Pembrolizumab (Keytruda) - CAM 093

Description
Pembrolizumab (Keytruda) is a humanized monoclonal antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) and, if BRAF V600 mutation positive, a BRAF inhibitor.

Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. Pembrolizumab blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 (programmed death receptor-ligand 1) and PD-L2 (programmed death receptor-ligand 2), and may affect both tumor cells and healthy cells. Immune-mediated adverse reactions occurred with Pembrolizumab including pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism and hypothyroidism. Based on the severity of the adverse reaction, Pembrolizumab should be withheld or discontinued and corticosteroids administered. Based on its mechanism of action, Pembrolizumab may cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus.

Policy
Pembrolizumab for the treatment of melanoma is considered MEDICALLY NECESSARY if all of the following criteria are met:

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated in:

Breast cancer, triple negative (high-risk, early stage)

Treatment of high-risk early stage triple-negative breast cancer, in combination with chemotherapy as neoadjuvant therapy, then continued as a single agent as adjuvant therapy following surgery

Breast cancer, triple negative (locally recurrent unresectable or metastatic)

Treatment of locally recurrent unresectable or metastatic triple-negative breast cancer (in combination with chemotherapy) in patients whose tumors express PD-L1 (combined positive score [CPS] ≥ 10) as determined by an approved test

Melanoma

For the treatment of patients with unresectable or metastatic melanoma. (1.1)
Adjuvant treatment of melanoma with lymph node(s) involvement following complete resection in adults and pediatric patients ≥12 years of age.

Non-Small Cell Lung Cancer (NSCLC)

As a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression [(Tumor Proportion Score (TPS) ≥ 50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations (1.2)
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 (1.2)
In combination with pemetrexed and carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC
As a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (t2a > 4 cm), II, or IIIA non-small cell lung cancer (NSCLC) with no PD-L1 testing required

Head and Neck Squamous Cell Cancer (HNSCC)

First-line treatment (in combination with platinum and fluorouracil) of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC)
First-line, single-agent treatment of metastatic or unresectable recurrent HNSCC in patients whose tumors express PD-L1 (CPS ≥ 1), as determined by an approved test

For the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy

Classical Hodgkin Lymphoma (cHL)

For the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after 2 or more prior lines of therapy

Urothelial Carcinoma

For treatment of Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors in patients who are ineligible for or have elected not to undergo cystectomy
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for platinum- containing chemotherapy
For the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (1.5)

Microsatellite Instability-High Cancer

For the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options
First line treatment for patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
Limitation of Use: The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established (1.6)

Gastric Cancer

First-line treatment (in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy) of locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.

Esophageal cancer

Treatment of recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in patients whose tumors express PD-L1 (CPS ≥ 10) as determined by an approved test, with disease progression after one or more prior lines of systemic therapy
Treatment of locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation (in combination with platinum- and fluoropyrimidine-based chemotherapy)

Cervical Cancer

Treatment of persistent, recurrent, or metastatic cervical cancer (in combination with chemotherapy, with or without bevacizumab) in patients whose tumors express PD-L1 (CPS ≥ 1), as determined by an approved test
Keytruda is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumor express PD-L1 [Combined Positive Score (CPS > 1)] as determined by an FDA-approved test

Primary Mediastinal large B-cell Lymphoma (PMBCL)

Keytruda is indicated for the treatment of adult and pediatric patients with refractory PMBCL who have relapsed after 2 or more prior lines of therapy.
Limitation of use: Not recommended for treatment of PMBCL in patients who require urgent cytoreductive therapy

Malignant pleural mesothelioma
Mycosis fungoides/Sézary syndrome, relapsed/refractory

Hepatocellular Carcinoma (HCC)

For the treatment of patients with HCC who have been previously treated with sorafenib

Merkel Cell Carcinoma (MCC)

For the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma

Renal Cell Carcinoma (RCC)

In combination with axitinib, for the first-line treatment of patients with advanced RCC

Endometrial Carcinoma

Treatment (in combination with lenvatinib) of advanced endometrial carcinoma that is mismatch repair proficient (pMMR) (as determined by an approved test), or not microsatellite instability-high (MSI-H), in patients with disease progression following prior systemic therapy (in any setting) and are not candidates for curative surgery or radiation.
Treatment (as a single agent) of advanced endometrial carcinoma that is MSI-H or mismatch repair deficient (dMMR) (as determined by an approved test) in patients with disease progression following prior systemic therapy (in any setting) and are not candidates for curative surgery or radiation.

Cutaneous squamous cell carcinoma

Treatment of recurrent or metastatic or locally advanced cutaneous squamous cell carcinoma not curable by surgery or radiation

Tumor mutational burden-high cancer

Treatment of unresectable or metastatic, tumor mutational burden-high solid tumors (TMB-H; ≥ 10 mutations/megabase [mut/Mb]; as determined by an approved test) in adult and pediatric patients who have progressed following prior treatment and have no satisfactory alternative treatment options

Uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) aremedically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Benefits Application
This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore, member benefit language should be reviewed before applying the terms of this medical policy.

References

U.S. Food and Drug Administration. (2014, September). Center for Drug Evaluation and Research. Keytruda^® (pembrolizumab) for injection, for intravenous use. Retrieved September 8, 2014 from http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf.
Pembrolizumab (Keytruda). Highlights of prescribing information. September 2014. Available at: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

Coding Section

Code	Number	Description
CPT	81210	BRAF (v-raf murine sarcoma viral oncogene homolog B1) (e.g., colon cancer), gene analysis, V600E variant
	96413	Chemotherapy administration, IV infusion technique; up to 1 hour, single or initial substance/drug
	96414	each additional hour (list in addition to code for primary procedure)
ICD-9 Diagnosis	172.0 – 172.9	Malignant melanoma of skin (incompletely resected or unresectable, metastatic or recurrent melanoma)
	162.0 – 162.9	Malignant neoplasm of Bronchus (incompletely resected or unresectable, metastatic or recurrent melanoma)
ICD-9 Procedure
HCPCS	J9271	Injection, pembrolizumab, 1mg
	J9228	Injection, ipilimumab, 1 mg
ICD-10-CM (effective 10/01/15)	C43.0 – C43.9	Malignant melanoma of skin (incompletely resected or unresectable, metastatic or recurrent melanoma)
	C34.0 – C34.92	Malignant neoplasm of Bronchus (incompletely resected or unresectable, metastatic or recurrent melanoma)
	D03.0 – D03.9	Melanoma in situ (incompletely resected or unresectable, metastatic or recurrent melanoma)
ICD-10-PCS (effective 10/01/15)		ICD-10 codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure.
Type of Service
Place of Service

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

History From 2014 Forward

11/16/2023	Annual review, updating criteria verbiage for melanoma, gastric cancer, endometrial carcinoma, and cutaneous squamous cell carcinoma in the policy section.
05/01/2023	Interim review, removing HCPCS code C9027, adding HCPCS code J9271.
02/20/2023	Interim review to add coverage for NSCLC for a single agent, for adjuvant treatment following resection and platinum-based chemotherapy for adult patients. See bullet point #4.
11/29/2022	Annual review, adding coverage for endometrial carcinoma, updating verbiage for gastric cancer, head and neck squamous cell cancer, NSCLC, and renal cell cancer.
11/17/2021	Annual review, adding criteria for triple negative breast cancer, mycosis fungoides, additional criteria for esophogeal and cervical cancer.
11/16/2020	Annual review, expanding coverage to include esophageal, small cell lung, and cutaneous squamous cell carcinomas. Also adding tumor mutational burden-high cancer verbiage. Expanded for clarity head and neck squamous cell and urothelial cell carcinoma verbiage. No other changes made.
10/29/2020	Interim review to add the statement: uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) are medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.
11/01/2019	Annual review, updating policy verbiage to include medical necessity for recent FDA approval for treatment of hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma and endometrial carcinoma. No other changes.
11/14/2018	Annual review, updating policy to include medical necessity coverage for cervical cancer and primary mediastinal large B-cell Lymphoma (PMBCL), also adding list of compendial uses. No other changes
11/02/2017	Annual review, updating medical necessity criteria to allow for additional conditions based on FDA updated approvals made in September 2017. No other changes made.
11/01/2016	Annual review, updating to allow for medical necessity for head and neck squamous cell carcinomas.
11/09/2015	Annual review, adding medical necessity criteria related to NSCLC and coding. No other changes.
11/04/2015	Change Category from Medicine to Prescription Drug
11/04/2014	NEW POLICY

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Pembrolizumab (Keytruda) - CAM 093