Medical Policy

Policy Num:       02.001.056
Policy Name:     Oncologic application for OPDIVO (nivolumab)
Policy ID:          [02.001.056]  [Ac / L /  M+ / P+]  [0.00.00]

Last Review:       October 24, 2024
Next Review:      Octuber 20, 2025
 

Related Policies: None

Oncologic application for  OPDIVO^® (nivolumab)

Summary

OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of:

• patients with unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab. 

• patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting. 

• patients with metastatic non-small cell lung cancer and progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO. 

• patients with metastatic small cell lung cancer with progression after platinum-based chemotherapy and at least one other line of therapy.

• patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. 

• patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with ipilimumab.

patients with advanced renal cell carcinoma, as a first-line treatment in combination with cabozantinib. 

• adult patients with classical Hodgkin lymphoma that has relapsed or progressed after:

• autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or

• 3 or more lines of systemic therapy that includes autologous HSCT.

• patients with recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. 

• patients with locally advanced or metastatic urothelial carcinoma who:

• have disease progression during or following platinum-containing chemotherapy

• have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (1.8)

• adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab.

• patients with hepatocellular carcinoma who have been previously treated with sorafenib, as a single agent or in combination with ipilimumab.

Objective

The objective of this topic review is to evaluate the use of OPDIVO in oncology.

Policy Statements

This policy statement applies to clinical review performed for pre-service (Prior Approval, Precertification, Advanced Benefit Determination, etc.) and/or post-service claims.

Nivolumab (Opdivo^®) is FDA-approved for the following indications. (1) :

• Classic Hodgkin lymphoma - as a single agent for adults with disease relapse or progression after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or after 3 or more lines of systemic therapy that included autologous HSCT
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as first-line therapy in combination with ipilimumab for unresectable advanced or metastatic esophageal squamous cell carcinoma
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as first-line therapy in combination with fluoropyrimidine- and platinum-containing chemotherapy for unresectable advanced or metastatic esophageal squamous cell carcinoma
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer - as first-line therapy in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastroesophageal junction cancer and esophageal adenocarcinoma
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as single agent adjuvant therapy in patients who have had neoadjuvant chemoradiotherapy and completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as single agent second-line or subsequent therapy in patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy
• Gastric cancer - in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic disease
• Head and neck cancer - as a single agent for recurrent or metastatic disease that has progressed on or after platinum-containing chemotherapy
• Melanoma (cutaneous) - as a single agent or in combination with ipilimumab for unresectable or metastatic disease
• Melanoma (cutaneous) - as single agent adjuvant therapy for patients with lymph node involvement or metastatic disease who have undergone complete resection
• Mesothelioma: Pleural – as first-line treatment for unresectable disease or disease not amenable to curative surgery in combination with ipilimumab
• Non-small cell lung cancer - as a single agent for stage IV or recurrent EGFR- or ALK-positive disease that has progressed on or after platinum-based chemotherapy
• Non-small cell lung cancer – in combination with platinum-doublet chemotherapy for neoadjuvant chemotherapy
• Non-small cell lung cancer – in combination with ipilimumab for metastatic disease with PD-L1 expression ≥ 1% and no EGFR or ALK genomic tumor aberrations
• Renal cell cancer (clear cell histology) - as first-line therapy in combination with ipilimumab for intermediate or poor risk advanced disease
• Renal cell cancer (clear cell histology) - as first-line therapy in combination with cabozantinib in patients with advanced disease
• Renal cell cancer (clear cell histology) - as single agent subsequent therapy for advanced disease in patients who have received prior anti-angiogenic therapy
• Urothelial (transitional cell) carcinoma -as a single agent adjuvant therapy for the treatment of bladder or upper genitourinary tract cancer in patients at high risk of recurrence after undergoing radical resection of urothelial carcinoma
• Urothelial (transitional cell) carcinoma - as subsequent single agent systemic therapy for locally advanced or metastatic urothelial carcinoma of the bladder, upper genitourinary tract, prostate, or primary carcinoma of the urethra that progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy or that progressed during or following platinum-containing chemotherapy

Opdivo may be considered medically necessary in patients 18 years of age or older for unresectable or metastatic melanoma, adjuvant treatment of melanoma, metastatic non-small cell lung cancer, renal cell carcinoma, relapsed or progressed classical Hodgkin lymphoma, recurrent or metastatic squamous cell carcinoma Head and Neck, locally advanced or metastatic urothelial carcinoma, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)metastatic colorectal cancer, hepatocellular carcinoma, malignant pleural mesothelioma, small cell lung cancer, Not FDA approved indication for metastatic anal carcinoma or Merkel cell carcinoma; and if the conditions indicated below are met.

Nivolumab (Opdivo) is recommended by the NCCN Drugs and Biologics Compendium^® for off-label use for the following indications:

• Ampullary adenocarcinoma - as first-line or subsequent therapy in combination with ipilimumab for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
• Anal carcinoma - as single agent, second-line or subsequent therapy for metastatic disease if neither nivolumab or pembrolizumab previously received, or for locally recurrent, progressive disease prior to abdominoperineal resection
• Appendiceal adenocarcinoma - as a single agent or in combination with ipilimumab as initial systemic therapy for advanced or metastatic disease, or subsequent therapy for progression of advanced or metastatic dMMR/MSI-H disease for tumors that are deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H)
• Cervical cancer - as single agent second-line or subsequent therapy for adenocarcinoma, adenosquamous, or squamous cell carcinoma with local/regional recurrence or stage IVB or distant metastases in tumors with a PD-L1 combined positive score ≥ 1
• Chondrosarcoma – in combination with ipilimumab for unresectable or metastatic tumor mutational burden-high (TMB-H) conventional chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma that has progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Chordoma - in combination with ipilimumab for unresectable or metastatic tumor mutational burden-high (TMB-H) conventional or chondroid chordoma that has progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) - additional therapy as a single agent or in combination with ibrutinib for either clonally related or unknown clonal status Richter's transformation to diffuse large B-cell lymphoma in patients with del(17p)/TP53 mutations and who are chemotherapy refractory and unable to receive chemoimmunotherapy
• Classic Hodgkin lymphoma - as single agent, palliative therapy for relapsed or refractory disease individuals over age 60
• Classic Hodgkin lymphoma - as single agent therapy in individuals aged 18 to 60 years for disease refractory to at least 3 prior lines of therapy or as palliative therapy for relapsed or refractory disease in patients with poor performance status or substantial comorbidities
• Classic Hodgkin lymphoma - in combination with brentuximab vedotin or ICE (ifosfamide, carboplatin, etoposide) as second-line or subsequent systemic therapy for relapsed or refractory disease in individuals aged 18 to 60 years
• Classic Hodgkin lymphoma (Pediatric) - as a single agent or in combination with brentuximab vedotin as subsequent therapy for relapsed or refractory disease in patients heavily treated with platinum or anthracycline-based chemotherapy who have decreased cardiac function
• Classic Hodgkin lymphoma (Pediatric) - in combination with brentuximab vedotin or brentuximab vedotin and involved site radiation therapy as reinduction therapy for relapsed or refractory disease in patients heavily treated with platinum or anthracycline-based chemotherapy who have decreased cardiac function
• CNS - Brain metastases (limited) - as a single agent or in combination with ipilimumab in patients with BRAF non-specific melanoma as initial treatment in select patients or for recurrent or relapsed disease
• CNS - Brain metastases (limited) - as a single agent in patients with PD-L1 positive non-small cell lung cancer as initial treatment in select patients or for recurrent or relapsed disease
• CNS - Brain metastases (extensive) - as a single agent or in combination with ipilimumab in patients with BRAF non-specific melanoma as primary treatment in select patients or for recurrent disease
• CNS - Brain metastases (extensive) - as a single agent in patients with PD-L1 positive non-small cell lung cancer as primary treatment in select patients or for recurrent disease
• Colon cancer - as primary treatment for locally unresectable or medically inoperable disease as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors
• Colon cancer - as neoadjuvant treatment as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors for resectable synchronous liver and/or lung metastases or clinical T4b disease
• Colon cancer - as primary treatment as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors for synchronous abdominal/peritoneal metastases, synchronous unresectable metastases, unresectable metachronous metastases, or resectable metachronous metastases
• Colon cancer - as subsequent treatment as a single agent or in combination with ipilimumab for unresectable advanced or metastatic deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
• Diffuse high-grade glioma (Pediatric) - as single agent, adjuvant treatment for patients with hypermutant tumors excluding diffuse midline glioma, H3 K26-altered or pontine location
• Diffuse high-grade glioma (Pediatric) - as single agent treatment for recurrent or progressive disease in hypermutant tumors excluding oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant
• Endometrial cancer - (endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma) as a single agent, second-line or subsequent therapy for recurrent microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) tumors
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as first-line palliative therapy in combination with ipilimumab for patients with squamous cell carcinoma who are not surgical candidates or have recurrent disease (if no prior tumor progression while on therapy with a checkpoint inhibitor)
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as first-line palliative therapy in combination with fluorouracil or capecitabine and cisplatin or oxaliplatin for patients who are not surgical candidates or have recurrent squamous cell carcinoma (if no prior tumor progression while on therapy with a checkpoint inhibitor)
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – first-line palliative therapy in combination with oxaliplatin and fluorouracil or capecitabine for HER2-negative adenocarcinoma in patients who are not surgical candidates or have unresectable locally advanced or recurrent disease if no prior tumor progression while on therapy with checkpoint inhibitor
• Esophageal and esophagogastric junction (gastroesophageal junction) cancer – as single agent second-line or subsequent therapy for esophageal squamous cell carcinoma if no prior tumor progression while on therapy with checkpoint inhibitor
• Ewing sarcoma - in combination with ipilimumab for unresectable or metastatic tumor mutational burden-high (TMB-H) tumors that have progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Extrahepatic cholangiocarcinoma - as primary treatment in combination with ipilimumab for tumor mutational burden-high unresectable or resected gross residual or metastatic disease
• Extrahepatic cholangiocarcinoma - as subsequent treatment in combination with ipilimumab for tumor mutational burden-high unresectable or resected gross residual or metastatic disease that progressed on or after systemic treatment and is refractory to standard therapies or no standard treatments are available
• Extrahepatic cholangiocarcinoma - as subsequent, single agent treatment for unresectable or resected gross residual or metastatic disease that progressed on or after systemic treatment when there has been no prior treatment with a checkpoint inhibitor 
• Extranodal NK/T-cell lymphoma, nasal type - as a single agent for relapsed or refractory disease following additional therapy with an alternate asparaginase-based combination chemotherapy regimen, not previously used and when a clinical trial is not available
• Gallbladder cancer - in combination with ipilimumab for tumor mutational burden-high (TMB-H) unresectable, resected gross residual (R2), or metastatic disease
• Gallbladder cancer - as single agent, subsequent therapy for unresectable, resected gross residual (R2), or metastatic disease that progressed on or after systemic treatment when there has been no prior treatment with a checkpoint inhibitor
• Gastric cancer – as first-line, palliative therapy in combination with oxaliplatin and fluorouracil or capecitabine for HER2-negative tumors in patients who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease
• Gastric cancer - as primary treatment in combination with oxaliplatin and fluorouracil or capecitabine in patients who are medically fit for surgery but with surgically unresectable locoregional HER2-negative disease
• Gestational trophoblastic neoplasia - as single agent therapy for recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen when the disease is multiagent chemotherapy resistant
• Gestational trophoblastic neoplasia - as single agent therapy for high-risk, multiagent chemotherapy resistant disease
• Head and neck cancer (supraglottic larynx, glottic larynx, subglottis, oropharynx, hypopharynx, ethmoid sinus, maxillary sinus, occult primary, and oral cavity including mucosal lip) - in combination with cetuximab as first-line therapy or subsequent-line therapy for metastatic (M1) disease at initial presentation, recurrent/persistent disease with distant metastases, unresectable locoregional recurrence with prior radiation therapy (RT), unresectable second primary with prior RT, unresectable persistent disease with prior RT or resectable locoregional recurrence or persistent disease without prior radiation therapy
• Head and neck cancer (supraglottic larynx, glottic larynx, subglottis, oropharynx, hypopharynx, ethmoid sinus, maxillary sinus, occult primary, and oral cavity including mucosal lip) – as single agent, subsequent-line systemic therapy for disease that progressed on or after platinum therapy in patients with no previous immunotherapy for persistent or progressive metastatic disease (M1) at initial presentation following first-line therapy; unresectable locoregional recurrence without prior radiation therapy (RT) or unresectable persistent disease without prior RT; unresectable locoregional recurrence with prior RT, unresectable second primary with prior RT, or unresectable persistent disease with prior RT, or recurrent/persistent disease with distant metastases
• Head and neck cancer (mucosal melanoma of the larynx, hypopharynx, oropharynx, nasal cavity, sinus cavity, and oral cavity) - as adjuvant single agent therapy with postoperative radiation for T3-4a, N0-1 disease
• Hepatocellular carcinoma - as first-line single agent or subsequent therapy in patients with Child-Pugh class B, unresectable disease who are not candidates for transplant; for liver-confined disease that is inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease; or for metastatic disease or extensive tumor burden
• Hepatocellular carcinoma - as first-line therapy in combination with ipilimumab in patients with tumor mutational burden-high, unresectable disease and who are not candidates for transplant; for liver-confined disease that is inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease; or for metastatic disease or extensive tumor burden 
• Hepatocellular carcinoma - as subsequent therapy in combination with ipilimumab for Child-Pugh class A disease that is  unresectable in patients who are not candidates for transplant; for disease that is confined to the liver and inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease; or for metastatic or extensive liver tumor burden
• Hepatocellular carcinoma - as subsequent therapy in combination with ipilimumab for tumor mutational burden-high disease that is unresectable in patients who are not candidates for transplant; for disease that is confined to the liver and inoperable by performance status, comorbidity or with minimal or uncertain extrahepatic disease; or for metastatic disease or extensive liver tumor burden
• High-grade undifferentiated pleomorphic sarcoma of the bone - in combination with ipilimumab for unresectable or metastatic tumor mutational burden-high (TMB-H) tumors that have progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Intrahepatic cholangiocarcinoma - as primary treatment in combination with ipilimumab for tumor mutational burden-high unresectable or resected gross residual or metastatic disease
• Intrahepatic cholangiocarcinoma - as subsequent treatment in combination with ipilimumab for tumor mutational burden-high unresectable or resected gross residual or metastatic disease that progressed on or after systemic treatment and is refractory to standard therapies or no standard treatments are available
• Intrahepatic cholangiocarcinoma - as subsequent, single agent treatment for unresectable or resected gross residual or metastatic disease that progressed on or after systemic treatment when there has been no prior treatment with a checkpoint inhibitor
• Kaposi sarcoma - in combination with ipilimumab for advanced cutaneous, oral, visceral, or nodal classic Kaposi sarcoma that progressed on first-line systemic therapy or did not respond to first-line systemic therapy, and progressed on alternate first-line systemic therapy
• Melanoma (cutaneous) - as single agent, adjuvant therapy for 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; resected stage III sentinel node positive disease during observation without additional nodal surgery and with mandatory radiographic nodal surveillance; resected stage III sentinel node positive disease after completion of lymph node dissection (CLND) based on risk of recurrence; stage III disease with clinically positive node(s) following wide exision of primary tumor and therapeutic lymph node dissection or neodadjuvant therapy; stage III disease with clinical satellite/in-transit metastases if no evidence of disease after initial local or regional therapy; local satellite/in-transit recurrence if no evidence of disease after complete excision to clear marginsH. Local satellite/in-transit recurrence if no evidence of disease after initial local or regional therapy; or for resectable disease limited to nodal recurrence following excision and CLND or neoadjuvant therapy
• Melanoma (cutanous) - as adjuvant therapy as a single agent or in combination with ipilimumab following metastasis-directed therapy (stereotactic ablative therapy, T-VEC/intralesional therapy, or complete resection) if no evidence of disease or as systemic therapy followed by resection for oligometastatic disease
• Melanoma (cutaneous) - initial therapy as a single agent for limited resectable stage III disease with clinical satellite/in transit metastases or limited resectable local satellite/in-transit recurrence
• Melanoma (cutaneous) - as a single agent or in combination with ipilimumab as re-induction therapy when prior anti-PD-1 immunotherapy resulted in disease control (complete response, partial response, or stable disease) with subsequent disease progression/relapse > 3 months after treatment discontinuation with no residual toxicity
• Merkel cell carcinoma - as a single agent neoadjuvant therapy for regional, pathologic N+ disease or with or without surgery and/or radiation therapy for primary or recurrent clinical M1 disseminated disease
• Mesothelioma: Peritoneal - as first-line systemic therapy in combination with ipilimumab for diffuse disease with unicavitary, epithelioid histology; for diffuse disease with biphasic/sarcomatoid histology or bicavitary disease; or for recurrence of benign multicystic or well-differentiated papillary disease after prior cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy
• Mesothelioma: Peritoneal - as subsequent systemic therapy as a single agent or in combination with ipilimumab when chemotherapy was not administered first line
• Mesothelioma: Pleural - as first-line systemic therapy or induction chemotherapy in combination with ipilimumab for clinical stage I-IIIA disease and epithelioid histology when induction chemotherapy was not given
• Mesothelioma: Pleural - as first-line systemic therapy or induction chemotherapy in combination with ipilimumab for clinical stage IIIB or IV disease, sarcomatoid or biphasic histology, or medically inoperable tumors when performance status is 0-2
• Mesothelioma: Pleural - as subsequent systemic therapy as a single agent or in combination with ipilimumab when chemotherapy was administered first line
• Neuroendocrine tumors - in combination with ipilimumab for extrapulmonary poorly differentiated neuroendocrine carcinoma/large or small cell carcinoma/mixed neuroendocrine-non-neuroendocrine neoplasm if progression on first-line chemotherapy for metastatic disease
• Neuroendocrine tumors - in combination with ipilimumab for locally advanced/metastatic well-differentiated grade 3 tumors with unfavorable biology
• Non-small cell lung cancer - as a single agent, or in combination with ipilimumab; pemetrexed; and platinum chemotherapy, or ipilimumab; paclitaxel; and carboplatin for stage IV or recurrent disease with no prior progression on a PD-1/PD-L1 inhibitor for first progression following initial cytotoxic therapy or for subsequent progression
• Non-small cell lung cancer – in combination with paclitaxel and carboplatin or gemcitabine and cisplatin for induction chemotherapy in resectable disease likely to receive adjuvant chemotherapy
• Non-small cell lung cancer – as a single agent or in combination with ipilimumab, ipilimumab; pemetrexed; and platinum chemotherapy, or ipilimumab; paclitaxel; and platinum chemotherapy for stage IV, recurrent or advanced, first-line or initial therapy
• Non-small cell lung cancer – in combination with ipilimumab for continuation maintenance therapy
• Osteosarcoma - in combination with ipilimumab for unresectable or metastatic tumor mutational burden-high (TMB-H) tumors that have progressed following prior treatment in adults who have no satisfactory alternative treatment options
• Primary mediastinal large B-cell lymphoma (Pediatric) - consolidation/additional therapy in combination with brentuximab vedotin in pediatric patients who achieved a partial response after therapy for relapsed or refractory disease
• Primary mediastinal large B-cell lymphoma (Pediatric) - as a single agent for the treatment of relapsed or refractory disease
• Rectal cancer - as primary treatment for stage 0-III disease as a single agent or in combination with ipilimumab for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), T3, N Any; T1-2, N1-2; T4, N Any or locally unresectable or medically inoperable tumors
• Rectal cancer - as neoadjuvant treatment as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors for resectable synchronous liver only and/or lung only metastases; or for resectable synchronous liver only and/or lung only metastases with involved CRM (by MRI) when previously treated with neoadjuvant radiation with or without concurrent chemotherapy
• Rectal cancer - as primary treatment as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors for synchronous abdominal/peritoneal metastases, synchronous unresectable metastases, unresectable metachronous metastases, resectable metachronous metastases, or potentially resectable or unresectable isolated pelvic/anastomotic recurrence
• Renal cell cancer (clear cell histology) - as first-line therapy in combination with ipilimumab for 4 cycles followed by single agent nivolumab for relapse or stage IV favorable risk disease
• Renal cell cancer (clear cell histology) - as subsequent therapy as a single agent, in combination with cabozantinib, or in combination with ipilimumab for 4 cycles followed by single agent nivolumab for relapse or stage IV disease
• Renal cell cancer (non-clear cell histology) - as a single agent, in combination with cabozantinib, or in combination with ipilimumab for 4 cycles followed by single agent nivolumab as systemic therapy for relapse or stage IV disease
• Small bowel adenocarcinoma - as a single agent or in combination with ipilimumab for advanced metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
• Small cell lung cancer - as a single agent for relapse following complete or partial response or stable disease with primary treatment or for primary progresive disease
• Urothelial (transitional cell) carcinoma - as single agent adjuvant therapy for the treatment of pathologic stage T2-4 or nodal disease (N+) of the renal pelvis or urothelial carcinoma of the ureter
• Urothelial (transitional cell) carcinoma - as single agent adjuvant therapy for urothelial carcinoma of the prostate as primary treatment for tumors with stromal invasion
• Urothelial (transitional cell) carcinoma - as single agent adjuvant therapy for pathologic stage T3-4 or N1-2 disease in the male bulbar urethra
• Urothelial (transitional cell) carcinoma - as single agent, subsequent systemic therapy post other chemotherapy for urothelial carcinoma of the bladder, the upper genitourinary tract, the prostate, and primary carcinoma of the urethra
• Uveal melanoma - as a single agent or in combination with ipilimumab for distant metastatic disease
• Vulvar cancer - as single agent, second-line therapy for HPV-related, advanced or recurrent/metastatic disease

Opdivo is considered investigational in all other patients and for all other indications.

Policy Guidelines

FDA-approved indication: Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with: (1)

1 Unresectable or metastatic melanoma
   d. BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent
   e. BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent
   f. Unresectable or metastatic melanoma, in combination with ipilimumab

 2 Adjuvant Treatment of Melanoma
    a. Melanoma with lymph node involvement or metastatic disease who have undergone complete resection, in the adjuvant setting

3 Metastatic Non-Small Cell Lung Cancer

• OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test [see Dosage and Administration (2.1)], with no EGFR or ALK genomic tumor aberrations.

• OPDIVO, in combination with ipilimumab and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK  genomic tumor aberrations.

• OPDIVO is indicated for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

• OPDIVO is indicated for adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer in the neoadjuvant setting, in combination with platinum-doublet chemotherapy.

4 Malignant Pleural Mesothelioma

OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma.

5 Advanced Renal Cell Carcinoma

• OPDIVO, in combination with ipilimumab, is indicated for the first-line treatment of patients with intermediate or poor risk advanced RCC.

• OPDIVO, in combination with cabozantinib, is indicated for the first-line treatment of patients with advanced RCC.

• OPDIVO as a single agent is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

6 Classical Hodgkin Lymphoma

OPDIVO is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after:

• autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or

• 3 or more lines of systemic therapy that includes autologous HSCT.

This indication is approved under accelerated approval based on the overall response rate [see Clinical Studies (14.6)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

7 Squamous Cell Carcinoma of the Head and Neck

OPDIVO is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

8 Urothelial Carcinoma

OPDIVO is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who:

• have disease progression during or following platinum-containing chemotherapy

• have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14.8)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

9 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.9)]. Continued approval for this indication maybe

10 Hepatocellular Carcinoma

OPDIVO, as a single agent or in combination with ipilimumab, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.10)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

11 Esophageal Squamous Cell Carcinoma

OPDIVO is indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine and platinum-based chemotherapy.

Off-Label Uses: (2) INVESTIGATIONAL

Small Cell Lung Cancer
Metastatic anal cancer
Merkel cell carcinoma

Clinically significant immune-mediated adverse reactions may occur with Opdivo therapy including pneumonitis, colitis, hepatitis, nephritis, renal dysfunction,

hyperthyroidism, and hypothyroidism. Patients should be monitored for signs and symptoms of adverse reactions and based on the severity, Opdivo should be withheld

or discontinued and corticosteroids administered. Opdivo may cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential

should be advised of the potential hazard to a fetus. Opdivo is administered every 2 weeks until disease progression or unacceptable toxicity (1).

The patient must have ONE of the following:

1. Unresectable or metastatic melanoma

• 240 mg every 2 weeks or 480 mg every 4 weeks 

• 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks

2. Adjuvant treatment of melanoma 

• 240 mg every 2 weeks or 480 mg every 4 weeks.

3. Metastatic non-small cell lung cancer

• 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks. (2.2)

• 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy. (2.2)

• 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)

4. Advanced renal cell carcinoma

• 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. (2.2)

• 240 mg every 2 weeks or 480 mg every 4 weeks administered in combination with cabozantinib 40 mg once daily without food. (2.2)

• 240 mg every 2 weeks or 480 mg every 4 weeks.  

5. Relapsed or progressed classical Hodgkin lymphoma

• 240 mg every 2 weeks or 480 mg every 4 weeks

6. Recurrent or metastatic squamous cell carcinoma of the head and neck

• 240 mg every 2 weeks or 480 mg every 4 weeks

7. Locally advanced or metastatic urothelial carcinoma

• 240 mg every 2 weeks or 480 mg every 4 weeks

8. Hepatocellular carcinoma

• 240 mg every 2 weeks or 480 mg every 4 weeks. 

• 1 mg/kg followed by ipilimumab 3 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks

9. Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer

• Adult and pediatric patients ≥ 40 kg: 240 mg every 2 weeks or 480 mg every 4 weeks. 

• Pediatric patients < 40 kg: 3 mg/kg every 2 weeks.  

• Adult and pediatric patients ≥ 40 kg: 3 mg/kg followed by ipilimumab 1 mg/kg on the same day every 3 weeks for 4 doses, then 240 mg every 2 weeks or 480 mg every 4 weeks. 

10.  Malignant pleural mesothelioma

• 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks. 

11.  Esophageal squamous cell carcinoma

• 240 mg every 2 weeks or 480 mg every 4 weeks

AND the following for ALL indications:

a. Prescriber agrees to discontinue treatment for any immune-mediated adverse reaction (encephalitis, nephritis, rash, decreased renal function and endocrinopathies) or disease progression

Hospital Admission of the patient for the sole and only purpose to administer Opdivo ® requires individual preauthorization for treatment in essence of service. The request must include the following documentation:

1. Insured's contract number.
2. It must be prescribed by a hematologist or oncologist.
3. Diagnostic code ICD-9 or ICD-10.
4. Documentation of medical necessity
5. Evidence of at least one metastasis
6. Number of milligrams to be administered, planned course to be undertaken.

 If a patient, with the diagnosis approved for payment by this policy, is admitted to the hospital, and as part of the treatment requires the use of Optivo ®, Triple-S will cover the treatment after the requirements above are met
.
Triple-S pays only the dose every 3 weeks of the medication.
Triple-S will not consider for payment the use of Opdivo® under the following circumstances:

a. The patient has hypersensitivity to the product or any of its
components.
b. Patient does not meet any of the above criteria.

Benefit Application

BlueCard/National Account Issues

N/A

Preferred drugs

Triple-S Salud will consider biosimilars Kanjinti, Ogivri and Trazimera as preferred agents for covered conditions.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Opdivo is a monoclonal antibody for the treatment of patients with unresectable (cannot be removed by surgery), metastatic (advanced) melanoma, adjuvant treatment of melanoma and metastatic non-small cell lung cancer, metastatic small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, relapsed or progressed classical Hodgkin

lymphoma, recurrent or metastatic squamous cell carcinoma of the head and neck, locally advanced or metastatic urothelial carcinoma, or microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer who are no longer responding to other drugs. Opdivo works by inhibiting the PD-1 protein on cell surfaces,

which blocks the immune system from attacking melanoma tumors. Opdivo is intended for patients who have been previously treated with ipilimumab and, for melanoma patients whose tumors express a gene mutation called BRAF V600, after treatment with ipilimumab and a BRAF inhibitor have lost effectiveness (1).

Advanced Melanoma

Melanoma accounts for approximately 5% of all new cases of cancer in the United States. It is the most dangerous form of skin cancer that develops by damage to the DNA of the skin cells causing mutations that generate a accelerated cell multiplication and the formation of malignant tumors. These tumors are produced in melanocytes (skin pigment

producing cells; melanin), located in the basement membrane of the epidermis. According to the American Society against Cancer, it is estimated that more than 120,000 new cases of melanoma are diagnosed in one year and that approximately 9,710 patients die due to this disease annually. This type of cancer if it is not identified or treated in time

it can spread to other cells of the body becoming metastatic melanoma.

Advanced Melanoma

The first clinical trial was multicenter, open label and randomly assigned (2: 1) patients with unresectable or metastatic melanoma who receive either OPDIVO administered intravenously at 3 mg / kg every 2 weeks or chosen by the chemotherapy investigator, either as a single agent dacarbazine 1000 mg / m2 every 3 weeks or combination of

carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg / m2 every 3 weeks. The patients needed to showprogression of the disease in or after treatment with ipilimumab and positive mutation of BRAF V600, an inhibitor of BRAF. The trial excluded patients with autoimmune diseases, medical conditions that require systemic immunosuppression,

ocular melanoma, metastatic active brain disease, or a history of grade 4 adverse reactions related to ipilimumab (with the exception of endocrinopathies) or grade 3 related to ipilimumab that had not been resolved or were insufficiently controlled within 12 weeks of the event. Tumor evaluations were performed 9 weeks after randomization and then

every 6 weeks during the first year, and finally every 12 weeks. Efficacy was evaluated in a single non-comparative arm of intermediate analysis of the first 120 patients who received OPDIVO in Trial 1 and in which the minimum follow-up duration was 6 months. The main efficiency outcome measures in this population were confirmed objective response

rate (ORR), measured by the independent central review without the use of response evaluation criteria in solid tumors (RECIST 1.1) and duration of the response.

Non-small Cell Lung Cancer Advanced

Lung cancer is the leading cause of death from cancer in the United States. About 85-90% of cancerous tumors in the lung are diagnosed as non-small cell lung cancer, by its size. This develops due to damage to DNA in the cells of the lining of the bronchi or other structures of the lung as bronchioles and alveoli. This genetic damage causes

mutations in the cells, it generates an accelerated cell multiplication and the formation of malignant tumors. According to American Cancer Society, it is estimated that more than 221,200 new cases are diagnosed in one year and that approximately 158,040 patients die due to this disease annually. If this type of cancer is not identified or treated in time it

can spread to other body cells becoming lung cancer non-small metastatic cells.

Advanced Non-Small Cell Lung Cancer

Nivolumab demonstrated significantly superior overall survival (OS) versus docetaxel, with a 41% reduction in the risk of death (hazard ratio: 0.59 [CI 95%: 0.44, 0.79; p = 0.00025]), in a pre-specified intermediate analysis of a phase III of clinical trials. The median OS was 9.2 months in the Opdivo group (IC of the 95%: 7.3, 13.3) and 6 months in

the docetaxel group (95% CI: 5.1, 7.3).

Advanced Renal Cancer

Kidney cancer is the most common form of kidney cancer in adults. It is formed by DNA damage to cells in the tissues of the kidneys where urine is produced. This genetic damage causes mutations in the cells, generates an accelerated cell multiplication and malignant tumor formation. According to the American Cancer Society, it is estimated that

more than 61,560 new cases of melanoma are diagnosed in one year and that approximately 14,080 patients die from this disease annually. If this type of cancer is not identified or treated early, it can spread to other cells in the body and metastatic kidney cancer.

Normative Situation

Advanced Renal Cancer

The FDA approved Opdivo® to treat patients with advanced kidney cancer, who have received previous treatment with anti-angiogenic therapy (treatment that interferes with the blood vessels that contribute to the growth of cancer cells). The efficacy and safety of Opdivo® was established in 821 patients participating in a clinical study with advanced

kidney cancer and whose disease progressed after receiving treatment with an anti-angiogenic agent. The participants were treated with Opdivo® 3 milligrams per kilogram (mg /kg) every 2 weeks. Those who were treated with Opdivo® lived approximately 25 months after starting treatment. This effect was observed despite the level of expression of PD-

L1 protein. In approximately 21.5% of the participants a reduction in the size of their tumors was observed. This effect lasted approximately 13.7 months. The most common side effects reported were weakness or lack of energy, cough, nausea, rash, shortness of breath, diarrhea, constipation, decreased appetite, back pain and

joint pain. Opdivo® can also cause severe side effects associated with immunological reactions or related to damage to healthy organs (such as the lungs, colon, liver, kidneys, hormone-producing glands and brain) are rare.

Classical Hodgkin's lymphoma

Hodgkin's lymphoma (HL), also known as Hodgkin's disease, is a cancer of the lymphatic system, which originates in the white blood cells. HL is one of the two main types of lymphomas. The five-year survival rate for advanced LH is approximately 65 percent in the US The average age of diagnosis is 38 in the US This year, it is estimated that more

than 9,100 new cases of be diagnosed with more than 1,100.

Normative Situation

Hodgkin's lymphoma

On May 17, 2016, the FDA granted accelerated approval of nivolumab for the treatment of patients with classic Hodgkin lymphoma who has relapsed or progressed after a transplant of autologous hematopoietic tissue (TPH) and Brentuximab vendotin (Adcetris®) post-transplant.

The NCCN guidelines (2016) recommend nivolumab for older adults of 18 years with classic Hodgkin's lymphoma, as an additional treatment for refractory disease, progression or relapse.

The safety of OPDIVO 3 mg / kg was evaluated every 2 weeks in 263 adult patients with CHL (240 patients in trial of 8 and 23 patients in trial 9). The treatment could continue until disease progression, maximum clinical benefit, or unacceptable toxicity. The median age was 34 years (range 18 to 72), 98% of the patients had received autologous TPH,

none had received allogeneic HSCT, and 74% had received Brentuximab vedotina. The median number of systemic regimens previous was 4 (range: 1 to 15). Patients received a median of 10 doses (cycles) of OPDIVO (range: 1 to 48), with a mild duration. Therapy 4.8 months (range: 0.3 to 24 months)

OPDIVO was discontinued due to adverse reactions in 4.2% of patients. In 23% of the patients, there was a delay in the dose for a serious adverse reaction. The reactions occurred in 21% of patients. Most frequent Serious adverse reactions reported in at least 1% of patients were related to infusion reaction, pneumonia, pleural effusion, fever,

rash, and pneumonitis. Ten patients died from different causes not related to disease progression, including 6 who died from complications of allogeneic HSCT. The most common reactions adverse events (reported in at least 20%) among all patients (safety population), were fatigue, upper respiratory tract infection, fever, diarrhea and cough.

For Adults With Previously Treated Advanced Bladder Cancer (urothelial carcinoma)

OPDIVO® (nivolumab) is a prescription medicine used to treat bladder cancer (urothelial carcinoma) that has spread or grown and you have tried chemotherapy that contains platinum, and it did not work or is no longer working.

OPDIVO was approved based on the response rate and how long patients' responses lasted. There is an ongoing evaluation of the clinical benefit of OPDIVO for this use.

The recommended dose of OPDIVO is either 240 mg every 2 weeks or 480 mg every 4 weeks administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity.

It is not known if OPDIVO is safe and effective in children less than 18 years of age.

OPDIVO® (nivolumab) for adults with previously treated head and neck cancer

Nivolumab — In the Checkmate-141 phase III trial, 361 patients with platinum-refractory, recurrent or metastatic disease were randomly assigned to either nivolumab (3 mg/kg

every two weeks) or a single-agent investigator's choice of therapy (methotrexate, docetaxel, or cetuximab) [19,72,73].

●With a minimum follow-up of 11.4 months, overall survival for the entire study population was significantly longer in patients treated with nivolumab (median 7.7 versus 5.1 months, one-year survival rate 34.0 versus 19.7 percent, HR 0.71, 95% CI 0.55-0.90). The objective response rate was also increased with nivolumab (13.3 versus 5.8 percent).

●In a prespecified exploratory analysis, overall survival was significantly increased with immunotherapy in patients with PD-L1 expression ≥1 percent (8.7 versus 4.6 months, HR 0.55, 95% CI 0.36-0.83). Overall survival was not significantly increased in patients with PD-L1 expression <1 percent (HR 0.89, 95% CI 0.54-1.45).

●In a post hoc exploratory analysis, overall survival was significantly increased in patients with HPV positive tumors treated with immunotherapy (median 9.1 versus 4.4 months, HR 0.56, 95% CI 0.32-0.99). The difference in overall survival was not statistically significant in those with HPV negative tumors (median 7.5 versus 5.8 months, HR 0.73, 95% CI 0.42-1.25).

Nivolumab was not routinely available for those patients randomized to chemotherapy, and routine use of nivolumab after second-line chemotherapy could negate or minimize the survival benefit of immediate nivolumab.

●Patient-reported outcomes on a quality of life questionnaire found that there was no clinically meaningful deterioration associated with treatment with nivolumab immunotherapy, in contrast to chemotherapy, where the quality of life significantly decreased in 8 of 15 domains [72].

Based upon the results of this phase III trial, nivolumab was approved by the FDA at a dose of 240 mg every two weeks [74]. Subsequently, an alternative schedule of nivolumab 480 mg every four weeks was approved based on clinical pharmacology analyses and safety assessments [75].

Regulatory Status

FDA-approved indication: Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with advanced melanoma, advanced non-small cell lung cancer, Malignant pleural mesothelioma, advanced renal cell carcinoma, classical Hodgkin lymphoma, advanced squamous cell carcinoma of the head andneck, urothelial carcinoma, MSI-H or dMMR metastatic colorectal cancer, and hepatocellular carcinoma.

Rationale

Opdivo is a monoclonal antibody indicated for the treatment of various types of cancers.
 

Opdivo (nivolumab) is a human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-

1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

Opdivo may cause fetal harm when administered to a pregnant woman (1).

Prior authorization is required to ensure the safe, clinically appropriate and cost-effective use of Opdivo while maintaining optimal therapeutic outcomes.

Population Reference No. 1 

 Metastatic Non-Small Cell Lung Cancer 

First-line Treatment of Metastatic Non-Small Cell Lung Cancer (NSCLC) Expressing PD-L1 (≥1%): In Combination with Ipilimumab

CHECKMATE-227 (NCT02477826) was a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC. The study included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer [ASLC] classification), ECOG performance status 0 or 1, and no prior anticancer therapy. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with treated brain metastases were eligible if neurologically returned to baseline at least 2 weeks prior to enrolment, and either off corticosteroids, or on a stable or decreasing dose of <10 mg daily prednisone equivalents.

Primary efficacy results were based on Part 1a of the study, which was limited to patients with PD-L1 tumor expression ≥1%. Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. Randomization was stratified by tumor histology (non-squamous versus squamous). The evaluation of efficacy relied on the comparison between:

OPDIVO 3 mg/kg administered intravenously over 30 minutes every 2 weeks in combination with ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks; or

• Platinum-doublet chemotherapy

Chemotherapy regimens consisted of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2 ) or pemetrexed (500 mg/m2 ) and carboplatin (AUC 5 or 6) for non-squamous NSCLC or gemcitabine (1000 or 1250 mg/m2 ) and cisplatin (75 mg/m2 ) or gemcitabine (1000 mg/m2 ) and carboplatin (AUC 5) (gemcitabine was administered on Days 1 and 8 of each cycle) for squamous NSCLC.

Study treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse event attributed to ipilimumab were permitted to continue OPDIVO as a single agent. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

In Part 1a, a total of 793 patients were randomized to receive either OPDIVO in combination with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397). The median age was 64 years (range: 26 to 87) with 49% of patients ≥65 years and 10% of patients ≥75 years, 76% White, and 65% male. Baseline ECOG performance status was 0 (34%) or 1 (65%), 50% with PD-L1 ≥50%, 29% with squamous and 71% with non-squamous histology, 10% had brain metastases, and 85% were former/ current smokers.

The study demonstrated a statistically significant improvement in OS for PD-L1 ≥1% patients randomized to the OPDIVO and ipilimumab arm compared with the platinumdoublet chemotherapy arm.

BICR-assessed PFS showed a HR of 0.82 (95% CI: 0.69, 0.97), with a median PFS of 5.1 months (95% CI: 4.1, 6.3) in the OPDIVO and ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm. The BICR-assessed confirmed ORR was 36% (95% CI: 31, 41) in the OPDIVO and ipilimumab arm and 30% (95% CI: 26, 35) in the platinum-doublet chemotherapy arm. Median duration of response observed in the OPDIVO and ipilimumab arm was 23.2 months and 6.2 months in the platinum-doublet chemotherapy arm.

First-line Treatment of Metastatic or Recurrent NSCLC: In Combination with Ipilimumab and Platinum-Doublet Chemotherapy

CHECKMATE-9LA (NCT03215706) was a randomized, open-label trial in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.

Patients were randomized 1:1 to receive either:

OPDIVO 360 mg administered intravenously over 30 minutes every 3 weeks, ipilimumab 1 mg/kg administered intravenously over 30 minutes every 6 weeks, and platinum-doublet chemotherapy administered intravenously every 3 weeks for 2 cycles, or

• platinum-doublet chemotherapy administered every 3 weeks for 4 cycles.

Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/m2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until  disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.

A total of 719 patients were randomized to receive either OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients ≥65 years and 10% of patients ≥75 years. The majority of patients were White  (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression ≥1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.

The study demonstrated a statistically significant benefit in OS, PFS, and ORR.

Population Reference No. 2 

Melanoma 

CHECKMATE-238 (NCT02388906) was a randomized, double-blind trial that enrolled patients with completely resected Stage IIIB/C or Stage IV melanoma. Patients were randomized (1:1) to receive 3 mg/kg of OPDIVO over 60 minutes by intravenous infusion every 2 weeks or ipilimumab administered as an intravenous infusion at 10 mg/kg every 3 weeks for 4 doses then every 12 weeks beginning at Week 24 for up to 1 year. Enrollment required complete resection of melanoma with margins negative for disease within 12 weeks prior to randomization. The trial excluded patients with a history of ocular/uveal melanoma, autoimmune disease, and any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, as well as patients with prior therapy for melanoma except surgery, adjuvant radiotherapy after neurosurgical resection for lesions of the central nervous system, and prior adjuvant interferon completed ≥6 months prior to randomization.

Randomization was stratified by PD-L1 status (positive [based on 5% level] vs negative/indeterminate) and American Joint Committee on Cancer (AJCC) stage (Stage IIIB/C vs Stage IV M1a-M1b vs Stage IV M1c).The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first and as assessed by the investigator.

Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter.

In CHECKMATE-238, a total of 906 patients were randomized: 453 to OPDIVO and 453 to ipilimumab. Median age was 55 years (range: 18 to 86), 58% were male, 95% were White, and 90% had an ECOG performance status of 0. Disease characteristics were AJCC Stage IIIB (34%), Stage IIIC (47%), Stage IV (19%), M1a-b (14%), BRAF V600 mutation positive (42%), BRAF wild-type (45%), elevated LDH (8%), PD-L1 ≥ 5% tumor cell membrane expression determined by clinical trial assay (34%), macroscopic lymph nodes (48%), and tumor ulceration (32%). CHECKMATE-238 demonstrated a statistically significant improvement in RFS for patients randomized to the OPDIVO arm compared with the ipilimumab 10 mg/kg arm.

OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma. 

Population Reference No. 3 

Advanced Renal Cell Carcinoma 

First-line Renal Cell Carcinoma

CHECKMATE-214

CHECKMATE-214 (NCT02231749) was a randomized (1:1), open-label trial in patients with previously untreated advanced RCC. Patients were included regardless of their PD-L1 status. CHECKMATE-214 excluded patients with any history of or concurrent brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients were stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score and region.

Efficacy was evaluated in intermediate/poor risk patients with at least 1 or more of 6 prognostic risk factors as per the IMDC criteria (less than one year from time of initial renal cell carcinoma diagnosis to randomization, Karnofsky performance status <80%, hemoglobin less than the lower limit of normal, corrected calcium of >10 mg/dL, platelet count greater than the upper limit of normal, and absolute neutrophil count greater than the upper limit of normal).

Patients were randomized to OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses followed by OPDIVO 3 mg/kg intravenously every two weeks (n=425), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (n=422). Treatment continued until disease progression or unacceptable toxicity

The trial population characteristics were: median age was 61 years (range: 21 to 85) with 38% ≥65 years of age and 8% ≥75 years of age. The majority of patients were male (73%) and White (87%) and 26% and 74% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively.

The major efficacy outcome measures were OS, PFS (independent radiographic review committee [IRRC]-assessed) and confirmed ORR (IRRC-assessed) in intermediate/ poor risk patients. In this population, the trial demonstrated statistically significant improvement in OS and ORR for patients randomized to OPDIVO and ipilimumab as compared with sunitinib (Table 51 and Figure 12). OS benefit was observed regardless of PD-L1 expression level. The trial did not demonstrate a statistically significant improvement in PFS.

CHECKMATE-214 also randomized 249 favorable risk patients as per IMDC criteria to OPDIVO and ipilimumab (n=125) or to sunitinib (n=124). These patients were not evaluated as part of the efficacy analysis population. OS in favorable risk patients receiving OPDIVO and ipilimumab compared to sunitinib has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The efficacy of OPDIVO and ipilimumab in previously untreated renal cell carcinoma with favorable-risk disease has not been established.

CHECKMATE-9ER CHECKMATE-9ER (NCT03141177) was a randomized, open-label study of OPDIVO combined with cabozantinib versus sunitinib in patients with previously untreated advanced RCC. CHECKMATE-9ER excluded patients with autoimmune disease or other medical conditions requiring systemic immunosuppression. Patients were stratified by IMDC prognostic score (favorable vs. intermediate vs. poor), PD-L1 tumor expression (≥1% vs. <1% or indeterminate), and region (US/Canada/Western Europe/Northern Europe vs. Rest of World).

Patients were randomized to OPDIVO 240 mg intravenously every 2 weeks and cabozantinib 40 mg orally daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328). Treatment continued until disease progression per RECIST v1.1 or unacceptable toxicity. Treatment beyond RECIST-defined disease progression was permitted if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Tumor assessments were performed at baseline, after randomization at Week 12, then every 6 weeks until Week 60, and then every 12 weeks thereafter

The trial population characteristics were: median age 61 years (range: 28 to 90) with 38% ≥65 years of age and 10% ≥75 years of age. The majority of patients were male (74%) and White (82%) and 23% and 77% of patients had a baseline KPS of 70% to 80% and 90% to 100%, respectively. Patient distribution by IMDC risk categories was 22% favorable, 58% intermediate, and 20% poor.

Population Reference No. 4 

Unresectable Malignant Pleural Mesothelioma 

CHECKMATE-743 (NCT02899299) was a randomized, open-label trial in patients with unresectable malignant pleural mesothelioma. The trial included patients with histologically confirmed and previously untreated malignant pleural mesothelioma with no palliative radiotherapy within 14 days of initiation of therapy. Patients with interstitial lung disease, active autoimmune disease, medical conditions requiring systemic immunosuppression, or active brain metastasis were excluded from the trial.

Patients were randomized 1:1 to receive either:

OPDIVO 3 mg/kg over 30 minutes by intravenous infusion every 2 weeks and ipilimumab 1 mg/kg over 30 minutes by intravenous infusion every 6 weeks for up to 2 years, or

• cisplatin 75 mg/m2 and pemetrexed 500 mg/m2, or carboplatin 5 AUC and pemetrexed 500 mg/m2 administered every 3 weeks for 6 cycles.

Stratification factors for randomization were tumor histology (epithelioid vs. sarcomatoid or mixed histology subtypes) and sex (male vs. female). Study treatment continued for up to 2 years, or until disease progression or unacceptable toxicity. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR utilizing modified RECIST criteria.

A total of 605 patients were randomized to receive either OPDIVO in combination with ipilimumab (n=303) or chemotherapy (n=302). The median age was 69 years (range: 25 to 89), with 72% of patients ≥65 years and 26% ≥75 years; 85% were White, 11% were Asian, and 77% were male. Baseline ECOG performance status was 0 (40%) or 1 (60%), 35% had Stage III and 51% had Stage IV disease, 75% had epithelioid and 25% had non-epithelioid histology, 75% had tumors with PD-L1 expression ≥1%, and 22% had tumors with PD-L1 expression <1%.  The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO in combination with ipilimumab compared to chemotherapy

Population Reference No. 5 

Gastric, Gastroesophageal Junction, and Esophageal Cancers

CHECKMATE-649 (NCT02872116) was a randomized, multicenter, open-label trial in patients (n=1581) with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. The trial enrolled patients regardless of PD-L1 status, and tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory. The trial excluded patients who were known human epidermal growth factor receptor 2 (HER2)  positive, or had untreated CNS metastases. Patients were randomized to receive OPDIVO in combination with chemotherapy (n=789) or chemotherapy (n=792). Patients received one of the following treatments:

OPDIVO 240 mg in combination with mFOLFOX6 (fluorouracil, leucovorin and oxaliplatin) every 2 weeks or mFOLFOX6 every 2 weeks.

• OPDIVO 360 mg in combination with CapeOX (capecitabine and oxaliplatin) every 3 weeks or CapeOX every 3 weeks.

Patients were treated until disease progression, unacceptable toxicity, or up to 2 years. In patients who received OPDIVO in combination with chemotherapy and in whom chemotherapy was discontinued, OPDIVO monotherapy was allowed to be given at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks up to 2 years after treatment initiation.

Randomization was stratified by tumor cell PD-L1 status (≥1% vs. <1% or indeterminate), region (Asia vs. US vs. Rest of World), ECOG performance status (0 vs. 1), and chemotherapy regimen (mFOLFOX6 vs. CapeOX). The major efficacy outcome measures, assessed in patients with PD-L1 CPS ≥5, were PFS assessed by BICR and OS. Additional efficacy outcome measures included OS and PFS in patients with PD-L1 CPS ≥1 and in all randomized patients, and ORR and DOR as assessed by BICR in patients with PD-L1 CPS ≥1 and ≥5, and in all randomized patients. Tumor assessments were conducted per RECIST v1.1 every 6 weeks up to and including week 48, then every 12 weeks thereafter.

The trial population characteristics were: median age 61 years (range: 18 to 90), 39% were ≥65 years of age, 70% were male, 24% were Asian, and 69% were White, and 1% were Black. Baseline ECOG performance status was 0 (42%) or 1 (58%). Seventy percent of patients had adenocarcinoma tumors in the stomach, 16% in the gastroesophageal junction, and 13% in the esophagus.

CHECKMATE-649 demonstrated a statistically significant improvement in OS and PFS for patients with PD-L1 CPS ≥5. Statistically significant improvement in OS was also demonstrated for all randomized patients

Population Reference No. 6 

Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck on or After Platinum-Based Therapy

CHECKMATE-141 (NCT02105636) was a randomized (2:1), active-controlled, open-label trial enrolling patients with metastatic or recurrent SCCHN who had experienced disease progression during or within 6 months of receiving platinum-based therapy administered in either the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. The trial excluded patients with autoimmune disease, medical conditions requiring immunosuppression, recurrent or metastatic carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary histology, salivary gland or non-squamous histologies (e.g., mucosal melanoma), or untreated brain metastasis. Patients with treated brain metastases were eligible if neurologically stable. Patients were randomized to receive OPDIVO 3 mg/kg by intravenous infusion every 2 weeks or investigator’s choice of cetuximab (400 mg/m2 initial dose intravenously followed by 250 mg/m2 weekly), or methotrexate (40 to 60 mg/m2 intravenously weekly), or docetaxel (30 to 40 mg/m2 intravenously weekly).

Randomization was stratified by prior cetuximab treatment (yes/no). The first tumor assessments were conducted 9 weeks after randomization and continued every 6 weeks thereafter. The major efficacy outcome measure was OS. Additional efficacy outcome measures were PFS and ORR.

A total of 361 patients were randomized; 240 patients to the OPDIVO arm and 121 patients to the investigator’s choice arm (docetaxel: 45%; methotrexate: 43%; and cetuximab: 12%). The trial population characteristics were: median age was 60 years (range: 28 to 83) with 31% ≥65 years of age, 83% were White, 12% Asian, and 4% were Black, and 83% male. Baseline ECOG performance status was 0 (20%) or 1 (78%), 76% were former/current smokers, 90% had Stage IV disease, 45% of patients received only one prior line of systemic therapy, the remaining 55% received two or more prior lines of systemic therapy, and 25% had HPV p16-positive tumors, 24% had HPV p16-negative tumors, and 51% had unknown status.

The trial demonstrated a statistically significant improvement in OS for patients randomized to OPDIVO as compared with investigator’s choice at a pre-specified interim analysis (78% of the planned number of events for final analysis). There were no statistically significant differences between the two arms for PFS (HR=0.89; 95% CI: 0.70, 1.13) or ORR (13.3% [95% CI: 9.3, 18.3] vs. 5.8% [95% CI: 2.4, 11.6] for nivolumab and investigator’s choice, respectively). 

Population Reference No. 7 

Hepatocellular Carcinoma (HCC) Previously Treated With Sorafenib 

CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial that evaluated the efficacy of OPDIVO as a single agent and in combination with ipilimumab in patients with hepatocellular carcinoma (HCC) who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.

Tumor assessments were conducted every 6 weeks for 48 weeks and then every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate as assessed by BICR using RECIST v1.1 and modified RECIST (mRECIST) for HCC. Duration of response was also assessed.

The efficacy of OPDIVO in combination with ipilimumab was evaluated in 49 patients (Cohort 4) who received OPDIVO 1 mg/kg and ipilimumab 3 mg/kg administered every 3 weeks for 4 doses, followed by single-agent OPDIVO at 240 mg every 2 weeks until disease progression or unacceptable toxicity. The median age was 60 years (range: 18 to 80), 88% were male, 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven (57%) percent of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic fatty liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had AFP levels ≥400 µg/L. Prior cancer treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies.  Efficacy results are shown in Table 60. The results for OPDIVO in combination with ipilimumab in Cohort 4 are based on a minimum follow-up of 28 months.

Population Reference No. 8 

Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma Who Have Disease Progression During or Following Platinum-Based Chemotherapy 

Adjuvant Treatment of Urothelial Carcinoma (UC) at High Risk of Recurrence

CHECKMATE-274 (NCT02632409) was a randomized, double-blind, placebo-controlled study of adjuvant OPDIVO in patients who were within 120 days of radical resection (R0) of UC of the bladder or upper urinary tract (renal pelvis or ureter) at high risk of recurrence. High risk of recurrence was defined as either 1) ypT2-ypT4a or ypN+ for patients who received neoadjuvant cisplatin or 2) pT3-pT4a or pN+ for patients who did not receive neoadjuvant cisplatin and who also either were ineligible for or refused adjuvant cisplatin. Patients were randomized 1:1 to receive OPDIVO 240 mg or placebo by intravenous infusion every 2 weeks until recurrence or until unacceptable toxicity for a maximum treatment duration of 1 year. Patients were stratified by pathologic nodal status (N+ vs. N0/x with <10 nodes removed vs. N0 with ≥10 nodes removed), tumor cells expressing PD-L1 (≥1% vs. <1%/indeterminate as determined by the central lab using the PD-L1 IHC 28-8 pharmDx assay), and use of neoadjuvant cisplatin (yes vs. no).

The trial population characteristics were: median age of 67 years (range: 30 to 92); 76% male; 76% White, 22% Asian, 0.7% Black, and 0.1% American Indian or Alaska Native. Of the 335 (47%) of patients with node-positive UC, 44 (6%) had non–muscle-invasive (

Prior neoadjuvant cisplatin had been given to 43% of patients; of the 57% who did not receive prior neoadjuvant cisplatin, reasons listed were ineligibility (22%), patient preference (33%), and other/not reported (2%). Tumor PD-L1 expression was ≥1% in 40% of patients, and 21% of patients had upper tract UC.

The major efficacy outcome measures were investigator-assessed DFS in all randomized patients and in patients with tumors expressing PD-L1 ≥1%. DFS was defined as time to first recurrence (local urothelial tract, local non-urothelial tract, or distant metastasis), or death. Additional efficacy outcome measures included OS.

Population Reference No. 9 

Adult Patients With MSI-H/dMMR Metastatic Colorectal Cancer That Has Progressed Following Treatment With a Fluoropyrimidine, Oxaliplatin, and Irinotecan 

CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients enrolled in the single agent OPDIVO MSI-H mCRC cohort received OPDIVO 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by OPDIVO as a single agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression.

Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1.1.

A total of 74 patients were enrolled in the single-agent MSI-H mCRC OPDIVO cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody.

A total of 119 patients were enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were White. Baseline ECOG performance  status was 0 (45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Population Reference No. 10 

Patients (≥12 years) With MSI-H/dMMR Metastatic Colorectal Cancer That Has Progressed Following Treatment With a Fluoropyrimidine, Oxaliplatin, and Irinotecan 

CHECKMATE-142 (NCT02060188) was a multicenter, non-randomized, multiple parallel-cohort, open-label trial conducted in patients with locally determined dMMR or MSI-H metastatic CRC (mCRC) who had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG performance status 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression.

Patients enrolled in the single agent OPDIVO MSI-H mCRC cohort received OPDIVO 3 mg/kg by intravenous infusion (IV) every 2 weeks. Patients enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort received OPDIVO 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for 4 doses, followed by OPDIVO as a single agent at a dose of 3 mg/kg as intravenous infusion every 2 weeks. Treatment in both cohorts continued until unacceptable toxicity or radiographic progression.

Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter. Efficacy outcome measures included ORR and DOR as assessed by BICR using RECIST v1.1.

A total of 74 patients were enrolled in the single-agent MSI-H mCRC OPDIVO cohort. The median age was 53 years (range: 26 to 79) with 23% ≥65 years of age and 5% ≥75 years of age, 59% were male and 88% were White. Baseline ECOG performance status was 0 (43%), 1 (55%), or 3 (1.4%) and 36% were reported to have Lynch Syndrome. Across the 74 patients, 72% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 7%, 30%, 28%, 19%, and 16% received 0, 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 42% of patients had received an anti-EGFR antibody.

A total of 119 patients were enrolled in the OPDIVO and ipilimumab MSI-H mCRC cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were White. Baseline ECOG performance  status was 0 (45%) and 1 (55%), and 29% were reported to have Lynch Syndrome. Across the 119 patients, 69% had received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Population Reference No. 11 

Esophageal Squamous Cell Carcinoma (ESCC)

indicated for the treatment of patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidineand platinum-based chemotherapy.

The safety of OPDIVO was evaluated in ATTRACTION-3, a randomized, active-controlled, open-label, multicenter trial in 209 patients with unresectable advanced, recurrent or metastatic ESCC refractory or intolerant to at least one fluoropyrimidine- and platinum-based chemotherapy [see Clinical Studies (14.12)]. The trial excluded patients who were refractory or intolerant to taxane therapy, had brain metastases that were symptomatic or required treatment, had autoimmune disease, used systemic corticosteroids or immunosuppressants, had apparent tumor invasion of organs adjacent to the esophageal tumor or had stents in the esophagus or respiratory tract. Patients received OPDIVO 240 mg by intravenous infusion over 30 minutes every 2 weeks (n=209) or investigator’s choice: docetaxel 75 mg/m2 intravenously every 3 weeks (n=65) or paclitaxel 100 mg/m2 intravenously once a week for 6 weeks followed by 1 week off (n=143). Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.6 months (range: 0 to 29.2 months) in OPDIVO-treated patients and 2.6 months (range: 0 to 21.4 months) in docetaxel- or paclitaxel-treated patients. Among patients who received OPDIVO, 26% were exposed for >6 months and 10% were exposed for >1 year.

Serious adverse reactions occurred in 38% of patients receiving OPDIVO. Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%).

OPDIVO was discontinued in 13% of patients and was delayed in 27% of patients for an adverse reaction.

Adults With Relapsed or Progressed cHL After Autologous HSCT and Brentuximab Vedotin, or After 3 or More Lines of Therapy Including Autologous HSCT 

• Two studies evaluated the efficacy of OPDIVO as a single agent in adult patients with cHL after failure of autologous HSCT.

CHECKMATE-205 (NCT02181738) was a single-arm, open-label, multicenter, multicohort trial in cHL. CHECKMATE-039 (NCT01592370) was an open-label, multicenter, dose escalation trial that included cHL. Both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN, creatinine clearance <40 mL/min, prior allogeneic HSCT, or chest irradiation within 24 weeks. In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received OPDIVO 3 mg/kg by intravenous infusion every 2 weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted.

Efficacy was evaluated by ORR as determined by an IRRC. Additional outcome measures included duration of response (DOR).

Efficacy was evaluated in 95 patients in CHECKMATE-205 and CHECKMATE-039 combined who had failure of autologous HSCT and post-transplantation brentuximab vedotin. The median age was 37 years (range: 18 to 72). The majority were male (64%) and White (87%). Patients had received a median of 5 prior systemic regimens (range: 2 to 15). They received a median of 27 doses of OPDIVO (range: 3 to 48), with a median duration of therapy of 14 months (range: 1 to 23 months).

Efficacy was also evaluated in 258 patients in CHECKMATE-205 and CHECKMATE-039 combined who had relapsed or progressive cHL after autologous HSCT. The analysis included the group described above. The median age was 34 years (range: 18 to 72). The majority were male (59%) and White (86%). Patients had a median of 4 prior systemic regimens (range: 2 to 15), with 85% having 3 or more prior systemic regimens and 76% having prior brentuximab vedotin. Of the 195 patients having prior brentuximab vedotin, 17% received it only before autologous HSCT, 78% received it only after HSCT, and 5% received it both before and after HSCT. Patients received a median of 21 doses of OPDIVO (range: 1 to 48), with a median duration of therapy of 10 months

Population Reference No. 12 

Vulvar cancer

Vulvar cancer - as single agent, second-line therapy for HPV-related, locally advanced or metastatic disease
 

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use

Population Reference No. 13 

CNS - Brain metastases

• CNS - Brain metastases (limited) – in combination with ipilimumab (preferred) or as a single agent for limited brain metastases in patients with melanoma as initial treatment in select patients, as treatment for recurrent brain metastases, or as treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options
• CNS Brain metastases (limited) - as a single agent for limited brain metastases in patients with PD-L1 positive non-small cell lung cancer as initial treatment in select patients, as treatment for recurrent brain metastases, or as treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options
• CNS - Brain metastases (extensive) - in combination with ipilimumab (preferred) or as a single agent for extensive brain metastases in patients with melanoma as primary treatment in select patients or as treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options
• CNS Brain metastases (extensive) - as a single agent for extensive brain metastases in patients with PD-L1 positive non-small cell lung cancer as primary treatment in select patients or as treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use

Population Reference No. 14 

Extranodal NK/T-cell lymphoma, nasal type

• Extranodal NK/T-cell lymphoma, nasal type - as a single agent for relapsed or refractory disease following additional therapy with an alternate asparaginase-based combination chemotherapy regimen, not previously used and when a clinical trial is not available

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use

Population Reference No. 15 

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)

• Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) - as initial therapy as a single agent or in combination with ibrutinib for either clonally related or unknown clonal status Richter's transformation to diffuse large B-cell lymphoma in patients with del(17p)/TP53 mutations and who are chemotherapy refractory and unable to receive chemoimmunotherapy

Recommended by the NCCN Drugs and Biologics Compendium^® for off-label use

Population Reference No. 16 

 fas irst-line or subsequent therapy in combination with ipilimumab for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease

Population Reference No. 17 

as single agent, second-line or subsequent therapy for metastatic disease and for locally recurrent, progressive disease prior to abdominoperineal resection

Population Reference No. 18 

Appendiceal adenocarcinoma - as subsequent therapy as a single agent or in combination with ipilimumab for progression of advanced or metastatic dMMR/MSI-H disease

Population Reference No. 19 

Cervical cancer - as a single agent for squamous cell, adenocarcinoma, adenosquamous with local/regional recurrence or stage IVB or distant metastases in tumors with a PD-L1 combined positive score ≥ 1% or for persistent, recurrent or metastatic small cell neuroendocrine carcinoma of the cervix with a PD-L1 combined positive score ≥ 1%
 

Population Reference No. 20 

Classic Hodgkin lymphoma - as single agent, palliative therapy for individuals aged 60 and older with relapsed or progressive disease following high-dose therapy and autologous stem cell rescue (HDT/ASCR) with or without brentuximab vedotin, relapsed/refractory disease and transplant-ineligible based on comorbidity or failure of second-line therapy, or post-allogeneic transplant.

Classic Hodgkin lymphoma - as single agent, third-line or subsequent therapy for relapsed or progressive disease after HDT/ASCR with or without brentuximab vedotin, for relapsed/refractory disease and transplant-ineligible based on comorbidity or failure of second-line chemotherapy, or post-allogeneic transplant in individuals age ≥ 18 and < 60
 

Population Reference No. 21

Colon cancer - as primary treatment for locally unresectable or medically inoperable disease as a single agent or in combination with ipilimumab in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors.

Colon cancer – as adjuvant treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors following resection and/or local therapy for resectable metachronous metastases, unresectable metachronous metastases that converted to resectable disease after primary treatment, and following synchronized or staged resection and/or local therapy for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment.

Colon cancer - as neoadjuvant treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors for resectable synchronous liver and/or lung metastases or as primary treatment for clinical T4b disease

Colon cancer - as primary treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors for unresectable synchronous liver and/or lung metastases only, synchronous abdominal/peritoneal metastases, synchronous unresectable metastases of other sites, or unresectable metachronous metastases
Colon cancer - as subsequent treatment as a single agent or in combination with ipilimumab for unresectable advanced or metastatic dMMR/MSI-H disease
 

Population Reference No. 22 

Endometrial cancer - (endometrioid adenocarcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma) as a single agent, second-line treatment for recurrent or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.
 

Population Reference No. 23

Extranodal NK/T-cell lymphoma, nasal type - as a single agent for relapsed or refractory disease following additional therapy with an alternate asparaginase-based combination chemotherapy regimen, not previously used and when a clinical trial is not available.

Population Reference No. 24 

Gestational trophoblastic neoplasia - as single agent therapy for recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen when the disease is multiagent chemotherapy resistant.
 

Population Reference No. 25 

Pediatric diffuse high-grade glioma - as single agent, adjuvant treatment for patients with hypermutant tumors excluding diffuse midline glioma, H3 K26-altered or pontine location

Pediatric diffuse high-grade glioma - as single agent treatment for recurrent or progressive disease in hypermutant tumors excluding oligodendroglioma, IDH-mutant and 1p/19q co-deleted or astrocytoma IDH-mutant
 

Population Reference No. 26 

Rectal cancer - as primary treatment for stage 0-III disease as a single agent or in combination with ipilimumab for deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H), T3, N Any; T1-2, N1-2; T4, N Any or locally unresectable or medically inoperable tumors when resection is contraindicated following neoadjuvant therapy or total neoadjuvant therapy
 

Rectal cancer - as adjuvant treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors following resection and/or local therapy for resectable metachronous metastases or for unresectable metachronous metastases that converted to resectable disease after primary treatment
 

Rectal cancer - as neoadjuvant treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors for resectable synchronous liver only and/or lung only metastases; or for resectable synchronous liver only and/or lung only metastases when previously treated with neoadjuvant radiation with or without concurrent chemotherapy
 

Rectal cancer - as primary treatment as a single agent or in combination with ipilimumab in patients with dMMR/MSI-H tumors for synchronous abdominal/peritoneal metastases, synchronous unresectable metastases of other sites, synchronous liver only and/or lung only metastases that are unresectable or medically inoperable, unresectable metachronous metastases, or unresectable isolated pelvic/anastomotic recurrence
 

Population Reference No. 27 

Small bowel adenocarcinoma

- as a single agent or in combination with ipilimumab for advanced metastatic, deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) disease
 

Population Reference No. 28 

Small cell lung cancer

- as a single agent for relapse following complete or partial response or stable disease with primary treatment, or for primary progressive disease
 

Population Reference No. 29 

Uveal melanoma

- as a single agent or in combination with ipilimumab for distant metastatic disease
 

Population Reference No. 30

Bone Cancer - Ewing Sarcoma

Used in combination with ipilimumab for unresectable or metastatic disease that has progressed following prior treatment and has no satisfactory alternative treatment options for tumor mutational burden-high (TMB-H) tumors with 10 or more mutations per megabase (useful in certain circumstances)

Other primary round cell tumors of the bone (eg, CIC::DUX4, BCOR::CCNB3) can be treated like Ewing Sarcoma

Population Reference No. 31

B-Cell Lymphomas - Diffuse Large B-Cell Lymphoma
Used with or without brentuximab vedotin to treat relapsed or refractory primary mediastinal large B-cell lymphoma

Population Reference No. 32

Biliary Tract Cancers - Gallbladder Cancer-Intrahepatic Cholangiocarcinoma-Extrahepatic Cholangiocarcinoma

• Consider as neoadjuvant systemic therapy in combination with ipilimumab for resectable locoregionally advanced disease that is tumor mutational burden-high (TMB-H) and presents as
  • incidental finding of suspicious mass during surgery where hepatobiliary surgery expertise unavailable
  • incidental finding on pathologic review (cystic duct node positive)
• mass on imaging
• jaundice
• Primary treatment in combination with ipilimumab (useful in certain circumstances) for unresectable or resected gross residual (R2) disease, or metastatic disease that is tumor mutational burden-high (TMB-H)
• Subsequent treatment for progression on or after systemic treatment for unresectable or resected gross residual (R2) disease, or metastatic disease as a single agent (useful in certain circumstances) in those who have not been previously treated with a checkpoint inhibitor

Population Reference No. 33

Kidney Cancer

Therapy for stage IV* or relapsed disease in combination with ipilimumab for 4 cycles followed by single-agent nivolumab as systemic therapy for non-clear cell histology (useful in certain circumstances)

*if first-line therapy and stage IV, then M1 or unresectable T4, M0 only

Population Reference No. 34

Bladder Cancer - Upper GU Tract Tumors-Primary Carcinoma of the Urethra

• Adjuvant therapy for pathologic stage T2-4 or nodal disease (N+) of the renal pelvis or urothelial carcinoma of the ureter may be considered if
  • platinum-based neoadjuvant chemotherapy not given and pT3, pT4, or pN+
  • platinum-based neoadjuvant chemotherapy given and ypT2-ypT4 or ypN+
• Used for recurrent or metastatic disease as
  • first-line systemic therapy in combination with cisplatin and gemcitabine in cisplatin eligible patients followed by nivolumab maintenance therapy
  • second-line systemic therapy as a single agent post-platinum or other chemotherapy (alternative preferred)
• Chemotherapy regimen based on histology. See Non-Urothelial and Urothelial with Subtype Histology (BL-D) if appropriate.

Supplemental Information

N/A

Practice Guidelines and Position Statements

Review criteria used by Triple-S to determine whether chemotherapy ± supportive agent(s) are medically necessary for anticancer treatment include the following:

• New drugs or regimens (combinations of drugs) approved by the United States Food and Drug Administration (FDA), i.e., that are used on-label
• Drugs and biologics may be used off-label, i.e., without FDA approval. They are considered medically accepted or necessary if supported by any of the following 5 compendia that Medicare uses to determine a “medically accepted indication” for off-label drugs and biologics in anticancer chemotherapeutic treatment and are not listed as unsupported, not indicated, or not recommended within any one of the compendia below.
  • o NCCN Drugs & Biologics Compendium®
    • Category 1-2A recommendations are considered medically accepted uses
    • Category 2B recommendations will be considered if identified as medically accepted if listed in at least one of the 5 Medicare-recognized compendia or supported by peer-reviewed scientific literature eligible for coverage as outlined below. Meeting abstracts and case reports are generally excluded from consideration
    • Category 3 listings are considered not medically accepted uses
  • Clinical Pharmacology
    • Medically accepted uses are identified by narrative text that is supportive
    • Not medically accepted uses are identified by narrative text that is “not supportive”
  • American Hospital Formulary Service Drug Information (AHFS DI)
    • Medically accepted uses are identified by narrative text that is supportive
    • Not medically accepted uses are identified by narrative text that is “not supportive”
  • Thompson Micromedex DrugDex®
    • Class I, IIA, or IIb recommendations are considered medically accepted uses
    • Class III listings are considered not medically accepted uses
  • Wolters Kluwer Lexi-Drugs®
    • Medically accepted uses are identified by an indication listed as “Use: Off-Label” and rated as “Evidence Level A”
    • Not medically accepted uses are those indications listed as “Use: Unsupported”
• Off-label use of drugs and biologics may also be considered medically accepted if supported as safe and effective according to peer-reviewed articles eligible for coverage from one of the following journals; this is in accordance with the medical literature used by local Medicare contractors to determine medically-accepted indications for drugs and biologics used in anticancer treatment:

o American Journal of Medicine;

o Annals of Internal Medicine;

o Annals of Oncology;

o Annals of Surgical Oncology;

o Biology of Blood and Marrow Transplantation;

o Blood; o Bone Marrow Transplantation;

o British Journal of Cancer;

o British Journal of Hematology;

o British Medical Journal;

o Cancer;

o Clinical Cancer Research;

o Drugs;

o European Journal of Cancer (formerly the European Journal of Cancer and Clinical Oncology);

o Gynecologic Oncology;

o International Journal of Radiation, Oncology, Biology, and Physics;

o The Journal of the American Medical Association;

o Journal of Clinical Oncology;

o Journal of the National Cancer Institute;

o Journal of the National Comprehensive Cancer Network (NCCN);

o Journal of Urology;

o Lancet;

o Lancet Oncology;

o Leukemia;

o The New England Journal of Medicine; or

o Radiation Oncology

o Pediatric Hematology and Oncology

o Pediatric Blood and Cancer

o Journal of Adolescent and Young Adult Oncology

• Coverage determination may also be directed by CMS National Coverage Determinations (NCDs) or state-specific Local Coverage Determinations (LCDs), state-specific Medicaid drug utilization requirements and/or health plan-specific drug coverage policies, where applicable.
• Unique cases that do not fit NCCN Categories 1-3:
  • Non-standard protocols may be approved based on unique clinical circumstances, especially for rare diseases that may lack guideline-based treatment recommendations
  • Non-standard protocols are entered into the database, as needed

Medicare National Coverage

Coverage determination may also be directed by CMS National Coverage Determinations (NCDs) or state-specific Local Coverage Determinations (LCDs), state-specific Medicaid drug utilization requirements and/or health plan-specific drug coverage policies, where applicable.

References

1. Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; .1/2021
2. The NCCN Drugs & Biologics Compendium® © 2018 National Comprehensive Cancer Network, Inc. http://www.nccn.org.
3. American Cancer Society. Cancer Facts & Figures 2015. http://www.cancer.org/acs/groups/cid/documents/webcontent/003107-pdf.pdf Accessed January 11, 2016. 2. Food and Drug Administration. Department of Health and Human Services. Opdivo Accelerated Approval Letter. Disponible en: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/125554Orig1s000ltr.pdf. Accesado en enero de 2015.
4. Lexicomp the Complete Drug Reference Web Site. Available at: https://online-lexi-com.ezproxylocal.library.nova.edu/lco/action/home?siteid=100
5. National Comprehensive Cancer Network (NCCN) Guidelines Kidney Cancer Version 2.2016. Available at: http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed on January, 2016.
6. Opdivo [package insert]. Princeton, NJ. Bristol-Myers Squibb Company. December 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf . Accessed on January, 2015.
7. U.S Food and Drug Administration. 2015. FDA approves Opdivo to treat advanced form of kidney cancer. Recuperado de: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473971.htm
8. A Reference Guide to Reimbursment and Coding OPDIVO Bristol-Myers Squibb 4/2018 

 9.NCCN Content © National Comprehensive Cancer Network, Inc 2011-2022, All Rights Reserved. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, NCCN TEMPLATES®, and NCCN COMPENDIUM® are trademarks owned by the National Comprehensive Cancer Network, Inc.

6.     10. Database: MICROMEDEX® 2.0 [online] Available: http://www.thomsonhc.com/home/dispatch [Accessed October, 2011]

7.     11. FDA Website:     http://www.fda.gov/orphan/designat/list.htm.

8       12. American Hospital Formulary Service (AHFS) (electronic version). Available at: http://www.ahfsdruginformation.com/

        13. Local Coverage Determination (LCD) For Label and Off-label Coverage of Outpatient Drugs and Biologics (L33915)

        14. Ley de Puerto Rico Núm. 194; Artículo 4.050

        15. Reglamento de Puerto Rico 7617, Reglamento para implantar las disposiciones de la ley número 194; Artículo 8, Sección 5, inciso A 10

    16. Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2019-000052)

    17. Normative Letter 21-0817: Política para asegurar el acceso a medicamentos, tratamiento y pruebas para el diagnóstico de Cáncer.

1       18. ASES-OC-2023/P003: Puerto Rico Health Insurance Administration Policy for Medication Exception Requests.

         19. Contract between Administración de Seguros de Salud de Puerto Rico (ASES) and Triple-S Salud, for Provision of Physical & Behavioral Health Services under the Government Health Plan Program (Contract No: 2023-000046)

Codes

Applicable Modifiers

N/A

Policy History