma;
  2. Prescribed by or in consultation with an oncologist or urologist;
  3. Age ≥ 18 years;
  4. Keytruda is prescribed in one of the following ways (a, b, or c): a. In combination with Padcev® for locally advanced or metastatic disease; b. As a single agent for locally advanced or metastatic disease, and member is ineligible for or has previously received platinum-containing chemotherapy (e.g., cisplatin, carboplatin); c. As a single agent for the treatment of BCG-unresponsive, high-risk, NMIBC with CIS, and member is ineligible for or has elected not to undergo cystectomy (see Appendix D for BCG shortage information);
  5. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer G. Microsatellite Instability-High/Mismatch Repair Deficient Cancer (must meet all):
  6. Diagnosis of a solid tumor classified as MSI-H or dMMR (indicative of MMR gene mutation or loss of expression) (see Appendix E for examples of MSI-H solid tumors);
  7. Prescribed by or in consultation with an oncologist;
  8. Member meets one of the following (a or b): a. Age ≥ 6 months to < 18 years and request is not for first-line therapy; b. Age ≥ 18 years;
  9. Keytruda is prescribed in one of the following ways (a or b): a. As first-line or subsequent therapy for ampullary adenocarcinoma, CRC, gallbladder cancer, gastric cancer, GEJ cancer, intrahepatic/extrahepatic cholangiocarcinoma, non-nasopharyngeal head and neck cancer, occult primary tumor, pancreatic adenocarcinoma, or small bowel adenocarcinoma; b. As subsequent therapy for other solid tumors;
  10. Prescribed in one of the following ways (a or b):
      a. As a single agent; b. For gastric or GEJ cancers: as a single agent or in combination with platinum- and fluoropyrimidine-based chemotherapy; Page 9 of 29

  CLINICAL POLICY
  Pembrolizumab

  6. Request meets one of the following (a, b, or c): a. Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer H. Gastric Cancer, Esophageal Cancer, or Gastroesophageal Junction Cancer (must meet all):
  7. Diagnosis of gastric cancer, esophageal cancer, or GEJ cancer;
  8. Prescribed by or in consultation with an oncologist;
  9. Age ≥ 18 years;
  10. Disease is unresectable, locally advanced, recurrent, or metastatic;
  11. Keytruda is prescribed in one of the following ways (a, b, or c): a. In combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, and both (i and ii): i. HER2-positive gastric or GEJ adenocarcinoma; ii. Tumor expresses PD-L1 (CPS ≥ 1); b. In combination with platinum- and fluoropyrimidine-based chemotherapy, and either (i or ii): i. HER2-negative gastric or GEJ adenocarcinoma; ii. Esophageal carcinoma or GEJ squamous cell carcinoma; c. As a single agent after one or more prior lines of systemic therapy for members with tumors of squamous cell GEJ that express PD-L1 (CPS ≥ 10) (see Appendix B);
  12. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
      Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer I. Cervical Cancer (must meet all):
  13. Diagnosis of cervical cancer;
  14. Prescribed by or in consultation with an oncologist;
  15. Age ≥ 18 years;
  16. Prescribed in one of the following ways (a, b, or c): a. As a single agent, and (i, ii, and iii): i. Tumor expresses PD-L1 (CPS ≥ 1); Page 10 of 29

  CLINICAL POLICY
  Pembrolizumab ii. Disease is recurrent or metastatic; iii. Disease has progressed on or after ≥ 1 line of systemic therapy (see Appendix B); b. In combination with chemotherapy (e.g., paclitaxel/cisplatin, paclitaxel/carboplatin) with or without bevacizumab, and (i and ii): i. Tumor expresses PD-L1 (CPS ≥ 1); ii. Disease is persistent, recurrent, or metastatic; c. In combination with CRT, and (i): i. Disease is FIGO 2014 Stage III-IVA (see Appendix F);

  5. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer J. Hepatocellular Carcinoma (must meet all):
  6. Diagnosis of HCC;
  7. Prescribed by or in consultation with an oncologist;
  8. Age ≥ 18 years;
  9. One of the following (a or b):
     a. Disease progressed on or after therapy with Nexavar®, Lenvima, Stivarga®, or
     Cabometyx®, and both of the following (i and ii): i. Disease is classified as Child-Pugh Class A;
     ii. Member has not previously been treated with immune checkpoint inhibitor therapy (PD-L1/PD-1, e.g., Tecentriq, Opdivo); *Prior authorization may be required for Nexavar, Lenvima and Stivarga b. Prescribed as first line treatment;
  10. Prescribed as a single agent;
  11. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
      Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer K. Biliary Tract Cancer (must meet all):
  12. Diagnosis of BTC;
  13. Prescribed by or in consultation with an oncologist;
  14. Age ≥ 18 years;
  15. Disease is locally advanced unresectable or metastatic;
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  CLINICAL POLICY
  Pembrolizumab

  5. Prescribed in one of the following ways (a or b):
     a. In combination with gemcitabine and cisplatin;
     b. In combination with Lenvima as subsequent treatment for gallbladder cancer or cholangiocarcinoma;
  6. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer L. Merkel Cell Carcinoma (must meet all):
  7. Diagnosis of MCC;
  8. Prescribed by or in consultation with an oncologist;
  9. Age ≥ 6 months;
  10. Disease is recurrent, locally advanced, or metastatic;
  11. Prescribed as a single agent;
  12. Request meets one of the following (a, b, or c): a. Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
      Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer M. Renal Cell Carcinoma (must meet all):
  13. Diagnosis of RCC;
  14. Prescribed by or in consultation with an oncologist;
  15. Age ≥ 18 years;
  16. Keytruda is prescribed in one of the following ways (a, b, or c): a. In combination with Inlyta® or Lenvima, and disease is advanced (i.e., relapsed or stage IV); Prior authorization may be required for Inlyta and Lenvima. b. As single-agent adjuvant treatment, and member is at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions; c. As a single agent for relapsed or stage IV disease with non-clear cell histology (off-label); Page 12 of 29

  CLINICAL POLICY
  Pembrolizumab

  5. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months (combination therapy) or 12 months (monotherapy); b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer N. Endometrial Carcinoma (must meet all):
  6. Diagnosis of endometrial carcinoma;
  7. Prescribed by or in consultation with an oncologist;
  8. Age ≥ 18 years;
  9. Prescribed in one of the following (a or b): a. In combination with Lenvima and both of the following (i and ii): Prior authorization may be required for Lenvima i. Disease is pMMR or not MSI-H; *See criteria set I.G. for MSI-H/dMMR endometrial carcinoma ii. Progressed following prior systemic therapy (e.g., carboplatin/paclitaxel); b. In combination with carboplatin and paclitaxel for recurrent or Stage III-IV tumor;
  10. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
      Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer O. Tumor Mutational Burden-High Cancer (must meet all):
  11. Diagnosis of a solid tumor classified as TMB-H (i.e., ≥ 10 mutations/megabase [mut/Mb]) (see Appendix E for examples of TMB-H solid tumors);
  12. Prescribed by or in consultation with an oncologist;
  13. Age ≥ 6 months;
  14. Disease is unresectable or metastatic;
  15. One of the following (a or b): a. Disease has progressed following prior treatment; b. Prescribed as a first-line therapy for ampullary adenocarcinoma or pancreatic adenocarcinoma;
  16. Prescribed as a single agent;
  17. Request meets one of the following (a, b, or c):* a. Adults: Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; Page 13 of 29

  CLINICAL POLICY
  Pembrolizumab b. Pediatrics: Dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
  Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer P. Cutaneous Squamous Cell Carcinoma (must meet all):

  1. Diagnosis of cSCC;
  2. Prescribed by or in consultation with an oncologist;
  3. Age ≥ 18 years;
  4. Member is not a candidate for curative surgery or radiation;
  5. Prescribed as a single agent;
  6. Request meets one of the following (a or b): a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer Q. Triple Negative Breast Cancer (must meet all):
  7. Diagnosis of TNBC (i.e., estrogen receptor/progesterone receptor [ER/PR] negative and human epidermal growth factor receptor 2 [HER2]-negative);
  8. Prescribed by or in consultation with an oncologist;
  9. Age ≥ 18 years;
  10. One of the following (a or b): a. Disease is high-risk early-stage (see Appendix F), and: i. Prescribed in combination with chemotherapy (e.g., carboplatin, paclitaxel, doxorubicin, cyclophosphamide) as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery;
      b. Disease is locally recurrent unresectable or metastatic, and both of the following (i and ii): i. Tumor expresses PD-L1 (CPS ≥ 10); ii. Prescribed in combination with chemotherapy (e.g., paclitaxel, paclitaxel protein-bound, gemcitabine and carboplatin);
  11. Request meets one of the following (a or b):* a. Dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of (i or ii): i. High-risk, early-stage TNBC: 24 weeks as neoadjuvant therapy and 27 weeks as adjuvant therapy; ii. Locally recurrent unresectable or metastatic TNBC: 24 months; Page 14 of 29

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  Pembrolizumab b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
  Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer R. Glioma (off-label) (must meet all):

  1. Diagnosis of hypermutant tumor diffuse high-grade glioma;
  2. Prescribed by or in consultation with an oncologist;
  3. Age ≥ 6 months and < 18 years;
  4. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer S. NCCN Recommended Uses (off-label) (must meet all):
  5. Diagnosis of one of the following (a or b): a. Keytruda is prescribed as first-line or subsequent therapy: i. Stage IIB or III mycosis fungoides; ii. Stage IV Sezary syndrome; iii. Unresectable or metastatic adrenocortical carcinoma; iv. Alveolar soft part sarcoma; v. Metastatic or unresectable thymic carcinoma, and prescribed as a single agent; b. Keytruda is prescribed as single-agent subsequent therapy: i. Metastatic anal carcinoma, and member has not previously received Keytruda or Opdivo; ii. Gestational trophoblastic neoplasia; iii. Extranodal NK/T-cell lymphoma; iv. Advanced, recurrent, or metastatic PD-L1-positive (CPS ≥ 1) vulvar carcinoma; v. Relapsed or refractory cutaneous anaplastic large cell lymphoma; vi. Relapsed or primary progressive small cell lung cancer; vii. Endemic or classic Kaposi Sarcoma;
  6. Prescribed by or in consultation with an oncologist;
  7. Age ≥ 18 years;
  8. Dose is within FDA maximum limit for any FDA-approved indication or is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
     Medicaid/HIM – 6 months Commercial – 6 months or to the member’s renewal date, whichever is longer Page 15 of 29

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  Pembrolizumab T. Other diagnoses/indications (must meet 1 or 2):

  1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     II. Continued Therapy A. All Indications in Section I (must meet all):
  3. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Keytruda for a covered indication and has received this medication for at least 30 days;
  4. Member is responding positively to therapy;
  5. If request is for a dose increase, request meets one of the following (a, b, or c):* a. Adults (i, ii, iii, iv, or v): i. Melanoma: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks (for a maximum of 12 months if adjuvant treatment); ii. High-risk, early-stage TNBC: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 weeks as neoadjuvant therapy and 27 weeks as adjuvant therapy; iii. RCC monotherapy: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 12 months; iv. NSCLC: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum duration of one of the following (a, b, or c):
     a) 24 months;
     b) 12 months if adjuvant treatment; c) 12 weeks if neoadjuvant treatment, followed by 39 weeks of adjuvant treatment; v. All other FDA-approved indications: New dose does not exceed 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 24 months; b. Pediatrics (i or ii):
     i. cHL, PMBCL, MSI-H or dMMR cancer, MCC, TMB-H cancer: New dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 24 months; Page 16 of 29

  CLINICAL POLICY
  Pembrolizumab ii. Melanoma: New dose does not exceed 2 mg/kg up to 200 mg every 3 weeks for a maximum of 12 months; c. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). *Prescribed regimen must be FDA-approved or recommended by NCCN. Approval duration:
  Medicaid/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):

  1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     III. Diagnoses/Indications for which coverage is NOT authorized:
     A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents; B. Pediatric patients with MSI-H or TMB-H central nervous cancers. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALK: anaplastic lymphoma kinase BCG: Bacillus Calmette-Guerin BTC: biliary tract cancer cHL: classical Hodgkin lymphoma CIS: carcinoma in situ CNS: central nervous system
     CPS: combined positive score CRC: colorectal cancer CRT: chemoradiotherapy
     cSCC: cutaneous squamous cell carcinoma dMMR: mismatch repair deficient EGFR: epidermal growth factor receptor FDA: Food and Drug Administration GEJ: gastroesophageal junction HCC: hepatocellular carcinoma HER2: human epidermal growth factor receptor 2 HNSCC: head and neck squamous cell carcinoma
     MCC: Merkel cell carcinoma Page 17 of 29

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  Pembrolizumab MSI-H: microsatellite instability-high mut/Mb: mutations/megabase
  NCCN: National Comprehensive Cancer Network NMIBC: non-muscle invasive bladder cancer NSCLC: non-small cell lung cancer PD-1: programmed death protein 1 PD-L1: programmed death-ligand 1 PMBCL: primary mediastinal large B-cell lymphoma pMMR: mismatch repair proficient
  RCC: renal cell carcinoma ROS1: ROS proto-oncogene 1 TMB-H: tumor mutational burden-high TNBC: triple-negative breast cancer TPS: tumor proportion score Appendix B: Therapeutic Alternatives This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization. Drug Name Dosing Regimen Varies Dose Limit/ Maximum Dose Varies Varies Varies Section I.B: Non-Small Cell Lung Cancer
  Examples of drugs used in combination with Keytruda:
  • Carboplatin, cisplatin, pemetrexed, paclitaxel Examples of targeted therapies:
  • EGFR S768I, L861Q, and/or G719X targeted therapies: afatinib, osimertinib, erlotinib, gefitinib, dacomitinib • EGFR exon 19 deletion or L858R targeted therapies: erlotinib ± (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, dacomitinib • ROS1 targeted therapies: crizotinib, entrectinib, ceritinib • ALK rearrangement targeted therapies: crizotinib, ceritinib, alectinib, brigatinib, lorlatinib Section I.D: Classical Hodgkin Lymphoma Adults: Examples of chemotherapy regimens: • ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) • Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone) • BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, probarbazine, prednisone) • Brentuximab vedotin + AVD (doxorubicin, vinblastine, dacarbazine) Pediatrics: Examples of chemotherapy regimens • AVPC (doxorubicin, vincristine, prednisone, cyclophosphamide) • ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) • Brentuximab vedotin + bendamustine • ICE (ifosfamide, carboplatin, etoposide) Page 18 of 29

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  Pembrolizumab Drug Name Section I.E: Primary Mediastinal Large B-Cell Lymphoma Examples of drugs used in single- or multi-drug chemotherapy regimens: • Bendamustine, brentuximab vedotin, carboplatin, cisplatin, cyclophosphamide, cytarabine, dexamethasone, doxorubicin, etoposide, gemcitabine, ibrutinib, ifosfamide, lenalidomide, mesna, mitoxantrone, methylprednisolone, oxaliplatin, prednisone, procarbazine, rituximab, vincristine, vinorelbine ____ Various combinations of the listed drugs are components of the following chemotherapy regimens: CEOP, CEPP, DHAP, DHAX, EPOCH-R, ESHAP, GDP, GemOx, ICE, MINE, RCDOP, RCEOP, RCEPP, RCHOP, RGCVP Section I.F: Urothelial Carcinoma TICE® BCG (attenuated, live culture preparation of the Bacillus of Calmette and Guerin strain of Mycobacterium bovis for intravesical use). __ References for BCG dosing, dosing in the setting of a BCG shortage, and BCG shortage status are listed below and at Appendix D:

  1. TICE BCG package insert: https://www.fda.gov/vaccines-blood- biologics/vaccines/tice-bcg
  2. American Urological Association: Important message about the BCG shortage: https://www.auanet.org/about-us/bcg-shortage-info
  3. Centers for Disease Control’s current shortages page: https://www.fda.gov/vaccines-blood-biologics/safety-availability- biologics/cber-regulated-products-current-shortages Section I.H: Gastric, EGJ, and Esophageal Cancer
     Examples of drugs used in single- or multi-drug chemotherapy regimens: • Cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, fluorouracil, capecitabine, irinotecan, leucovorin, epirubicin, ramucirumab (for EGJ adenocarcinoma or esophageal adenocarcinoma only)
     ____ Trastuzumab may be added to some chemotherapy regimens for HER2 overexpression. Section I.I: Cervical Cancer
     Examples of drugs used in single- or multi-drug chemotherapy regimens:
     • Cisplatin, carboplatin, paclitaxel, docetaxel, bevacizumab, topotecan, fluorouracil, gemcitabine, ifosfamide, irinotecan, topotecan, mitomycin, pemetrexed, vinorelbine Page 19 of 29 Dosing Regimen Varies Dose Limit/ Maximum Dose Varies Varies Varies Varies
     Varies Varies Varies

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  Pembrolizumab Drug Name Examples of CRT regimens:
  • Cisplatin plus external beam radiation therapy (EBRT), followed by brachytherapy (BT) Section I.J: Hepatocellular Carcinoma
  Nexavar (sorafenib) Section I.J: Hepatocellular Carcinoma
  Lenvima (lenvatinib) Section I.J: Hepatocellular Carcinoma
  Stivarga (regorafenib) Section I.J: Hepatocellular Carcinoma
  Cabometyx (cabozantinib) Section I.M: Endometrial Carcinoma
  Examples of chemotherapy regimens: • Carboplatin/paclitaxel, cisplatin/docetaxel, cisplatin/doxorubicin, carboplatin/paclitaxel/bevacizumab, carboplatin/paclitaxel/trastuzumab, ifosfamide/paclitaxel, cisplatin/ifosfamide, everolimus/letrozole, temsirolimus, Keytruda (pembrolizumab) Dosing Regimen Dose Limit/ Maximum Dose 400 mg PO BID 12 mg PO QD (patients ≥ 60 kg) or 8 mg PO QD (patients < 60 kg)
  160 mg PO QD for the first 21 days of each 28- day cycle 60 mg PO QD Varies 800 mg/day 12 mg/day 160 mg/day on days 1 to 21, every 28 days
  60 mg/day Varies ____ Individual drugs used in combination regimens may also be used as monotherapy (refer to NCCN Uterine Neoplasms Guidelines) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings None reported Appendix D: Keytruda Therapy for Urinary Bladder CIS in the Event of a BCG Shortage • National Comprehensive Cancer Network (NCCN) information and recommendations: o Standard urinary bladder CIS therapy includes lesion resection followed by intravesical BCG.
  o The NCCN advises that in the event of a BCG shortage, BCG should be prioritized for induction of high-risk patients (e.g., high-grade T1 and CIS) and that, if feasible, Page 20 of 29

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  Pembrolizumab the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage. o If BCG is unavailable, the NCCN recommends the following alternatives:   Intravesical chemotherapy agents as first-line and subsequent therapy (e.g., gemcitabine, mitomycin, epirubicin, valrubicin, docetaxel, sequential gemcitabine/docetaxel, gemcitabine/mitomycin); Initial radical cystectomy if patient is a surgical candidate. • o The NCCN recommendations do not include off-label use of Keytruda as first-line or subsequent therapy in the absence of BCG failure. In its BCG June 2020 supply update sent to providers, Merck confirms a path forward to expand BCG manufacturing but cautions that the expansion could take years to fully realize. Merck directs providers to their wholesalers and distributors for supply questions and also provides its National Service Center number (800-672-6372) for additional information. __

  1. National Comprehensive Cancer Network Guidelines. Bladder Cancer Version 5.2020. Available at https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed July 10, 2020.
  2. Merck Supply Update: TICE BCG LIVE (for intravesical use). June 2020. Appendix E: Examples of Solid Tumors per Pivotal Trials by “N” (descending)
     MSI-H Solid Tumors CRC Endometrial cancer Biliary cancer Gastric or GE junction cancer Pancreatic cancer Small intestinal cancer Breast cancer Prostate cancer Bladder cancer Esophageal cancer Sarcoma Thyroid cancer Retroperitoneal adenocarcinoma Small cell lung cancer
     Renal cell cancer Additional examples – NCCN compendium: Adrenal tumor, ampullary adenocarcinoma, cervical / vulvar / ovarian / fallopian tube / primary peritoneal cancer, chondroma, Ewing sarcoma, occult primary carcinoma, osteosarcoma, penile cancer, small bowel adenocarcinoma, testicular cancer, vulvar cancer TMB-H Solid Tumors Small cell lung cancer Cervical cancer Endometrial cancer Anal cancer Vulvar cancer Neuroendocrine cancer Salivary cancer Thyroid cancer Mesothelioma cancer Additional examples – NCCN compendium: Adrenal tumor, ampullary adenocarcinoma, breast cancer, chondroma, cutaneous angiosarcoma, Ewing sarcoma, myxofibrosarcoma, nasopharynx cancer, occult primary carcinoma, osteosarcoma, pancreatic cancer, prostate cancer, testicular cancer, undifferentiated sarcoma or pleomorphic sarcoma Page 21 of 29

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  Pembrolizumab Appendix F: General Information • High-risk early-stage TNBC was defined as tumor size > 1 cm but ≤ 2 cm in diameter with nodal involvement or tumor size > 2 cm in diameter regardless of nodal involvement in the pivotal KEYNOTE-522 study. • Although Keytruda’s approval for small cell lung cancer was withdrawn due to lack improvement in overall survival in phase 3 randomized trial data, the NCCN continues to recommend this use, stating that “pembrolizumab [is] just as effective as, and sometimes better than, the other subsequent therapy options.” • Per NCCN, contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents, or presence of an oncogene (i.e., EGFR exon 19 deletion or exon 21 L858R, ALK rearrangements), which has been shown to be associated with less benefit. • FIGO 2014 Stage III-IVA cervical cancer is defined as tumor involvement of the lower vagina with or without extension onto pelvic sidewall or hydronephrosis/non-functioning kidney or has spread to adjacent pelvic organs.
  V. Dosage and Administration Indication Pediatrics cHL, PMBCL, MSI-H or dMMR cancer, MCC, TMB-H cancer
  Melanoma Dosing Regimen Maximum Dose 2 mg/kg IV every 3 weeks up to 24 months 200 mg every 3 weeks 2 mg/kg IV every 3 weeks up to 12 months 200 mg every 3 weeks Adults Melanoma NSCLC HNSCC, cHL, PMBCL, urothelial carcinoma, MSI-H or dMMR cancer (including endometrial carcinoma), gastric cancer, esophageal cancer, cervical cancer, HCC, 200 mg IV every 3 weeks OR 400 mg every 6 weeks If adjuvant therapy up to 12 months 200 mg IV every 3 weeks OR 400 mg every 6 weeks up to 24 months OR up to 12 months for adjuvant treatment* OR 12 weeks for neoadjuvant treatment* followed by adjuvant treatment for 39 weeks __ As single-agent therapy or in combination with chemotherapy *As single-agent therapy ** In combination with chemotherapy 200 mg IV every 3 weeks OR 400 mg every 6 weeks up to 24 months __ *Esophageal cancer, gastric cancer, or HNSCC: as single-agent therapy or in combination with chemotherapy. 200 mg every 3 weeks OR 400 mg every 6 weeks 200 mg every 3 weeks OR 400 mg every 6 weeks 200 mg every 3 weeks OR 400 mg every 6 weeks Page 22 of 29

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  Pembrolizumab Indication BTC, MCC, TMB-H cancer, cSCC RCC (combination therapy) RCC (monotherapy) Non-MSI-H/pMMR endometrial carcinoma (combination therapy) TNBC Maximum Dose 200 mg every 3 weeks OR 400 mg every 6 weeks 200 mg every 3 weeks OR 400 mg every 6 weeks 200 mg every 3 weeks OR 400 mg every 6 weeks 200 mg every 3 weeks OR 400 mg every 6 weeks Dosing Regimen For cervical cancer: as single-agent therapy or in combination with chemotherapy or CRT For urothelial carcinoma: as single-agent therapy or in combination with Padcev. For BTC: in combination with chemotherapy 200 mg IV every 3 weeks OR 400 mg every 6 weeks in combination with axitinib or lenvatinib up to 24 months 200 mg IV every 3 weeks OR 400 mg every 6 weeks for up to 12 months 200 mg IV every 3 weeks OR 400 mg every 6 weeks in combination with lenvatinib up to 24 months 200 mg IV every 3 weeks OR 400 mg every 6 weeks for the following durations: • High-risk early-stage TNBC – neoadjuvant: 24 weeks • High-risk early-stage TNBC – adjuvant: 27 weeks • Locally recurrent unresectable metastatic TNBC: 24 months __ In combination with chemotherapy for high- risk early-stage TNBC when used as neoadjuvant treatment and for locally recurrent unresectable or metastatic TNBC. VI. Product Availability
  Solution, single-dose vial: 100 mg/4 mL VII.