Commercial

Medical Policy

Notification

Nivolumab (Opdivo®)

Notification Issue Date:

This version of the policy will become effective 09/14/2020.

This policy was updated to communicate the Company's coverage position for nivolumab (Opdivo®), in accordance with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN). Applicable codes have been added to the policy due to criteria changes.

Title:

Nivolumab (Opdivo®)

Policy #:

08.01.62c

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

INDEX OF MEDICALLY NECESSARY INDICATIONS

This policy addresses numerous medically necessary indications for the use of nivolumab (Opdivo) (listed in order of appearance within the Policy section). Please see below for the specific medical necessity criteria. (NOTE: Experimental/Investigational section below must also be reviewed).

Types of Cancer	Subtypes of Cancer
Anal carcinoma
Bone cancer
Central nervous system (CNS) cancers	Adults Pediatrics
Cervical cancer
Gastric cancer	HER2 overexpression negative disease Microsatellite instability-high cancer
Gastroesophageal junction cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma	Microsatellite instability-high cancer
Gestational trophoblastic neoplasia
Hepatocellular carcinoma (HCC)
Head and neck carcinoma	Squamous cell carcinoma of the head and neck Cancer of the nasopharynx Very advanced head and neck cancer
Hodgkin lymphoma	Adults Pediatrics
Kaposi sarcoma
Peritoneal mesothelioma
Malignant pleural mesothelioma
Melanoma	Cutaneous Uveal
Merkel cell carcinoma
Microsatellite instability-high (MSI-H)/ Tumor mutation burden-high (TMB-H)	Ampullary adenocarcinoma Appendiceal adenocarcinoma Colorectal Colon Biliary tract cancer Rectal Small bowel adenocarcinoma
Non-small cell lung cancer (NSCLC)
Pediatric aggressive mature B-cell lymphomas
Renal cell carcinoma (RCC)
Small cell lung cancer
Soft tissue sarcoma	Extremity/Body Wall, Head/Neck Retroperitoneal/Intra-Abdominal Rhabdomyosarcoma Angiosarcoma
T-cell lymphomas - extranodal NK/T-cell lymphomas
Urothelial carcinoma	Bladder Primary carcinoma of the urethra Upper genitourinary tract tumors Urothelial carcinoma of the prostate
Uterine neoplasms
Vulvar cancer

MEDICALLY NECESSARY

INITIAL THERAPY

ANAL CARCINOMA
Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent for metastatic squamous cell anal carcinoma as a National Comprehensive Cancer Network (NCCN)-preferred second-line or subsequent therapy, if neither nivolumab or pembrolizumab were previously received.

BONE CANCER

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of chondrosarcoma, osteosarcoma, chordoma, or Ewing sarcoma in combination with ipilimumab for unresectable or metastatic disease that has progressed following prior treatment and who have no satisfactory alternative treatment options for tissue tumor mutation burden-high (TMB-H) tumors with 10 or more mutations per megabase.

CENTRAL NERVOUS SYSTEM CANCERS
Limited brain metastases in adults

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the following:

Single-agent for limited brain metastases in individuals with PD-L1–positive NSCLC, in one of the following scenarios:
- Initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
- For recurrent brain metastases
- Treatment for relapsed disease with either stable systemic disease or reasonable systemic treatment options
In combination with ipilimumab (NCCN-preferred) or as a single agent for limited brain metastases in individuals with BRAF nonspecific melanoma, in one of the following scenarios:
- Initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
- For recurrent brain metastases
- Treatment for relapsed disease with either stable systemic disease or reasonable systemic treatment options

Extensive brain metastases in adults

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the following:

Single-agent treatment for extensive brain metastases in individuals with PD-L1–positive NSCLC
- Primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
- Treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options
In combination with ipilimumab (NCCN-preferred) or as a single agent for extensive brain metastases in individuals with BRAF nonspecific melanoma, in one of the following scenarios:
- Primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
- Treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options

Diffuse high-grade gliomas in pediatrics

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in one of the following scenarios:

Adjuvant treatment in individuals less than 3 years old for hypermutant tumor (excluding diffuse midline glioma, H3 K27-altered or pontine location)
Adjuvant treatment in individuals 3 years or older following standard brain radiation therapy (RT) with or without concurrent temozolomide
Systemic treatment (NCCN preferred) in individuals with recurrent or progressive disease for hypermutant tumor (excluding oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant)

CERVICAL CANCER

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for cervical cancer as NCCN-preferred second-line or subsequent therapy as a single agent if PD-L1 positive (combined positive score [CPS] ≥1) as determined by a US Food and Drug Administration (FDA)-approved assay or a validated test performed in a CLIA-certified lab for one of the following:

Local/regional recurrence
Stage IVB or recurrence with distant metastases

GASTRIC CANCER

HER2 overexpression negative disease

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for HER2 overexpression negative disease for any of the following:

Primary treatment for medically fit individuals with surgically unresectable locoregional disease, in combination with oxaliplatin and fluorouracil or capecitabine (PD-L1 CPS ≥5) (NCCN-preferred)
Palliative therapy for individuals who are not surgical candidates or have unresectable, locally advanced, recurrent, or metastatic disease and Karnofsky performance score 60% or greater or Eastern Cooperative Oncology Group (ECOG) performance score 2 or less as first-line therapy in combination with oxaliplatin and fluorouracil or capecitabine (PD-L1 CPS ≥5) (if no prior tumor progression while on therapy with a checkpoint inhibitor) (NCCN-preferred)

Microsatellite instability-high (MSI-H)/ Deficient mismatch repair (dMMR) cancer

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for dMMR/MSI-H tumors for any of the following:

Primary treatment in combination with ipilimumab for dMMR/MSI-H tumors with one of the following scenarios

Unresectable locoregional disease and are medically fit for surgery (NCCN-preferred regimen)
Neoadjuvant or perioperative immunotherapy for potentially resectable locoregional disease (cT2 or higher, any N) and if medically fit for surgery

Perioperative treatment as a single agent as postoperative management following R0 resection in individuals who received preoperative treatment with nivolumab and ipilimumab
First-line palliative therapy in combination with ipilimumab (if no prior tumor progression while on treatment with a checkpoint inhibitor) in individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and good PS 60% or greater [ECOG 0-2]
First-line palliative therapy in combination with oxaliplatin and fluorouracil or capecitabine (if no prior tumor progression while on treatment with a checkpoint inhibitor) in individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and good PS 60% or greater [ECOG 0-2]
Subsequent or second-line palliative therapy in combination with ipilimumab (if no prior tumor progression while on treatment with a checkpoint inhibitor) for individuals with locoregional disease who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and good PS 60% or greater [ECOG 0-2]

GASTROESOPHAGEAL JUNCTION CANCER, ESOPHAGEAL ADENOCARCINOMA/SQUAMOUS CELL

Non-microsatellite instability-high cancer

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for any of the following:
First-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC), in combination with ipilimumab (Yervoy)
First-line treatment of unresectable advanced or metastatic ESCC, in combination with fluoropyrimidine- and platinum-based chemotherapy
Unresectable advanced, recurrent, or metastatic ESCC after prior fluoropyrimidine- and platinum-based chemotherapy
Adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in individuals who have received neoadjuvant chemoradiotherapy (CRT)
Advanced or metastatic gastric cancer, gastroesophageal junction cancer or esophageal adenocarcinoma, in combination with fluoropyrimidine- and platinum-containing chemotherapy
Postoperative therapy (NCCN-preferred) for individuals who have received preoperative chemoradiation and R0 resection and residual disease (yp T positive and/or N positive)
Palliative therapy for HER2 overexpression–negative individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and Karnofsky performance score 60% or greater [ECOG 0-2] as preferred first-line therapy in combination with oxaliplatin and fluorouracil or capecitabine (PD-L1 CPS ≥5) for adenocarcinoma only (if no prior tumor progression while on therapy with a checkpoint inhibitor)
Palliative therapy in individuals with esophageal squamous cell carcinoma (SCC) if no prior tumor progression while on therapy with a checkpoint inhibitor and are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and Karnofsky performance score 60% or greater [ECOG 0-2] as

second-line or subsequent therapy (NCCN-preferred) as a single agent
first-line therapy (NCCN-preferred) in combination with fluorouracil or capecitabine and cisplatin or oxaliplatin
first-line therapy (NCCN-preferred) in combination with ipilimumab

Microsatellite instability-high cancer (MSI-H)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for dMMR/MSI-H tumors for any of the following:

Primary treatment as neoadjuvant or perioperative immunotherapy in individuals medically fit for surgery in combination with ipilimumab for adenocarcinoma tumors that is cT2, N0 (high-risk lesions: lymphovascular invasion, ≥ 3cm, poorly differentiated), cT1b-cT2, N+ or cT3-cT4a, Any N disease
Palliative treatment in individuals with good PS 60% or greater [ECOG 0-2] who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease in one of the following scenarios:

First-line treatment with ipilimumab regardless of PD-L1 status if no tumor progression while on therapy with a checkpoint inhibitor (NCCN-preferred regimen)
First-line treatment with oxaliplatin and fluorouracil or capecitabine regardless of PD-L1 status if no tumor progression while on therapy with a checkpoint inhibitor (NCCN-preferred regimen)
Second-line or subsequent therapy with ipilimumab if no tumor progression while on therapy with a checkpoint inhibitor

Perioperative treatment as a single agent for adenocarcinoma tumors as postoperative management following R0 resection in individuals who received preoperative treatment with nivolumab and ipilimumab

GESTATIONAL TROPHOBLASTIC NEOPLASIA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for gestational trophoblastic neoplasia that is resistant to multiagent chemotherapy in those with one of the following conditions:

High-risk disease (NCCN-preferred regimen)
Recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor)

HEPATOCELLULAR CARCINOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with ipilimumab (Yervoy) for the treatment of individuals with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

First-line treatment as a single agent (Child-Pugh Class B only) in those with one of the following conditions:

Unresectable disease and are not a transplant candidate
Liver-confined disease, inoperable by performance status or comorbidity, or with minimal or uncertain extrahepatic disease
Metastatic disease or extensive liver tumor burden

Subsequent treatment as a single agent (Child-Pugh Class A or B only) who have not been previously treated with a checkpoint inhibitor, or in combination with ipilimumab (Child-Pugh Class A only) for progressive disease in individuals who have one of the following:

Unresectable disease and are not a transplant candidate
Liver-confined disease, inoperable by performance status or comorbidity, or with minimal or uncertain extrahepatic disease
Metastatic disease or extensive liver tumor burden

HEAD AND NECK CANCERS

Squamous cell carcinoma of the head and neck

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for the treatment of recurrent or metastatic SCC of the head and neck with disease progression on or after a platinum-based therapy.

Cancer of the nasopharynx (squamous cell carcinoma with mixed subtypes)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in the following regimens:

First-line systemic therapy, in combination with cisplatin and gemcitabine for T1-4, N0-3, M1 disease for (NCCN-preferred regimen):

Oligometastatic disease and PS 0-2
Widely metastatic disease and good PS (0-2)

Subsequent-line systemic therapy, if not previously used, in combination with cisplatin and gemcitabine for T1-4, N0-3, M1 disease for:

Oligometastatic disease and PS 0-2
Widely metastatic disease and good PS (0-2)

Very advanced head and neck cancer (squamous cell carcinoma with mixed subtypes)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in the following regimens:

Systemic therapy as a first-line or subsequent-line (note: if not previously used, may be considered in subsequent lines) option for nasopharyngeal cancer in combination with cisplatin and gemcitabine in individuals with performance status 0-1 for: unresectable locoregional recurrence with prior radiation therapy (RT), unresectable second primary with prior RT, unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases

Systemic therapy as a preferred alternate single agent subsequent-line option, if immunotherapy not previously used, for non-nasopharyngeal cancer if disease progression on or after platinum therapy in:
- PS 0-3 and persistent or progressive metastatic disease (M1) at initial presentation following first-line therapy
- Recurrent/persistent disease with distant metastases and PS 0-3
- Unresectable locoregional recurrence, unresectable second primary, or unresectable persistent disease with prior RT and PS 0-3
- Unresectable locoregional recurrence or persistent disease without prior RT and PS 3

Systemic therapy as a first-line or subsequent-line option for non-nasopharyngeal cancer in combination with cetuximab in individuals with performance status 0-1 for:

Metastatic (M1) disease at initial presentation

Recurrent/persistent disease with distant metastases

Unresectable locoregional recurrence, unresectable second primary, or unresectable persistent disease with prior radiation therapy (RT)

Systemic therapy for non-nasopharyngeal cancer in combination with cetuximab in individuals with resectable locoregional recurrence or persistent disease without prior radiation therapy (RT)

HODGKIN LYMPHOMA

Classical Hodgkin lymphoma in adults

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of adult individuals with classical Hodgkin lymphoma (cHL) that have relapsed, refractory, or refractory disease after any of the following:

Autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin (Adcetris)
Second-line in combination with brentuximab vedotin or ICE (ifosfamide, carboplatin, etoposide)
Subsequent therapy (if not previously used) for Deauville 4 or 5 following restaging with FDG-PET/CT in combination with brentuximab vedotin or ICE
Therapy as a single agent for refractory disease to at least 3 or more lines of therapy
Three or more lines of systemic therapy that includes autologous HSCT
Palliative therapy as a single agent, in adults ages 60 years and older with poor performance status or substantial comorbidities

Classical Hodgkin lymphoma in pediatric individuals

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of relapsed or refractory cHL in pediatric individuals who are heavily pretreated (with platinum or anthracycline-based chemotherapy) or if a decrease in cardiac function observed as:

Re-induction therapy or subsequent therapy (if not previously used) in combination with brentuximab vedotin
Re-induction therapy in combination with brentuximab vedotin and Involved-Site RT (ISRT), in highly favorable individuals (i.e., those who may avoid autologous stem cell rescue [ASCR]: initial stage other than IIIB or IVB, no prior exposure to RT, duration of CR1 >1 year, absence of extranodal disease or B symptoms at relapse)
Subsequent therapy (if not previously used) as a single agent

KAPOSI SARCOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of classic Kaposi Sarcoma in individuals with relapsed/refractory advanced cutaneous, oral, visceral, or nodal disease

Subsequent therapy in combination with ipilimumab (Yervoy) if progressed on or not responded to first-line systemic therapy, and progressed on alternate first-line systemic therapy

PERITONEAL MESOTHELIOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of peritoneal mesothelioma (including mesothelioma and tunica vaginalis testis mesothelioma), in combination with ipilimumab (Yervoy) (NCCN-preferred for biphasic or sarcomatoid histology; NCCN-other recommended regimen for epithelioid histology) as first-line systemic therapy for unresectable disease:

Diffuse peritoneal mesothelioma (PeM) with unicavitary, epithelioid histology that is medically inoperable and/or complete cytoreduction not achievable (including high-risk features, e.g., Ki-67 >9%, nodal metastasis, high tumor burden [Peritoneal Cancer Index (PCI) >17], completeness of cytoreduction [CC] score >1, biphasic disease, or bicavitary disease) and ECOG PS 0-2
Diffuse PeM with biphasic/sarcomatoid histology or bicavitary disease and ECOG PS 0-2
Recurrence of diffuse PeM with unicavitary, epithelioid histology after prior cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), if no previous adjuvant systemic therapy given and ECOG PS 0-2
Recurrence of benign multicystic or well-differentiated papillary peritoneal mesothelioma after prior CRS ± HIPEC for ECOG PS 0-2

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of PeM (including pericardial mesothelioma and tunica vaginalis testis mesothelioma), as a single agent or in combination with ipilimumab (Yervoy) as NCCN-preferred subsequent systemic therapy, if chemotherapy administered first-line and ECOG PS 0-2

MALIGNANT PLEURAL MESOTHELIOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of MPeM (including mesothelioma and tunica vaginalis testis mesothelioma):

First-line systemic therapy, in combination with ipilimumab (NCCN-preferred for biphasic epithelioid or sarcomatoid histology)

Unresectable clinical stage I-IIIA disease after surgical exploration (if induction chemotherapy was not given) and epithelioid histology
Clinical stage I-IIIA disease and have not undergone surgical exploration (if induction chemotherapy was not given) and epithelioid histology
Clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors in individuals with PS 0-2

First-line therapy for unresectable malignant pleural mesothelioma in combination with ipilimumab (Yervoy)
Subsequent systemic therapy (NCCN-preferred), as a single agent or in combination with ipilimumab (Yervoy), if chemotherapy administered first-line

MELANOMA

Cutaneous melanoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy or in combination with ipilimumab (Yervoy) for the treatment in individuals ages 12 years and older with unresectable or metastatic melanoma^** in one of the following regimen:

First-line systemic^* therapy (NCCN-preferred) combination checkpoint blockade preferred

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for the following regimens:

Adjuvant treatment in individuals ages 12 years and older with Stage IIB, Stage IIC, Stage III, or Stage IV melanoma who have undergone complete resection
Adjuvant treatment option for one of the following:

pathologically staged IIB/IIC disease following wide excision alone or wide excision with negative sentinel lymph node (SLN) biopsy
clinical stage IIIB/C/D disease following wide excision alone or wide excision with negative sentinel lymph node (SLN) biopsy after microscopic satellites found in biopsy specimen from primary lesion
clinical stage IIIB/C/D disease that is SLN negative or SLN biopsy not performed after microscopic satellites found in wide excision specimen

NCCN-preferred adjuvant systemic therapy option for one of the following:

Resected stage III sentinel node–positive disease during observation without additional nodal surgery and with mandatory radiographic nodal surveillance (NCCN-preferred) or after completion of lymph node dissection (CLND), based on risk of recurrence
Stage III disease with clinically positive node(s) following wide excision of primary tumor and therapeutic lymph node dissection (TLND) or neoadjuvant therapy
Stage III disease with clinical satellite/in-transit metastases if no evidence of disease (NED) after complete excision to clear margins
Local satellite/in-transit recurrence if NED after complete excision to clear margins
Resectable disease Ffollowing complete TLND, neoadjuvant therapy and/or complete excision of disease limited to nodal recurrence
If NED following metastasis-directed therapy (stereotactic ablative therapy or complete resection), or systemic therapy followed by resection for oligometastatic disease NCCN 1

NCCN-preferred systemic therapy option for initial treatment of limited resectable:

Stage III disease with clinical satellite/in-transit metastases
Local satellite/in-transit recurrence

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with ipilimumab (Yervoy) as NCCN-preferred second-line or subsequent systemic therapy^* option for metastatic or unresectable disease^** after progression, intolerance and/or projected risk of progression with BRAF targeted therapy:

as a single agent (if not previously used) or in combination with ipilimumab (Yervoy) if anti-PD-1 therapy was not previously used

in combination with ipilimumab (Yervoy) for disease progression on single-agent anti-PD-1 therapy

may be considered as re-induction therapy (as a single agent or in combination with ipilimumab (Yervoy)) if prior anti-PD-1 immunotherapy resulted in disease control (complete response, partial response, or stable disease) with no residual toxicity, and disease progression/relapse occurred >3 months after treatment discontinuation

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as adjuvant systemic therapy in combination with with ipilimumab (Yervoy) (NCCN-preferred) if NED following metastasis-directed therapy (stereotactic ablative therapy, T-VEC/intralesional therapy or complete resection), or systemic therapy followed by resection for oligometastatic disease

^*Systemic therapy is preferred by NCCN for unresectable or widely disseminated distant metastatic disease.
^**Metastatic disease includes stage III unresectable/borderline resectable disease with clinically positive node(s) or clinical satellite/in-transit metastases, or as well as unresectable local satellite/in-transit recurrence, unresectable nodal recurrence, and widely disseminated distant metastatic disease.

Uveal melanoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy or in combination with ipilimumab (Yervoy) for the treatment of individuals with uveal melanoma who have metastatic or unresectable disease (NCCN-preferred regimen).

MERKEL CELL CARCINOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent for neoadjuvant treatment for the treatment of individuals with Merkel cell carcinoma as neoadjuvant treatment for regional, pathologic N+ disease.

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as systemic therapy for individuals with Merkel cell carcinoma M1 disseminated disease with or without surgery and/or radiation therapy as single-agent therapy or in combination with ipilimumab (Yervoy) if anti-PDL1 or anti-PD-1 therapy is contraindicated or there is disease progression on anti-PDL1 or anti-PD-1 therapy.

MICROSATELLITE INSTABILITY-HIGH AND Tumor mutational burden CANCER

Ampullary adenocarcinoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as first-line therapy in combination with ipilimumab (Yervoy)‡ in individuals with intestinal type disease if deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] for:

Unresectable localized disease
Stage IV resected ampullary cancer
Metastatic disease at initial presentation

‡May be followed by chemoradiation for palliative indications in those with good performance status (ECOG 0-1, with good biliary drainage and adequate nutritional intake).

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with ipilimumab as subsequent therapy for disease progression if dMMR/MSI-H.

Appendiceal adenocarcinoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy), if no previous treatment with a checkpoint inhibitor, for one of the following appendiceal adenocarcinoma regimens:

Initial systemic therapy for advanced or metastatic disease (dMMR/MSI-H only) if no previous treatment with immunotherapy, in individuals who are candidates for immunotherapy (excludes coverage when used in combination with ipilimumab in individuals who are not appropriate for intensive therapy)

Colorectal

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) for treatment for individuals ages 12 years and older with MSI-H or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following previous oxaliplatin-, irinotecan-, and fluoropyrimidine-based therapy

Colon 

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for as a single agent or in combination with ipilimumab (dMMR/MSI-H only)

As neoadjuvant therapy for clinical T4b disease (NCCN-preferred regimen)
As neoadjuvant therapy for resectable synchronous liver and/or lung metastases, if no previous treatment with a checkpoint inhibitor (NCCN-preferred regimen)
As Initial treatment for resectable metachronous metastases if no previous immunotherapy
For locally unresectable or medically inoperable disease (NCCN-preferred regimen)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for as a single agent or in combination with ipilimumab (dMMR/MSI-H only) if no previous treatment with a immunotherapy (note: regimens are excluded when used in combination with ipilimumab in individuals who are not appropriate for intensive therapy):

Following primary treatment for locally unresectable or medically inoperable disease
As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
For synchronous unresectable metastases
Treatment for unresectable metachronous metastases

Biliary tract cancer

(Gallbladder cancer, Intrahepatic Cholangiocarcinoma, Extrahepatic Cholangiocarcinoma)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as in combination with ipilimumab (Yervoy) in individuals with tumor mutational burden-high (TMB-H) as subsequent therapy (refractory to standard therapy or with no standard treatment options available) for progression on or after systemic treatment for unresectable or resected gross residual (R2) disease, or metastatic disease in those who have not been previously treated with a checkpoint inhibitor.

Rectal 

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) in individuals (dMMR/MSI-H only)if candidate for immunotherapy and if no prior immunotherapy received (note: regimens are excluded when used in combination with ipilimumab in individuals who are not appropriate for intensive therapy):

As primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant/definitive immunotherapy (NCCN preferred) or total neoadjuvant therapy
As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
As primary treatment for synchronous unresectable metastases of other sites
As primary treatment for unresectable isolated pelvic/anastomotic recurrence
As primary treatment for unresectable metachronous metastases

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for as a single agent or in combination with ipilimumab for individuals (dMMR/MSI-H only) with no previous treatment with a checkpoint inhibitor:

As neoadjuvant treatment for resectable synchronous liver only and/or lung only metastases (NCCN preferred)
As neoadjuvant treatment for resectable synchronous liver only and/or lung only metastases with CRM (by MRI) and previously treated with neoadjuvant radiation with or without concurrent chemotherapy (NCCN preferred)
As initial treatment for resectable metachronous metastases and no previous immunotherapy

Small bowel adenocarcinoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) for one of the following small bowel adenocarcinoma regimens:

Initial therapy for advanced or metastatic disease (dMMR/MSI-H only), if no previous treatment with a checkpoint inhibitor
Subsequent therapy for advanced or metastatic disease (dMMR/MSI-H only), if no previous treatment with a checkpoint inhibitor and no prior oxaliplatin exposure in the adjuvant setting or contraindication to oxaliplatin

NON-SMALL CELL LUNG CANCER

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with platinum-doublet chemotherapy as neoadjuvant treatment of adults with resectable (tumors 4 cm or larger or node positive) NSCLC.

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the following:

Induction systemic therapy as an alternative for individuals likely to receive adjuvant chemotherapy (for resectable disease, i.e., tumors 4 cm or larger or node positive), when both of the following criteria are met:

In combination with one of the following regimens:

Paclitaxel and carboplatin
Paclitaxel and cisplatin
Pemetrexed and cisplatin or carboplatin for those not candidates for cisplatin-based therapy (nonsquamous cell histology)
Gemcitabine and cisplatin or carboplatin for those not candidates for cisplatin-based therapy (squamous cell histology)

For one of the following conditions:

Operable stage IB (peripheral T2a, N0), stage I (central T2a, N0), stage II (T1abc-2ab, N1 or T2b, N0), stage IIB (T3, N0), or stage IIIA (T3, N1)
T3 invasion or resectable T4 extension, N0-1 disease in the chest wall, proximal airway, or mediastinum
Stage IIIA (T4, N0-1)
T1, N1 or T2-3, N0-1 (including T3 with multiple nodules in the same lobe)
Separate pulmonary nodule(s), same lobe (T3, N0-1), or ipsilateral nonprimary lobe (T4, N0-1)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with ipilimumab (Yervoy) for the following conditions:

First-line treatment of adults with recurrent, advanced, or metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, that are negative for actionable molecular biomarkers^†and no contraindications^†^† to PD-1 or PD-L1 inhibitors and PS 0-2 (not including locoregional recurrence or symptomatic local disease [except mediastinal lymph node recurrence with prior RT] with no evidence of disseminated disease)

In combination with ipilimumab
In combination with ipilimumab, pemetrexed and either carboplatin or cisplatin for nonsquamous cell histology
In combination with ipilimumab, paclitaxel and carboplatin for squamous cell histology

First-line treatment of adults with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations, in combination with ipilimumab and two cycles of platinum-doublet chemotherapy
First-line treatment of adults with metastatic NSCLC, with no EGFR or ALK genomic tumor aberrations, whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test in combination with ipilimumab
Recurrent, advanced or metastatic disease (not including locoregional recurrence or symptomatic local disease [except mediastinal lymph node recurrence with prior RT] with no evidence of disseminated disease) in individuals with PS 0-1 and no contraindications^†^† to PD-1 or PD-L1 inhibitors, when both of the following criteria are met:

In combination with one of the following regimens:

Ipilimumab
Ipilimumab, pemetrexed, and either carboplatin or cisplatin for nonsquamous cell histology
Ipilimumab, paclitaxel and carboplatin for squamous cell histology

For one of the following conditions:

Initial systemic therapy for PD-L1 <1% and negative for actionable molecular biomarkers^†
First-line therapy for

EGFR exon 20 mutation–positive tumors
KRAS G12C mutation–positive tumors
ERBB2 (HER2) mutation positive tumors

First-line or subsequent therapy for:

BRAF V600E-mutation–positive tumors
NTRK1/2/3 gene fusion–positive tumors
MET exon 14 skipping mutation–positive tumors
RET rearrangement–positive tumors

Subsequent therapy for EGFR S768I, L861Q, and/or G719X mutation–positive tumors and prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib therapy
Subsequent therapy for ROS1 rearrangement–positive tumors and prior crizotinib, entrectinib, or ceritinib therapy
Subsequent therapy for EGFR exon 19 deletion or exon 21 L858R tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib therapy
Subsequent therapy for ALK rearrangement positive tumors and prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib therapy

Continuation maintenance therapy in combination with ipilimumab for recurrent, advanced, or metastatic disease for PD-L1 expression–positive (≥1%) or PD-L1 expression <1% tumors that are negative for actionable molecular markers^† and no contraindications^†^† to PD-1 or PD-L1 inhibitors in individuals with PS 0-2 who achieve a response or stable disease following first-line therapy if nivolumab + ipilimumab ± chemotherapy given (not including locoregional recurrence or symptomatic local disease [except mediastinal lymph node recurrence with prior RT] with no evidence of disseminated disease)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for the following conditions:

Metastatic NSCLC who had progression on or after platinum-based chemotherapy
- Prior to receiving nivolumab (Opdivo), individuals with EGFR or ALK genomic tumor aberrations should have disease progression on an FDA-approved therapy (e.g., afatinib [Gilotrif], alectinib [Alecensa], brigatinib [Alunbrig], ceritinib [Zykadia], crizotinib [Xalkori], dacomitinib [Vizimpro], entrectinib [Rozlytrek], erlotinib [Tarceva], gefitinib [Iressa], lorlatinib [Lorbrena], osimertinib [Tagrisso])
NCCN-preferred subsequent therapy for recurrent, advanced, or metastatic disease in individuals with PS 0-2 and no prior progression on a PD-1/PD-L1 inhibitor (not including locoregional recurrence or symptomatic local disease [except mediastinal lymph node recurrence with prior RT] with no evidence of disseminated disease)

^†If there is insufficient tissue to allow testing for all of EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET and RET, repeat biopsy and/or plasma testing should be done. If these are not feasible, treatment is guided by available results and, if unknown, these individuals are treated as though they do not have driver oncogenes.

^††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 L858R, ALK rearrangements), which would predict lack of benefit.

Pediatric aggressive mature B-cell lymphomas

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent (NCCN-preferred) for primary mediastinal large B-cell lymphoma (PMBL) for individuals with relapsed or refractory disease.

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with brentuximab vedotin (Adcentris) (NCCN-preferred) for PMBL as consolidation/additional therapy for individuals with partial response after therapy for relapsed or refractory disease.

RENAL CELL CARCINOMA (RCC)/KIDNEY CANCER

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for the treatment of individuals with RCC, for the following regimens:

As single-agent therapy in individuals with advanced disease who have received prior antiangiogenic therapy (e.g., sorafenib [Nexavar], sunitinib [Sutent], bevacizumab [Avastin], pazopanib [Votrient], axitinib [Inlyta])
As single-agent therapy for relapse or stage IV disease
- As subsequent therapy for clear cell histology if immune-oncology therapy naïve
- As systemic therapy for non-clear cell histology
In combination with ipilimumab, for the first-line treatment of individuals with intermediate or poor risk
In combination with ipilimumab for four cycles, followed by single-agent nivolumab (Opdivo) for relapse or stage IV disease with clear cell histology as:

First-line therapy for favorable risk
NCCN-preferred first-line therapy for poor/intermediate risk
Subsequent therapy if immune-oncology therapy naïve or prior history immune-oncology therapy

In combination with cabozantinib for relapse or stage IV disease with clear cell histology as:

NCCN-preferred first-line therapy
Subsequent therapy if immune-oncology therapy naïve or prior history immune-oncology therapy

In combination with cabozantinib for relapse or stage IV disease as systemic therapy for non-clear cell histology
In combination with cabozantinib as first-line therapy

SMALL CELL LUNG CANCER (SCLC)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent for small cell lung cancer with no previous treatment with a checkpoint inhibitor with a chemotherapy-free interval of 6 months or less, as subsequent systemic therapy for individuals with PS 0-2 for one of the following:

Relapse following complete or partial response or stable disease with primary treatment

Primary progressive disease

SOFT TISSUE SARCOMA

Extremity/Body Wall, Head/Neck

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) as palliative therapy for advanced/metastatic disease with disseminated metastases for either of the following:

myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma, cutaneous angiosarcoma, and undifferentiated sarcomas

Unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase (mut/Mb) or greater] tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options regardless of soft tissue sarcoma sub-type

Retroperitoneal/Intra-Abdominal

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) for unresectable or progressive disease as alternative systemic therapy after initial therapy for unresectable or stage IV disease or as subsequent lines of therapy for recurrent unresectable or recurrent stage IV disease for either of the following:

myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma, cutaneous angiosarcoma, and undifferentiated sarcomas

Unresectable or metastatic TMB-H tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options regardless of soft tissue sarcoma sub-type

Pleomorphic Rhabdomyosarcoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as a single agent or in combination with ipilimumab (Yervoy) for advanced/metastatic disease as subsequent line of therapy (including for unresectable or metastatic TMB-H tumors, that have progressed following prior treatment and who have no satisfactory alternative treatment options

Angiosarcoma

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered in combination with ipilimumab (Yervoy) for advanced/metastatic or unresectable disease

T-CELL LYMPHOMAS - EXTRANODAL NK/T-CELL LYMPHOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as NCCN-preferred therapy for relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used, if a clinical trial is unavailable.

UROTHELIAL CARCINOMA (UC)

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for the treatment of one of the following indications: FDA

Adjuvant therapy for UC in individuals who are at high risk of recurrence after undergoing radical resection of UC
Locally advanced or metastatic UC in individuals with disease progression, in one of the following scenarios:

During or following platinum-containing chemotherapy
Within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

Bladder cancer

Adjuvant therapy for bladder cancer, in one of the following scenarios:

Stage II (cT2, N0) disease following cystectomy based on pathologic risk if no cisplatin neoadjuvant treatment was given and pT3,pT4a, or pN+

Stage II (cT2, N0) disease following cystectomy based on pathologic risk if cisplatin neoadjuvant treatment was given and ypT2-ypT4a or ypN+

Stage IIIA (cT3, N0; cT4a, N0; cT1-4a, N1) disease following cystectomy based on pathologic risk if no cisplatin neoadjuvant treatment was given and pT3, pT4a, or pN+

Stage IIIA (cT3, N0; cT4a, N0; cT1-4a, N1) disease following cystectomy based on pathologic risk if cisplatin neoadjuvant treatment was given ypT2-ypT4a or ypN+

Second-line systemic therapy postplatinum or other chemotherapy for bladder cancer, as a single agent (NCCN-alternative preferred) in one of the following scenarios:

Stage II (cT2, N0) disease or stage IIIA (cT3, N0; cT4a, N0; cT1-T4a, N1) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent bladder preserving chemoradiotherapy and maximal TURBT

Stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy or concurrent chemoradiotherapy

Stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with first-line systemic therapy or concurrent chemoradiotherapy

Stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy

Metastatic stage IVB (any T, any N, M1b) disease

Muscle invasive local recurrence or persistent disease in a preserved bladder treated with curative intent

Metastatic or local recurrence postcystectomy treated with curative intent

Primary carcinoma of the urethra

Adjuvant treatment may be considered for pathologic stage T3-4 or N1-2 disease in the male bulbar urethra:

If platinum-based neoadjuvant chemotherapy not given and pT3, pT4a, pN+

If platinum-based neoadjuvant chemotherapy given and ypT2-ypT4a or ypN+

Single agent for recurrent or metastatic disease as second-line systemic therapy postplatinum or other chemotherapy (NCCN-alternative preferred) (regimen excludes coverage for the recurrence of clinical stage T3-4 disease or palpable inguinal lymph nodes)

Upper genitourinary tract tumors

Adjuvant therapy for pathologic stage T2-4 or nodal disease (N+) of the renal pelvis or UC of the ureter, if platinum-based neoadjuvant chemotherapy given and ypT2-ypT4 or ypN+

Therapy for metastatic disease as a single agent for second-line systemic therapy postplatinum or other chemotherapy (NCCN-alternative preferred)

Urothelial carcinoma of the prostate

Primary treatment for tumors with stromal invasion as adjuvant therapy if platinum-based neoadjuvant chemotherapy not given and pT3, pT4a, pN+

Therapy for metastatic disease as a single agent for second-line systemic therapy postplatinum or other chemotherapy (NCCN-alternative preferred)

UTERINE NEOPLASMS - ENDOMETRIAL CARCINOMA

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for second-line

or subsequent treatment for recurrent MSI-H or dMMR tumors, in one of the following scenarios:

for isolated metastases

for disseminated metastases with or without sequential palliative external beam radiation therapy (EBRT)

with sequential EBRT and with or without brachytherapy for locoregional recurrence in individuals with no prior RT to site of recurrence, or previous vaginal brachytherapy only

after surgical exploration, with sequential EBRT for locoregional recurrence in individuals with disease confined to the vagina or paravaginal soft tissue, or in pelvic or para-aortic lymph nodes

after surgical exploration, with or without sequential EBRT for locoregional recurrence in individuals with upper abdominal or peritoneal disease

with or without sequential palliative EBRT or brachytherapy for locoregional recurrence in individuals who have received prior EBRT to site of recurrence

VULVAR CANCER

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered as single-agent therapy for second-line or subsequent treatment of human papillomavirus (HPV)-related advanced, recurrent, or metastatic disease

CONTINUATION OF THERAPY

Nivolumab (Opdivo) is considered medically necessary and, therefore, covered for Continuation therapy when treatment guidelines do not specify a limited number of total doses (see National Comprehensive Cancer Network (NCCN) and/or Attachment A - Dosing and Frequency Requirements For Ipilimumab (Yervoy®)) and there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

MANDATES

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive agents (08.01.08)" for additional information regarding the applicable coverage of drugs and biologics.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for nivolumab (Opdivo) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, nivolumab (Opdivo) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

THE CHILD-PUGH SCORE

Note: The Child-Pugh score is calculated by adding the scores of the five factors and can range from 5 to 15. Child-Pugh class is A (a score of 5-6), B (7-9), or C (10 or above). Decompensation indicates cirrhosis with a Child-Pugh score of 7 or more (class B). This level has been the accepted criterion for listing for liver transplantation.

Factor	Units	1	2	3
Serum bilirubin	mol/L mg/dL	<34 <2.0	34-51 2.0-3.0	>51 >3.0
Serum albumin	g/L g/dL	>35 >3.5	30-35 3.0-3.5	<30 <3.0
Prothrombin time	Seconds prolonged INR	0-4 <1.7	4-6 1.7-2.3	>6 >2.3
Ascites		None	Easily controlled	Poorly controlled
Hepatic encephalopathy		None	Minimal	Advanced

Note: Table 163-3: Child-Pugh Classification of Cirrhosis: In Harrison's Manual of Medicine 17th ed.

THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS

The Eastern Cooperative Oncology Group (ECOG), established in 1955, was one of the first groups to coordinate multicenter cancer clinical trials. The National Cancer Institute (NCI) is the primary funding source, and ECOG has evolved from a small consortium of institutions in the eastern United States to one of the largest clinical cancer research organizations in the country. As part of their work in the treatment of cancer, ECOG has developed the ECOG Performance Status (EPS), originally published in 1982 in the American Journal of Clinical Oncology. The use of the scales and the criteria in the EPS allows clinicians and researchers to determine an individual’s disease progression in terms of how the activities of daily living (ADL) are affected.

ECOG Performance Status
Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work)
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3	Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4	Completely disabled. Cannot carry on any self-care: totally confined to bed or chair
5	Dead

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

THE DEAUVILLE CRITERIA

The Deauville five-point scale (Deauville 5PS) is an internationally-recommended scale for routine clinical reporting and clinical trials using FDG PET-CT in the initial staging and assessment of treatment response.

PET 5-POINT SCALE
Score		PET/CT Scan Result
Negative	1	No uptake
	2	Uptake ≤ mediastinum
	3	Uptake > mediastinum but ≤ liver
Positive	4	Uptake moderately higher than liver and visually above adjacent background activity
	5	Uptake markedly higher than liver and/or new lesions
	X^a	New areas of uptake unlikely to be related to lymphoma

Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014;32:3048-3058.

US FOOD AND DRUG ADMINISTRATION STATUS

Nivolumab (Opdivo) was approved by the US Food and Drug Administration (FDA) on December 22, 2014, for the treatment of individuals with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) and, if BRAF V600 mutation–positive, a BRAF inhibitor. Supplemental approvals for nivolumab (Opdivo) have since been issued by the FDA.

PEDIATRIC USE

The safety and effectiveness of nivolumab (Opdivo) as a single agent and in combination with ipilimumab have been established in pediatric individuals age 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Supplemental approvals for nivolumab (Opdivo) for the pediatric population have since been issued by the FDA.

Description

In a normal immune response, the body can recognize the presence of tumors and mount a response to eradicate them. The process of eradicating a tumor begins with antigen-presenting cells that gather and process the antigens released by tumors. This activates the T cells, which proliferate and attack the tumor.

Tumors have learned to evade the normal immune response by exploiting the immune checkpoint pathway. The Programmed Death Receptor-1 (PD-1) is a checkpoint protein expressed on the membrane of activated T cells. The Programmed Death-Ligand 1 (PD-L1) and The Programmed Death-Ligand 2 (PD-L2) are checkpoint proteins expressed on tumor cells and tumor-infiltrating immune cells. When PD-L1 and PD-L2 attach to PD-1 receptors on the T cells, the T cells become inhibited and will not attack the tumor; thus, the tumor can continue to proliferate.

Nivolumab (Opdivo) is a human monoclonal antibody and immune checkpoint inhibitor that competes with the tumor for the PD-1 receptor on T cells and blocks the T cells' interaction with the tumor's PD-L1 and PD-L2 ligands. Consequently, the tumor is no longer able to inactivate the T cells and the antitumor response continues.

CLASSICAL HODGKIN LYMPHOMA

Hodgkin lymphoma is an uncommon malignancy involving the lymph nodes and lymphatic system. The World Health Organization (WHO) divides Hodgkin lymphoma into two types: classical (cHL), which accounts for 95% of cases, and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), which accounts for the other 5%. cHL is characterized by the presence of Reed-Sternberg cells in an inflammatory background. NLPHL lacks the Reed-Sternberg cells and instead has lymphocyte-predominant cells, also known as popcorn cells. With all of the advancements and treatment options available, cHL is curable in at least 80% of individuals.

ESOPHAGEAL ADENOCARCINOMA AND SQUAMOUS CELL CARCINOMA/GASTRIC CANCER/GASTROESOPHAGEAL JUNCTION CANCER

There were an estimated 19,260 new cases of esophageal cancer in the United States in 2021, with esophageal squamous cell carcinoma (ESCC) being more prevalent than adenocarcinoma. The median age of individuals with esophageal cancer is 68 years old and is more frequently seen in males. ESCC is usually asymptomatic until an advanced disease stage, with common presenting symptoms being dysphagia and weight loss. ESCC tumors are typically found in the middle and the upper third of the esophagus; esophageal adenocarcinomas typically start in the lower esophagus. Esophageal cancer is a treatable disease, but it is rarely curable. The 5-year relative survival rate is 19.9%. Individuals with early-stage disease have a better chance of survival; 17.5% of individuals are diagnosed at the local stage and have a 5-year relative survival rate of 46.4%.

It is estimated that 28,000 individuals are diagnosed with stomach cancer in the United States each year. Individuals are typically diagnosed between 60 and 80 years of age, and is more frequently seen in males.

HEAD AND NECK CANCER

It is estimated that head and neck cancers will account for 3.7% of new cancers in the United States in 2022, which is approximately 63,000 new cases of oral cavity, pharyngeal, and larygneal cancers. Squamous cell carcinoma is the histological type in more than 90% of these tumors, and may occur on the lip, oral cavity, pharynx, larynx, sinuses, salivary glands, or mucosal membranes. Treatment is complex and is dependent on specific site, stage, and pathological findings.

HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma (HCC) is consider a rare disease in the United States, but it is also the most common primary tumor of the liver. There are approximately six new cases of HCC per every 100,000 people in the general population of the United States. If diagnosed early, there are curative treatments available; however, HCC often does not cause any symptoms, especially early in the course of the disease.

MELANOMA

Melanoma can arise in the cutaneous regions (skin) or in the mucosal regions (mucus membranes such as the gastrointestinal or genitourinary tracts). Cutaneous melanoma is the deadliest form of skin cancer; it is characterized by the uncontrolled growth of melanocytes (pigment cells). Mucosal melanoma is the rarer form of the two types of melanoma and exhibits a poorer prognosis. Melanoma can be contained to one site or it can spread locally to areas within the same region. Metastatic melanoma is the terminology used to describe a setting in which the melanoma spreads beyond the skin surface or mucosal epithelium lining and invades other organs of the body.

According to The American Joint Commission on Cancer (AJCC), individuals with melanoma are categorized into three groups:

Stage I-II: no evidence of metastases; localized no evidence cancer has spread to lymph nodes
Stage III: regional disease (spread to regional lymph nodes)
Stage IV: distant metastatic disease

MERKEL CELL CARCINOMA

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with an incidence of approximately 1500 cases per year in the United States, with 12% of these cases presenting at stage 4. Merkel cell carcinoma has a high mortality rate, with a 5-year survival of only 30% to 64%. Common sites of metastasis are the lymph nodes and distant skin sites.

MICROSATELLITE INSTABILITY-HIGH CANCER

Microsatellite instability (MSI) is a change that occurs in the DNA of some cells in which the number of repeats of microsatellites, which are short repeated DNA sequences, is different than the number of repeats that was in the DNA when it was inherited. This may be caused by a defect in the ability to repair mistakes made when DNA is copied in the cell. MSI may result in colon, endometrial, gastric, ovarian, hepatobiliary, urinary tract, brain, or skin cancers, but is most prevalent in colon cancers, accounting for about 15% of all colorectal cancers. MSI-high (MSI-H) is defined as instability in the majority of tested markers. MSI-H tumors have a distinct pathologic phenotype: poorly differentiated, right-sided, expansile growth pattern, histologic heterogeneity, and increased tumor infiltrating lymphocytes with a prominent inflammatory reaction.

Deficient mismatch repair (dMMR)

A deficient MMR (dMMR) system results in the persistence of DNA mismatches in microsatellites that may then be incorporated into the genetic code as mutations. A dMMR system can be hereditary or sporadic in nature. Tumors that have a dMMR system can develop MSI. dMMR is prevalent in several different cancer types i.e endometrial, small bowel, colorectal, colon and gastric cancers.

Tumor Mutational Burden-HIGH CANCER

Tumor mutational burden (TMB) is the genetic characteristic of non-inherited mutations within tumor tissue of a cancer cell, often reported as the total number of DNA mutations per one million bases (megabase). These cells keep making more errors as they divide. When that happens, the tumors have a high mutational burden (TMB-H). TMB may serve as a biomarker to identify patients likely to have a favorable response to immunotherapy, as high TMB levels correlate with objective response rates to immunotherapy in several different cancer types i.e lung, liver, kidney, bladder, head and neck, and skin cancers.

NON-SMALL CELL LUNG CARCINOMA

Lung cancer is the leading cause of cancer-related mortality in both men and women, not only in the United States but also throughout the world. In the United States, lung cancer is the second most common cancer. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers, and its subtype, squamous cell lung cancer, accounts for 25% to 30% of all lung cancers.

MALIGNANT PLEURAL MESOTHELIOMA

Malignant pleural mesothelioma (MPM) is a rare cancer that is difficult to treat because most individuals have advanced disease at presentation. There are approximately 2500 individuals diagnosed with mesothelioma each year in the United States. MPM mostly occurs in older men who have been exposed to asbestos. The median overall survival is about 1 year. There are three subtypes of mesothelioma, which include epithelioid, sarcomatoid, and biphasic (mixed) epithelioid and sarcomatoid. Epithelioid mesothelioma is the most common of the subtypes and also has the better outcome.

RENAL CELL CARCINOMA

In adults, renal cell carcinoma (RCC) accounts for 80% to 95% of all primary kidney cancers. When diagnosed, 65% of individuals have localized disease confined to the kidney. At 75% to 85%, the clear cell subtype of RCC accounts for the highest percentage among other subtypes of the disease.

UROTHELIAL CARCINOMA

The urinary tract comprises the the renal pelvis, ureters, bladder, and urethra. The innermost lining of the urinary tract is composed of urothelial cells. Urothelial carcinoma (UC), also known as transitional cell carcinoma (TCC), is the ninth most common cancer overall worldwide and accounts for 90% of all bladder cancers. Squamous cell carcinoma comprises 1% to 7% of upper tract urothelial tumors. Adenocarcinoma accounts for less than 1% of upper tract tumors. Urothelial tumors of the renal pelvis and ureters are rare. Tumors of the renal pelvis account for approximately 5% of all urothelial tumors of the urinary tract.

NIVOLUMAB (OPDIVO) INDICATIONS

CLASSICAL HODGKIN LYMPHOMA
On April 25, 2017, the FDA granted accelerated approval of nivolumab (Opdivo) for the treatment of cHL in adult individuals that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin (Adcetris®), or after three or more lines of systemic therapy that includes HSCT.

ESOPHAGEAL CARCINOMA
On June 10, 2020, the US Food and Drug Administration (FDA) granted accelerated approval of nivolumab (Opdivo) for the treatment of individuals with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. Additional approval was later granted for:

Adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in individuals who have received neoadjuvant chemoradiotherapy (CRT)
Unresectable advanced or metastatic ESCC as first-line treatment in combination with fluoropyrimidine- and platinum-containing chemotherapy
Unresectable advanced or metastatic ESCC as first-line treatment in combination with ipilimumab

GASTRIC CANCER, GASTROESOPHAGEAL JUNCTION CANCER, ESOPHAGEAL ADENOCARCINOMA

Nivolumab (Opdivo) is FDA approved in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the treatment of individuals with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

HEAD AND NECK CANCER
On November 10, 2016, the FDA granted supplemental approval of nivolumab (Opdivo) for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after platinum-based therapy.

HEPATOCELLULAR CARCINOMA
Nivolumab (Opdivo) is FDA approved in combination with ipilimumab for the treatment of individuals with HCC who have been previously treated with sorafenib.

MALIGNANT PLEURAL MESOTHELIOMA

Nivolumab (Opdivo) is FDA approved in combination with ipilimumab for the first-line treatment of adults with unresectable MPM.

MELANOMA
Nivolumab (Opdivo) is FDA approved as a single agent or in combination with ipilimumab and is indicated for the treatment of individuals with unresectable or metastatic melanoma. The FDA previously approved (nivolumab) Opdivo for the adjuvant treatment of individuals with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection. A subsequent approval was FDA-approved to include Stage IIB and IIC completely resected melanoma.

MICROSATELLITE INSTABILITY-HIGH CANCER
The FDA granted accelerated approval of nivolumab (Opdivo) as a single agent or in combination with ipilimumab for the treatment of adult and pediatric individuals (ages 12 years and older) with MSI-H or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

NON-SMALL CELL LUNG CANCER
Nivolumab (Opdivo) is FDA approved:

In combination with platinum-doublet chemotherapy for the treatment of adults with resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting.
In combination with ipilimumab for the first-line treatment of adults with metastatic NSCLC whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
In combination with ipilimumab and two cycles of platinum-doublet chemotherapy, for the first-line treatment of adults with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations.
For the treatment of individuals with metastatic NSCLC with progression on or after platinum-based chemotherapy. Individuals with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab (Opdivo).

RENAL CELL CARCINOMA

Nivolumab (Opdivo) is FDA approved:

As a single agent for the treatment of advanced RCC in those who have received prior antiangiogenic therapy
In combination with ipilimumab for the treatment of individuals with intermediate or poor risk, previously untreated advanced RCC
In combination with cabozantinib, for the first-line treatment of individuals with advanced RCC

UROTHELIAL CARCINOMA
On February 2, 2017, the FDA gave accelerated approval of nivolumab (Opdivo) for the treatment of locally advanced or metastatic UC in individuals who have disease progression during or following platinum-containing chemotherapy, or those who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Supplemental approval was later given for the adjuvant treatment of individuals with UC who are at high risk of recurrence after undergoing radical resection of UC.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Cancer Society. Cancer Staging. Last revised: 02/18/2022. Available at: https://www.cancer.org/treatment/understanding-your-diagnosis/staging.html. Accessed November 10, 2023.

American Cancer Society. Key statistics for lung cancer. Last Medical Review: 02/14/2022. Available at: https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed July 13, 2022.

American Cancer Society. What is bladder cancer? Last Medical Review: 01/30/2019. Available at: http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-what-is-bladder-cancer. Accessed July 13, 2022.

American Cancer Society. What is lung cancer? Last Medical Review: 10/01/2019. Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed July 13, 2022.

American Hospital Formulary Service (AHFS). Drug Information 2023. Nivolumab (Opdivo). [Lexicomp Online Web Site] Updated 02/23/2023. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed October 23, 2023.

Atkins MB, Choueiri TK. Epidemiology, pathology, and pathogenesis of renal cell carcinoma. 06/03/2022. UpToDate®. Available at: http://www.uptodate.com/contents/epidemiology-pathology-and-pathogenesis-of-renal-cell-carcinoma?source=search_result&search=renal+cell+carcinoma&selectedTitle=3~150 [via subscription only]. Accessed July 13, 2022.

Bellmunt J. Treatment of metastatic urothelial cancer of the bladder and urinary tract. 05/19/2022. UpToDate®. Available at: https://www.uptodate.com/contents/treatment-of-metastatic-urothelial-cancer-of-the-bladder-and-urinary-tract?source=search_result&search=tecentriq&selectedTitle=4~22 [via subscription only]. Accessed July 13, 2022.

Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-39.

Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-35.

Carvajal RD, Hamid O, Ariyan C. Locoregional mucosal melanoma: epidemiology, clinical diagnosis, and treatment. Updated: 04/29/2022. UpToDate Web Site. Available at: http://www.uptodate.com/contents/mucosal-melanoma?source=search_result&search=mucosal+melanoma&selectedTitle=1~10 [via subscription only]. Accessed July 13, 2022.

Elsevier's Clinical Pharmacology Compendium. Nivolumab.[Clinical Key Web site]. 10/23/2023. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed October 23, 2023.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.

Lexi-Drugs Compendium. Nivolumab (Opdivo). 11/03/2023. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 03, 2023.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-13.

National Cancer Institute. Esophageal Cancer Treatment (Adult) (PDQ®)–Health Professional Version. Updated 07/15/2021. Available at: https://www.cancer.gov/types/esophageal/hp/esophageal-treatment-pdq . Accessed July 13, 2022.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 02.2023. Ampullary Adenocarcinoma. Updated 08/03/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ampullary.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 3.2023; revised 09/12/2023. Anal Cancer. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf [via free subscription]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 02.2023. Biliary Tract cancer. Updated 05/10/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/btc.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 03.2023. Bladder cancer. Updated 05/25/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf [via free subscription only]. Accessed November 8, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 01.2024. Bone cancer. Updated 08/07/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf [via free subscription only]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 01.2023. CNS cancers. Updated 03/24/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf [via free subscription only]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 01.2024. Cervical cancer. Updated 09/20/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf [via free subscription only]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 3.2023; revised 09/21/2023. Colon Cancer. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf [via free subscription]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 3.2023; revised 08/29/2023. Esophageal and Esophagogastric Junction Cancers. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf [via free subscription]. Accessed October 26, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2023; revised 08/29/2023. Gastric Cancer. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf [via free subscription]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024; revised 10/27/2023. Gestational Trophoblastic Neoplasia. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gtn.pdf [via free subscription]. Accessed October 27, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024; revised 10/09/2023. Head and Neck Cancers. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf [via free subscription]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2023; revised 09/14/2023. Hepatocellular Carcinoma. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf [via free subscription]. Accessed October 27, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024; revised 10/12/2023. Hodgkin Lymphoma. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf [via free subscription]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 02.2023. Kaposi Sarcoma. Updated 10/03/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kaposi.pdf [via free subscription only]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024; revised 06/21/2023. Kidney Cancer. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf [via free subscription only]. Accessed November 07, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2023; revised 07/20/2023. Mesothelioma: Peritoneal. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/meso_peritoneal.pdf [via free subscription]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023; revised 12/15/2022. Mesothelioma: Pleural. [NCCN Website]. Available at: nccn.org/professionals/physician_gls/pdf/meso_pleural.pdf [via free subscription]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 3.2023; revised 10/27/2023. Melanoma: Cutaneous. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf [via free subscription]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023. Melanoma: Uveal. Updated 05/04/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uveal.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023. revised 04/10/2023. Merkel Cell Carcinoma. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf [via free subscription]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 4.2023. Non-small cell lung cancer. Updated 10/18/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2023; revised 03/09/2023. Pediatric Hodgkin Lymphoma. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf [via free subscription]. Accessed November 01, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2023; revised 10/31/2022. Pediatric Central Nervous System Cancers. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_hodgkin.pdf [via free subscription]. Accessed October 25, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023; revised 04/04/2023. Pediatric Aggressive Mature B-Cell Lymphomas. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_b-cell.pdf [via free subscription]. Accessed November 07, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 5.2023. Rectal cancer. Updated 09/21/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023. Small bowel adenocarcinoma. Updated 01/09/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf [via free subscription only]. Accessed November 06, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024; revised 09/05/2023. Small Cell Lung Cancer. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf [via free subscription]. Accessed November 07, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 02.2023. Soft tissue sarcoma. Updated 04/25/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf [via free subscription only]. Accessed November 07, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2023. T-Cell Lymphomas. Updated 01/05/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf [via free subscription only]. Accessed November 08, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2024. Uterine Neoplasms. Updated 09/20/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf [via free subscription only]. Accessed November 08, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 2.2024. Vulvar Cancer. Updated 10/26/2023. [NCCN Website]. Available at: https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf [via free subscription only]. Accessed November 08, 2023.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Nivolumab. [NCCN Web site]. 2023. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed October 25, 2023.

National Organization of Rare Diseases (NORD). Hepatocellular carcinoma (HCC). Updated 2017. Available at: https://rarediseases.org/rare-diseases/hepatocellular-carcinoma/. Accessed July 13, 2022.

National Organization for Rare Disorders (NORD). Stomach Cancer. Updated 2019. Available at: https://rarediseases.org/rare-diseases/stomach-cancer/. Accessed July 13, 2022.

Nivolumab (Opdivo®). package insert. Bristol-Myers Squibb Company: Princeton, NJ. 10/2023. Available at: https://www.opdivohcp.com/. Accessed October 19, 2023.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-55.

PD-1 Pathway. Bristol-Myers Squibb Company. 2021. Available at: https://www.immunooncologyhcp.com/immune-pathways/pd1. Accessed July 13, 2022.

Postow MA, Hamid O, Carvajal RD. Mucosal melanoma: pathogenesis, clinical behavior, and management. Curr Oncol Rep. 2012;14(5):441-8.

Richards KA. Urothelial Tumors of the Renal Pelvis and Ureters. Updated 08/07/2020. Available at: http://emedicine.medscape.com/article/452449-overview. Accessed July 13, 2022.

Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320-30.

Sachdeva K, Jana BRP, Curti B. Renal Cell Carcinoma. 11/20/2021. Available at: http://emedicine.medscape.com/article/281340-overview#showall. Accessed July 13, 2022.

Sosman JA. Systemic treatment of metastatic melanoma lacking a BRAF mutation. UpToDate®. 07/05/2022. Available at: http://www.uptodate.com/contents/immunotherapy-of-advanced-melanoma-with-immune-checkpoint-inhibition?source=machineLearning&search=pembrolizumab&selectedTitle=4~14&sectionRank=1&anchor=H175770315#H175770315 [via subscription only]. Accessed July 13, 2022.

Squamous cell carcinoma of the esophagus. 01/2013. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=99977. Accessed July 13, 2022.

Tan W, Huq S. Non-Small Cell Lung Cancer. 03/10/2021. [Emedicine Web Site]. Available at: http://emedicine.medscape.com/article/279960-overview#showall. Accessed July 13, 2022.

Tanabe KK, Tyler D. Cutaneous melanoma: In transit metastases. [UpToDate Web Site]. Updated: 03/18/2022. Available at: https://www.uptodate.com/contents/cutaneous-melanoma-in-transit-metastases?search=cutaneous-melanoma-management-of-in-transit-metastases&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 [via subscription only]. Accessed July 13, 2022.

Truven Health Analytics Inc. Micromedex DrugDex® Compendium. Nivolumab (Opdivo). [Micromedex® Solutions Web site]. Updated 10/17/2023. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed October 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @FDA. Nivolumab (Opdivo) approval letter and prescribing information. [FDA Website]. Updated 10/2023. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed October 19, 2023.

Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-84.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment A.

HCPCS Level II Code Number(s)

J9299 Injection, nivolumab, 1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.01.62c:

01/02/2024

This version of the policy will become effective 01/02/2024.

This policy was updated to communicate the Company's coverage position for nivolumab (Opdivo), in accordance with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN). Applicable codes have been added to the policy due to criteria changes.

The following conditions with criteria were added, per FDA and NCCN:
- Central nervous system cancers in pediatrics
- Kaposi sarcoma
- Biliary tract cancer
- Pediatric aggressive mature B-cell lymphoma
- Soft tissue sarcoma

The criteria for the following conditions were revised, per FDA and NCCN:
- Cervical cancer
- Gastric cancer
- Gastroesophageal junction cancer, Esophageal Adenocarcinoma, or Esophageal Squamous Cell Carcinoma
- Gestational trophoblastic neoplasia
- Head and Neck Cancers
- Hepatocellular carcinoma
- Hodgkin Lymphoma
- Mesothelioma: Peritoneal
- Malignant pleural mesothelioma
- Melanoma: Cutaneous
- Melanoma: Uveal
- Merkel cell carcinoma
- Microsatellite Instability-High Cancers: Ampullary Adenocarcinoma, Appendiceal adenocarcinoma, Colorectal, Colon, Rectal
- Non-small cell lung cancer (NSCLC)
- Renal cell carcinoma (RCC)
- Urothelial Cancer
- Uterine neoplasms/Endometrial carcinoma
- Vulvar cancer

The following ICD-10 CM codes have been added to this policy:
C22.1, C22.3, C23, C24.0, C24.8, C24.9, C44.520, C45.2, C45.7, C45.9, C46.0, C46.1, C46.2, C46.3, C46.4, C46.50, C46.51, C46.52, C46.7, C46.9, C47.0, C47.10, C47.11, C47.12, C47.20, C47.21, C47.22, C47.3, C47.4, C47.5, C47.6, C47.8, C47.9, C48.0, C48.1, C48.2, C48.8, C49.0, C49.10, C49.11, C49.12, C49.20, C49.21, C49.22, C49.3, C49.4, C49.5, C49.6, C49.8, C49.9, C69.30, C69.40, C69.50, C69.60, C71.0, C71.1, C71.2, C71.3, C71.4, C71.5, C71.6, C71.7, C71.8, C71.9, C72.0, C72.1, C72.9, C77.0, C84.90, C84.91, C84.92, C84.93, C84.94, C84.95, C84.96, C84.97, C84.98, C84.99, C84.Z0, C84.Z1, C84.Z2, C84.Z3, C84.Z4, C84.Z5, C84.Z6, C84.Z7, C84.Z8, C84.Z9, C85.20, C85.21, C85.22, C85.23, C85.24, C85.25, C85.26, C85.27, C85.28, C85.29

Revisions From 08.01.62b:

10/10/2022

This version of the policy will become effective 10/10/2022.

The following conditions with criteria were added, per FDA and NCCN:
- Appendiceal Adenocarcinoma
- Bone cancer
- Cervical cancer
- Malignant Peritoneal Mesothelioma
- Small Cell Lung Cancer

The criteria for the following conditions were revised, per FDA and NCCN:
- Central nervous system cancers
- Gastroesophageal junction cancer, Esophageal Adenocarcinoma, or Esophageal Squamous Cell Carcinoma
- Gestational trophoblastic neoplasia
- Head and Neck Cancers
- Malignant pleural mesothelioma
- Melanoma: Cutaneous
- Merkel cell carcinoma
- Microsatellite Instability-High Cancer: Ampullary Adenocarcinoma, Colon, Rectal, Small bowel adenocarcinoma
- Non-small cell lung cancer (NSCLC)
- Renal cell carcinoma (RCC)
- Urothelial Cancer
- Uterine Neoplasms/Endometrial Carcinoma

The following ICD-10 CM codes have been added to this policy:
C22.9, C30.0, C40.01, C40.02, C40.11, C40.12, C40.21, C40.22, C40.31, C40.32, C40.81, C40.82, C40.91, C40.92, C41.0, C41.1, C41.2, C41.3, C41.4, C41.9, C44.00, C44.02, C44.09, C44.1221, C44.1222, C44.1291, C44.1292, C44.222, C44.229, C44.320, C44.321, C44.329, C44.82, C44.92, C45.1, C4A.122, C53.0, C53.1, C53.8, C53.9, C62.01, C62.02, C62.11, C62.12, C62.91, C62.92, C76.0, C7A.1

The following ICD-10 CM codes have been removed from this policy:
C38.4, C43.10, C43.20, C43.60, C43.70, C4A.10, C4A.20, C4A.60, C4A.70, C52, C63.00, C63.01, C63.02, C63.10, C63.11, C63.12, C69.10, C69.11, C69.12, C69.20, C69.21, C69.22, C69.30, C69.40, C69.50, C69.60, C69.80, C69.90, C69.91, C69.92

Revisions From 08.01.62a:

08/30/2021

This version of the policy will become effective 08/30/2021.

The following conditions with criteria were added, per FDA and NCCN:
- Gastric cancer
- Gastroesophageal junction cancer or Esophageal adenocarcinoma
- Hodgkin Lymphoma in Pediatric Individuals
- Advanced Ampullary Cancer
- Uterine neoplasms
- Vulvar cancer

The criteria for the following conditions were revised, per FDA and NCCN:
- Esophageal squamous cell carcinoma
- Hepatocellular carcinoma (HCC)
- Hodgkin Lymphoma, classical (cHL) in Adults
- Malignant pleural mesothelioma
- Merkel cell carcinoma
- Microsatellite Instability-High Cancer
- Non-small cell lung cancer (NSCLC)
- Renal cell carcinoma (RCC)
- Urothelial Cancer

The criteria for Small cell lung cancer (SCLC) was removed, due to withdraw from the FDA and NCCN recommendations.

The following ICD-10 CM codes have been added to this policy:

C16.0 Malignant neoplasm of cardia

C16.1 Malignant neoplasm of fundus of stomach

C16.2 Malignant neoplasm of body of stomach

C16.3 Malignant neoplasm of pyloric antrum

C16.4 Malignant neoplasm of pylorus

C16.5 Malignant neoplasm of lesser curvature of stomach, unspecified

C16.6 Malignant neoplasm of greater curvature of stomach, unspecified

C16.8 Malignant neoplasm of overlapping sites of stomach

C16.9 Malignant neoplasm of stomach, unspecified

C24.1 Malignant neoplasm of ampulla of Vater

C38.4 Malignant neoplasm of pleura

C54.0 Malignant neoplasm of isthmus uteri

C54.1 Malignant neoplasm of endometrium

C54.2 Malignant neoplasm of myometrium

C54.3 Malignant neoplasm of fundus uteri

C54.8 Malignant neoplasm of overlapping sites of corpus uteri

C54.9 Malignant neoplasm of corpus uteri, unspecified

C55 Malignant neoplasm of uterus, part unspecified

C81.90 Hodgkin lymphoma, unspecified, unspecified site

C81.91 Hodgkin lymphoma, unspecified, lymph nodes of head, face, and neck

C81.92 Hodgkin lymphoma, unspecified, intrathoracic lymph nodes

C81.93 Hodgkin lymphoma, unspecified, intra-abdominal lymph nodes

C81.94 Hodgkin lymphoma, unspecified, lymph nodes of axilla and upper limb

C81.95 Hodgkin lymphoma, unspecified, lymph nodes of inguinal region and lower limb

C81.96 Hodgkin lymphoma, unspecified, intrapelvic lymph nodes

C81.97 Hodgkin lymphoma, unspecified, spleen

C81.98 Hodgkin lymphoma, unspecified, lymph nodes of multiple sites

C81.99 Hodgkin lymphoma, unspecified, extranodal and solid organ sites

The following ICD-10 CM codes have been removed from this policy:

D39.2 Neoplasm of uncertain behavior of placenta

D39.8 Neoplasm of uncertain behavior of other specified female genital organs

Revisions From 08.01.62:

09/14/2020

New policy number 08.01.62 nivolumab (Opdivo®) supersedes 08.01.20j for Programmed Death Receptor-1 (PD-1) Antagonists (e.g., Keytruda®, Opdivo®) and Programmed Death-Ligand 1 (PD-L1) Antagonists (e.g., Tecentriq®, Bavencio®, Imfinzi™)

The information for the following drugs now resides in their own separate drug policies:

Atezolizumab (Tecentriq®)
Avelumab (Bavencio®)
Cemiplimab-rwlc (Libtayo)
Durvalumab (Imfinzi™)
Nivolumab (Opdivo®)
Pembrolizumab (Keytruda®)

This policy was updated to communicate the Company's coverage position for nivolumab (Opdivo®), in accordance with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN). Applicable codes have been added to the policy due to criteria changes.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

1/2/2024

Version Issued Date:

1/8/2024

Version Reissued Date: