Nivolumab (Opdivo)

Number: 0892

Policy

Note: REQUIRES PRECERTIFICATIONFootnotes for precertification^*

Aetna considers nivolumab (Opdivo) medically necessary for the following indications:

• Anal cancer - Second-line therapy for metastatic squamous cell carcinoma as a single agent

• Bladder cancer - used as a single agent as subsequent systemic therapy post-platinum for:

  • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy; or
  • stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy; or
  • stage IVB (any T, any N, M1b) disease; or
  • recurrence post cystectomy; or
  • metastatic disease 
     

• Central nervous system - Used in combination with ipilimumab in persons with melanoma and

  • Newly diagnosed limited brain metastases (e.g., small asymptomatic brain metastases) or stable systemic disease or reasonable systemic treatment options; or 
  • Recurrent limited brain metastases; or
  • Recurrent extensive brain metastases and stable systemic disease or reasonable systemic treatment options.
    

• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma - As a single agent or in combination with ibrutinib for treatment of histologic (Richter's) transformation to diffuse large B-cell lymphoma (clonally related or unknown clonal status) in persons with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy
  

• Classical Hodgkin lymphoma

  • In adults age 18 and older as subsequent therapy as a single agent for relapsed or progressive disease following autologous hematopoietic stem cell transplant (HSCT) and brentuximab vedotin; or 
  • In adults age 18 and older as subsequent therapy as a single agent for relapsed or progressive disease following autologous three or more lines of systemic therapy that includes autologous HSCT; or
  • In adults older than 60 years of age as palliative therapy as a single agent for relapsed or progressive disease following autologous hematopoietic stem cell transplant (HSCT) and brentuximab vedotin; or 
  • In adults older than 60 years of age as palliative therapy as a single agent for relapsed or progressive disease following relapsed or progressive disease following autologous three or more lines of systemic therapy that includes autologous HSCT
     
    

• Colorectal cancer, small bowel adenocarcinoma, appendiceal carcinoma, and anal adenocarcinoma (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) for

  • Primary treatment, as a single agent or in combination with ipilimumab, for unresectable metachronous metastases and previous adjuvant FOLFOX or CapeOX within the past 12 months; or
  • Initial therapy, as a single agent or in combination with ipilimumab, for unresectable advanced or metastatic disease who are not appropriate for intensive therapy; or
  • Subsequent therapy, as a single agent (if nivolumab or pembrolizumab not previously given) or in combination with ipilimumab (if no previous treatment with a checkpoint inhibitor), for unresectable advanced or metastatic disease following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy
     
    

• Gestational Trophoblastic Neoplasia

  • As a single agent for recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen; or
  • As a single agent for methotrexate-resistant high-risk disease
     
    

• Head and neck cancer - Therapy for very advanced and recurrent/persistent squamous cell head and neck cancer as a preferred single agent second-line for non-nasopharyngeal cancer if disease progression on or after platinum-containing chemotherapy or for previously treated, recurrent, or metastatic non-keratinizing nasopharyngeal disease in:

  • newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or for persons who are unfit for surgery and performance status (PS) 3
  • metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy (RT) and PS 0-2
  • unresectable locoregional recurrence without prior RT and PS 3
    
    

• Hepatocellular carcinoma - as a single agent for adults who received previous treatment with sorafenib (Child-Pugh Class A or B7 only) who

  • are nontransplant candidates with unresectable disease; or
  • are inoperable by performance status or comorbidity (local disease or local disease with minimal extrahepatic disease only); or
  • have extensive liver tumor burden or metastatic disease
     
    

• Kidney cancer - for relapse or surgically unresectable stage IV disease as

  • Preferred subsequent therapy for predominant clear cell histology as a single agent; or
  • Systemic therapy for non-clear cell histology as a single agent; or
  • Preferred first-line therapy for predominant clear cell histology in combination with ipilimumab; or
  • Subsequent therapy for predominant clear cell histology in combination with ipilimumab
     
    

• Malignant pleural mesothelioma - subsequent systemic therapy as a single agent or in combination with ipilimumab

• Cutaneous melanoma - Therapy for metastatic or unresectable disease

  • As first-line therapy as a single agent or in combination with ipilimumab for metastatic or unresectable disease; or
  • As second-line or subsequent therapy after progression or maximum clinical benefit from BRAF targeted therapy; or
  • Adjuvant treatment as a single agent
    
    

• Melanoma -

  • Adjuvant treatment as a single agent; or 
  • Adjuvant treatment of distant metastatic disease after complete resection with no evidence of disease; or
  • Therapy for metastatic or unresectable disease as a single agent or in combination with ipilimumab
     
    

• Uveal Melanoma - for metastatic or unresectable disease as a single agent or in combination with ipilimumab
  

• Merkel Cell Carcinoma

• Non-small cell lung cancer (adenocarcinoma (with mixed subtypes), squamous cell carcinoma, large cell carcinoma)

  • As preferred single agent (if pembrolizumab not already given) as subsequent therapy for metastatic disease in persons with performance status 0-2; or
  • Following progression on a first-line cytotoxic regimen; or
  • For further progression on other systemic therapy.
     
    

• Primary carcinoma of the urethra - Used as a single agent as subsequent systemic therapy for recurrent or metastatic disease.

• Small cell lung cancer - Subsequent systemic therapy for persons with performance status 0-2 as a single agent or in combination with ipilimumab for:

  • relapse within 6 months following complete or partial response or stable disease with initial treatment; or
  • primary progressive disease.
    
    

• Upper GU tract tumors - Used as a single agent as subsequent systemic therapy for metastatic disease.

• Urothelial carcinoma of the prostate - Used as a single agent as subsequent systemic therapy post-platinum containing therapy for metastatic disease

Other than as second-line or subsequent therapy for melanoma as noted above, Aetna considers nivolumab experimental and investigational for disease progression while on anti-PD-1 therapy (e.g. Opdivo [nivolumab], Keytruda [pembrolizumab], atezolizumab [Tecentriq], avelumab [Bavencio], durvalumab [Imfinzi]).

Aetna considers nivolumab experimental and investigational for all other indications including the following (not an all-inclusive list):

• Breast cancer
• Cervical cancer
• Gastric cancer
• Glioblastoma
• Non-Hodgkin lymphoma
• Ovarian cancer
• Pancreatic cancer
• Sarcomatoid carcinoma of the lung
• Sarcomas (e.g., Ewing's family of tumors, osteosarcoma, rhabdomyosarcoma, and soft tissue sarcomas)

Note: Footnotes for precertification^* Precertification of Opdivo is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Opdivo, call (866) 752-7021, or fax (866) 267-3277.

Background

Melanoma

Melanoma is a serious form of skin cancer that arises from melanocytes; however, in rare instances, it can originate in the eye or other non-skin organs.  Risk factors for melanoma entail freckling, genetic factors, history of sunburns, light skin or eye color, poor tanning ability, sun exposure, as well as tanning bed use.  About 80 % of melanomas are detected in a localized stage.  When detected early, the 5-year survival rate of melanoma is 98.5 %.  However, when melanoma is diagnosed after distant metastasis, the 5-year survival rate decreases to 15 % with a median survival between 8 and 9 months.  Tumor thickness, along with nodal involvement, is a prognostic factor for melanoma.  As tumor thickness increases to greater than 1.0 mm, the survival rate is reduced by 50 %.  The incidence of melanoma is rapidly increasing.  According to the National Cancer Institute (NCI), melanoma is the leading cause of death from skin disease.  Approximately 76.100 new cases of melanoma will be diagnosed in the United States in 2014 and about 9,700 people will die from the disease.  Treatments of melanoma include chemotherapy, immunotherapy, radiation therapy, surgery, as well as vaccine therapy (NCI, 2014).  Moreover, the National Comprehensive Cancer Network (NCCN)’s clinical practice guideline on Melanoma” (Version 1.2015) states that little consensus exists regarding the optimal standard chemotherapy for patients with metastatic melanoma.

The past several years were marked by the emergence of new molecules for the treatment of metastatic cutaneous melanoma with a significant benefit on the survival -- ipilimumab (Yervoy), peginterferon alfa-2b (PEG-Intron) and vemurafenib (Zelboraf) were approved by the Food and Drug Administration (FDA) in 2011; dabrafenib (Tafinlar) and trametinib (Mekinist) were approved in 2013.  More recently, much attention has been devoted to the blockade of programmed death 1 (PD-1) signaling to activate an immune response to cancer.  PD-1, a protein expressed on T cells, is a member of the CD28 superfamily, and it transmits co-inhibitory signals upon engagement with its ligands PD-L1 and PD-L2.  Accumulating evidence suggests that the PD-1 system plays pivotal roles in the regulation of autoimmunity, transplantation immunity, infectious immunity, and tumor immunity.  Because the interaction of PD-1 with its ligands occurs in the effector phase of killer T cell responses in peripheral blood, anti-PD-1 and anti-PD-L1 monoclonal antibodies are ideal as specific agents to augment T cell responses to tumors with fewer adverse events than with the inhibition of CTLA-4, because the interaction of CTLA-4 with its ligands occurs in the priming phase of T cell responses within lymph nodes.  In recent phase I clinical trials, objective responses were observed in patients with melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC) who underwent immunotherapy with an anti-PD-1 monoclonal antibody.  In addition, the anti-tumor activity of an anti-PD-L1 monoclonal antibody was observed in patients with melanoma, RCC, NSCLC, and ovarian cancer (Tanaka and Okamura, 2013). 

Opdivo (nivolumab) is a human programmed death receptor-1 (PD-1)-blocking monoclonal antibody. Nivolumab, a fully human IgG4 monoclonal antibody, acts as an immunomodulator by blocking ligand activation of the PD-1 receptor on activated T-cells. 

Binding of the programmed death-1 (PD-1) ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Opdivo (nivolumab) is a 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. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 

Opdivo (nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. Opdivo (nivolumab) is also indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In a clinical study, Topalian et al (2014) examined the survival, durable tumor remission, and long-term safety of nivolumab in patients with advanced melanoma.  Patients with advanced melanoma (n = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an out-patient setting every 2 weeks for up to 96 weeks and were observed for overall survival (OS), long-term safety, and response duration after treatment discontinuation.  Median OS in nivolumab-treated patients (62 % with 2 to 5 prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62 % and 43 %, respectively.  Among 33 patients with objective tumor regressions (31 %), the Kaplan-Meier estimated median response duration was 2 years.  Furthermore, 17 patients discontinued therapy for reasons other than disease progression, and 12 (71 %) of 17 maintained responses off-therapy for at least 16 weeks (range of 16 to 56+ weeks).  Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative.  The authors concluded that OS following nivolumab treatment in patients with advanced treatment-refractory melanoma compared favorably with that in literature studies of similar patient populations.  Responses were durable and persisted after drug discontinuation; long-term safety was acceptable.  They stated that ongoing randomized controlled trials (RCTs) will further evaluate the impact of nivolumab therapy on OS in patients with metastatic melanoma.

A phase III clinical trial testing nivolumab for the treatment of advanced melanoma was stopped early due to improved OS compared with standard chemotherapy (No authors listed, 2014).

On December 22, 2014, the FDA approved nivolumab (Opdivo) for patients with unresectable or metastatic melanoma who no longer respond to other drugs (ipilimumab and a BRAF inhibitor).  Opdivo was approved under the FDA’s accelerated approval program; its efficacy was demonstrated in 120 clinical trial participants with unresectable or metastatic melanoma.  Results showed that 32 % of subjects receiving Opdivo had their tumors shrink (objective response rate [ORR]).  This effect lasted for more than 6 months in approximately 1/3 of the subjects who experienced tumor shrinkage.  Opdivo’s safety was evaluated in the overall trial population of 268 participants treated with Opdivo and 102 participants treated with chemotherapy.  The most common side effects of the drug were rash, itching, cough, upper respiratory tract infections, and edema.  The most serious side effects were severe immune-mediated side effects involving healthy organs, including the colon, kidneys, liver, lung, and endocrine glands.  Serious adverse reactions occurred in 41 % of patients receiving Opdivo; grade 3 and 4 adverse reactions occurred in 42 % of patients receiving Opdivo.  The most frequent grade 3 and 4 adverse drug reactions reported in 2 % to less than 5 % of patients receiving Opdivo were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.  The most common adverse reaction (greater than or equal to 20 %) reported with Opdivo was rash (21 %).  Opdivo is administered as an intravenous infusion (3 mg/kg) over 60 minutes every 2 weeks.

The National Comprehensive Cancer Network Drug & Biologics Compendium (NCCN, 2018) recommends nivolumab in melanoma as

• Adjuvant therapy as a single agent
   
  
  • for resected stage IIIB/C sentinel node positive disease following active nodal basin surveillance or complete lymph node dissection (CLND) (preferred immunotherapy regimen)
  • for stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection (preferred immunotherapy regimen)
  • for stage III disease with clinical satellite or in-transit metastases if no evidence of disease post-surgery
  • for local, satellite and/or in-transit recurrence if no evidence of disease post-surgery
  • following CLND and/or complete resection of nodal recurrence (preferred immunotherapy regimen)
     
• Adjuvant treatment of distant metastatic disease after complete resection with no evidence of disease
• Therapy for metastatic or unresectable disease as a single agent or in combination with ipilimumab as
   
  
  • first-line therapy
  • second-line or subsequent therapy after disease progression or maximum clinical benefit from BRAF targeted therapy if anti PD-1 therapy (either alone or in combination with ipilimumab) not previously used
  • second-line or subsequent therapy after disease progression or maximum clinical benefit from BRAF targeted therapy if prior anti-PD-1 therapy (either alone or in combination with ipilimumab) resulted in disease control (complete response, partial response, or stable disease) and no residual toxicity, and disease progression/relapse occurred >3 months after treatment discontinuation.

NCCN (2015) guidelines state that, "while pembrolizumab and nivolumab are indicated for disease progression after treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, there is consensus among the NCCN panel that both drugs have higher response rates and less toxicity compared to ipilimumab, and that both drugs should be included as options for first-line treatment." The NCCN guidelines state that nivolumab may cause immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, nephritis, hypothyroidism, and hyperthyroidism. Depending on the adverse event and the severity of the reaction, discontinuation of therapy and administration of corticosteroids may be required.

Warnings and Precautions:

• Immune-Mediated Pneumonitis: Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with Opdivo (nivolumab) treatment. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue Opdivo (nivolumab) for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold Opdivo (nivolumab) until resolution for moderate (Grade 2) pneumonitis.
• Immune-Mediated Colitis: Immune-mediated colitis is defined as colitis requiring use of corticosteroids with no clear alternate etiology. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold Opdivo (nivolumab) for Grade 2 or 3 immune-mediated colitis. Permanently discontinue Opdivo (nivolumab) for Grade 4 colitis or for recurrent colitis upon restarting Opdivo (nivolumab).
• Immune-Mediated Hepatitis: Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold Opdivo (nivolumab) for moderate (Grade 2) and permanently discontinue Opdivo (nivolumab) for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis.
• Immune-Mediated Nephritis and Renal Dysfunction: monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue Opdivo (nivolumab). For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold Opdivo (nivolumab) and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue Opdivo (nivolumab).
• Immune-Mediated Hypothyroidism and Hyperthyroidism: Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of Opdivo (nivolumab) for hypothyroidism or hyperthyroidism.

Nivolumab for melanoma is administered 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.  The average treatment duration for individuals with advanced melanoma is slightly over 6 months.

Combined Ipilimumab and Nivolumab for Advanced Melanoma

Postow and colleagues (2015) noted that in a phase I dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including CRs, among patients with advanced melanoma. In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, these researchers randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg/kg of body weight) combined with either nivolumab (1 mg/kg) or placebo once every 3 weeks for 4 doses, followed by nivolumab (3 mg/kg) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end-point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61 % (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11 % (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (p < 0.001), with CRs reported in 16 patients (22 %) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median PFS was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (HR associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95 % CI: 0.23 to 0.68; p < 0.001). Similar results for response rate and PFS were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54 % of the patients who received the combination therapy as compared with 24 % of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase I study, and most of these events resolved with immune-modulating medication. The authors concluded that the objective-response rate and the PFS among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy; combination therapy had an acceptable safety profile.

In a randomized, double-blind, phase III clinical trial, Larkin and associates (2015) compared nivolumab alone or nivolumab plus ipilimumab with ipilimumab alone in patients with metastatic melanoma. These investigators assigned, in a 1:1:1 ratio, 945 previously untreated patients with unresectable stage III or IV melanoma to nivolumab alone, nivolumab plus ipilimumab, or ipilimumab alone; PFS and OS were co-primary end-points. Results regarding PFS were presented here. The median PFS was 11.5 months (95 % CI: 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95 % CI: 2.8 to 3.4) with ipilimumab (HR for death or disease progression, 0.42; 99.5 % CI: 0.31 to 0.57; p < 0.001), and 6.9 months (95 % CI: 4.3 to 9.5) with nivolumab (HR for the comparison with ipilimumab, 0.57; 99.5 % CI: 0.43 to 0.76; p < 0.001). In patients with tumors positive for the PD-L1, the median PFS was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, PFS was longer with the combination therapy than with nivolumab alone (11.2 months [95 % CI: 8.0 to not reached] versus 5.3 months [95 % CI: 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3 % of the patients in the nivolumab group, 55.0 % of those in the nivolumab-plus-ipilimumab group, and 27.3 % of those in the ipilimumab group. The authors concluded that among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer PFS than ipilimumab alone. In patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.

Furthermore, an UpToDate review on “Overview of the management of advanced cutaneous melanoma” (Sosman, 2015) recommends immunotherapy with ipilimumab and nivolumab for advanced melanoma for the following indications:

• For patients without a V600 BRAF mutation, we recommend immunotherapy with nivolumab in combination with ipilimumab rather than with an anti-PD-1 antibody (nivolumab, pembrolizumab) alone (Grade 1A). Targeted therapy is not indicated in patients without a characteristic V600 mutation.
• For patients with a V600 BRAF mutation and a good performance status, we suggest immunotherapy rather than targeted therapy as the initial systemic therapy (Grade 2C). The preference for immunotherapy rather than targeted therapy is based upon the prolonged disease control achieved with immunotherapy in some patients, whereas those treated with targeted therapy almost always relapse relatively rapidly. In addition, BRAF inhibition in patients who have progressed after immunotherapy appears to have similar efficacy compared with BRAF inhibition prior to immunotherapy.

  When immunotherapy is indicated in this situation, checkpoint inhibition with nivolumab plus ipilimumab rather than an anti-PD-1 antibody alone is the preferred option.

  For patients with a V600 BRAF mutation who were initially treated with an anti-PD1 antibody and whose disease can no longer be controlled with immunotherapy, we recommend targeted therapy against the MAP kinase pathway with a combination of BRAF plus MEK inhibition (e.g., dabrafenib plus trametinib) rather than chemotherapy (Grade 1B).

• For patients with a V600 BRAF mutation and a poor performance status, we suggest MAP kinase pathway targeted therapy (e.g., dabrafenib plus trametinib) rather than immunotherapy (Grade 2C). Targeted therapy is associated with more rapid responses in this situation. Immunotherapy with a checkpoint inhibitor is an alternative. Immunotherapy may be an option for second line therapy when patients progress after targeted therapy.

Piulats et al (ongoing clinical trial) stated uveal melanoma is the most common primary intraocular malignant tumor in adults. Overall Survival (OS) at 5 years(y) is 62% due high incidence of liver metastasis, fatal within 4-9 months (m) from diagnosis. No standard treatment exists for metastatic uveal melanoma (MUM). Combination nivolumab (NIVO) and ipilimumab (IPI) has shown efficacy in metastatic cutaneous melanoma. However, MUM patients were excluded in these trials. GEM1402 is a phase-2 trial evaluating NIVO+IPI in untreated adult patients with MUM; is being conducted in 10 centers in Spain, leading by the Spanish Melanoma Group. Eligible patients had histologically-confirmed MUM, ECOG-PS 0/1, and no prior systemic treatment for MUM. Treatment consisted in NIVO (1mg/kg, iv, q3 weeks [wk]) and 4 doses of IPI (3mg/kg iv q3wk) followed by NIVO (3mg/kg q2wk) until progressive disease (PD), toxicity or withdrawal. Primary endpoint is OS and secondary progression free survival (PFS), Overall Response Rate (ORR) (per RECIST 1.1) and safety. Radiologic evaluations q6wk. Interim analysis (n = 19) was planned per protocol to assess safety and ORR. Intention to treat analysis includes patients with PD at first radiological evaluation. Safety population includes all patients receiving at least one dose of study treatment. Nineteen patients enrolled from April to July 2016: Median age 62y (43y-82y), 63% male, liver M1 84% patients and extra-liver M1 42% patients, 31% elevated baseline LDH. 11 patients completed cycle 2 and 8 patients stopped after 1 dose (6 PD, 2 toxicity). Treatment-related adverse events were reported in 12 patients and lead to end of treatment in 2 patients. Grade ≥3 toxicities were seen in 7 patients (36.8%): diarrhea, transaminitis, dermatological events, anemia, acute thyroiditis. All G3/4 were resolved following the toxicity guideline. One G5 acute thyroiditis related to NIVO+IPI was reported. ORR was observed in 15.8% and disease stabilization in 47.4%. With a median follow-up of 4.6m, PFS was 4.99m. Median OS was not reached at time of this analysis. The authors concluded combination of NIVO+IPI is feasible for MUM. In this INTERIM ANALYSIS, ORR did not reach yet 20%, but PFS seems promising. The clinical trial is ongoing and final results will be updated.

Melanoma - Adjuvant Therapy

On December 20, 2017, the Food and Drug Administration approved nivolumab (Opdivo) for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or in patients with metastatic disease who have undergone complete resection. FDA approval was based on improvement in recurrence-free survival (RFS) as reported in the CHECKMATE-238 trial.

Weber et al (2017) stated that nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. The objective of this study (CheckMate 238) was to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. This was a randomized, double-blind, phase 3 trial where 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma were randomly assigned to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. The study authors concluded that among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

The National Comprehensive Cancer Network Drug & Biologics Compendium (NCCN, 2018) recommends nivolumab in melanoma as adjuvant therapy as a single agent

• for resected stage IIIB/C sentinel node positive disease following active nodal basin surveillance or complete lymph node dissection (CLND) (preferred immunotherapy regimen)
• for stage III disease with clinically positive node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection (preferred immunotherapy regimen)
• for stage III disease with clinical satellite or in-transit metastases if no evidence of disease post-surgery
• for local, satellite and/or in-transit recurrence if no evidence of disease post-surgery
• following CLND and/or complete resection of nodal recurrence (preferred immunotherapy regimen)

NCCN (2018) guidelines state that nivolumab for resected state IIIB/C was added as an option with the caveat that although nivolumab has shown a clinically significant improvement in relapse-free survival (RFS) compared to high-dose ipilimumab, the impact on overall survival (OS) has not yet been reported.

The NCCN Drugs & Biologics Compendium (NCCN, 2018) recommends nivolumab for treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy. The NCCN guidelines state that preliminary data from non-randomized trials in patients with MCC demonstrated that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy.

Walocko et al (2016) stated that Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC. This was a case report of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody. The authors concluded that immunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.

Central Nervous System - Brain Metastases in Patients With Melanoma

NCCN’s clinical practice guideline on ”Central Nervous System Cancers” (Version 1.2018) mentions nivolumab in combination with ipilimumab as a therapeutic option for newly diagnosed or for recurrent brain metastases in patients with melanoma.

Tawbi et al (2018) stated brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. The authors evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. The authors concluded that nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (CheckMate 204 ClinicalTrials.gov number, NCT02320058).

Long et al (2018) stated nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. The autors aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases. This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy-naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred. The authors concluded that nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. This study is ongoing for the final survival analysis (ClinicalTrials.gov number NCT02374242).

Merkel Cell Carcinoma

The NCCN Drugs & Biologics Compendium (NCCN, 2018) recommends nivolumab for treatment for disseminated, clinical M1 disease with or without surgery and/or radiation therapy. The NCCN guidelines state that preliminary data from non-randomized trials in patients with MCC demonstrated that rates of durable response are improved with PD-1/PD-L1 blockade compared with cytotoxic therapy.

Walocko et al (2016) stated that Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC. This was a case report of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody. The authors concluded that immunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.

Non-small cell lung cancer

Lung cancer is one of the leading causes of cancer deaths in the United States. Non-small cell lung cancer (NSCLC) accounts for approximately 85 percent of cases of lung cancer (FDA, 2015; BMS, 2015). Squamous cell NSCLC accounts for approximately 25 to 30 percent of all lung cancers. Survival rates vary depending on the stage and type of the cancer and when it is diagnosed.

Shimanovsky and Dasanu (2014) stated that immunotherapy has made significant progress in patients with NSCLC in the last years.  Early tumor vaccine studies showed trends toward better clinical outcomes, and larger trial results are currently being awaited.  Immune check-point inhibitors are promising therapeutic agents in advanced NSCLC.  While ipilimumab has clearly improved outcomes in metastatic malignant melanoma, its safety and efficacy in NSCLC are not yet known.  The authors noted that PD-1 and PD-1 ligand inhibitors such as nivolumab, MK3475 and MPDL3280 have demonstrated clinical efficacy in patients with advanced/metastatic NSCLC in early clinical trials.  Their validation in larger phase III trials is being awaited.  Furthermore, exploring efficacy of these molecules in patients with early stages of lung cancer is also needed.

The FDA approved nivolumab for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy (FDA, 2015).

The approval was based on the results of CheckMate -017 and CheckMate -063 (BMS, 2015).  Nivolumab demonstrated significantly superior overall survival (OS) vs. docetaxel, with a 41% reduction in the risk of death (hazard ratio: 0.59 [95% CI: 0.44, 0.79; p=0.00025]), in a prespecified interim analysis of a Phase III clinical trial. The median OS was 9.2 months in the Opdivo arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3). 

CheckMate -017 was a Phase III, open-label, randomized, multinational, multicenter clinical trial that evaluated nivolumab (3 mg/kg intravenously over 60 minutes every two weeks) (n=135) versus standard of care, docetaxel (75 mg/m2 intravenously administered every 3 weeks) (n=137) (BMS, 2015), in patients with metastatic squamous NSCLC who had progressed during or after prior platinum doublet-based chemotherapy regimen. This trial included patients regardless of their PD-L1 (programmed death ligand-1) status. The primary endpoint of this trial was overall survival (OS). In January, the trial was stopped based on an assessment conducted by the independent Data Monitoring Committee (DMC), which concluded that the study met its endpoint, demonstrating superior OS in patients receiving nivolumab compared to docetaxel. The prespecified interim analysis was conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the nivolumab arm and 113 in the docetaxel arm). The median OS was 9.2 months in the nivolumab arm (95% CI: 7.3, 13.3) and 6 months in the docetaxel arm (95% CI: 5.1, 7.3). The hazard ratio was 0.59 (95% CI: 0.44, 0.79; p=0.00025).

The safety profile of nivolumab in squamous NSCLC was addressed in CheckMate -063, a phase II single-arm, open-label, multinational, multicenter trial of nivolumab, administered as a single agent in patients with metastatic squamous NSCLC who have progressed after receiving a platinum-based therapy and at least 1 additional systemic treatment regimen (n = 117) (BMS, 2015; Rizvi et al, 2015).  Patients received 3 mg/kg of nivolumab administered intravenously over 60 minutes every 2 weeks.  This trial included patients regardless of their PD-L1 status.  The most common adverse reactions (reported in greater than or equal to 20 % of patients) were fatigue (50 %), dyspnea (38 %), musculoskeletal pain (36 %), decreased appetite (35 %), cough (32 %), nausea (29 %), and constipation (24 %).  Serious adverse reactions occurred in 59 % of patients receiving nivolumab.  The most frequent serious adverse reactions reported in greater than or equal to 2 % of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.  Nivolumab was discontinued due to adverse reactions in 27 % of patients; 29 % of patients receiving nivolumab had a drug delay for an adverse reaction.  With at least 10 months of minimum follow-up for all patients, the confirmed objective response rate (ORR), the study’s primary end-point, was 15 % (17/117) (95 % CI: 9 to 22) of which all were partial responses (BMS, 2015).  The median time to onset of response was 3.3 months (range of 1.7 to 8.8 months) after the start of nivolumab treatment; 76 % of nivolumab responders (13/17 patients) had ongoing responses with durability of response ranging from 1.9+ to 11.5+ months; 10 of these 17 (59 %) patients had durable responses of 6 months or longer.

Nivolumab is associated with immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, other adverse reactions; and embryofetal toxicity (BMS, 2015). 

In Trial 3, serious adverse reactions occurred in 59 % of patients receiving nivolumab (BMS, 2015).  The most frequent serious adverse drug reactions reported in greater than or equal to 2 % of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. 

The most common adverse reactions (greater than or equal to 20 %) reported with nivolumab in Trial 3 were fatigue (50 %), dyspnea (38 %), musculoskeletal pain (36 %), decreased appetite (35 %), cough (32 %), nausea (29 %), and constipation (24 %) (BMS, 2015). 

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with nivolumab treatment (BMS, 2015).  Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7 % (5/691) of patients receiving nivolumab; no cases occurred in Trial 3.  In Trial 3, immune-mediated pneumonitis occurred in 6 % (7/117) of patients receiving nivolumab including 5 Grade 3 and 2 Grade 2 cases.  The labeling recommends that patients be monitored for signs and symptoms of pneumonitis.  Corticosteroids should be administered for Grade 2 or greater pneumonitis.  The labeling recommends withholding nivolumab for Grade 2 pneumonitis until resolution, and permanently discontinuing nivolumab for Grade 3 or 4 pneumonitis. 

In Trial 3, diarrhea occurred in 21 % (24/117) of patients receiving nivolumab (BMS, 2015).  Grade 3 immune-mediated colitis occurred in 0.9 % (1/117) of patients.  The labeling states that patients should be monitored for immune-mediated colitis.  Corticosteroids should be administered for Grade 2 (of more than 5 days duration), 3, or 4 colitis.  Nivolumab should be withheld for Grade 2 or 3 colitis.  Nivolumab should be permanently discontinued for Grade 4 colitis or recurrent colitis upon restarting nivolumab. 

In Trial 3, the incidences of increased liver test values were AST (16 %), alkaline phosphatase (14 %), ALT (12 %), and total bilirubin (2.7 %) (BMS, 2015).  The labeling recommends monitoring patients for abnormal liver tests prior to and periodically during treatment.  Corticosteroids should be administered for Grade 2 or greater transaminase elevations.  Nivolumab should be withheld for Grade 2 and permanently discontinued for Grade 3 or 4 immune-mediated hepatitis. 

In Trial 3, the incidence of elevated creatinine was 22 %. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9 % (1/117) of patients (BMS, 2015).  The labeling states that patients should be monitored for elevated serum creatinine prior to and periodically during treatment.  For Grade 2 or 3 serum creatinine elevation, nivolumab should be withheld and corticosteroids administered; if worsening or no improvement occurs, nivolumab should be permanently discontinued.  Corticosteroids should be administered for Grade 4 serum creatinine elevation and nivolumab permanently discontinued. 

In Trial 3, hypothyroidism occurred in 4.3 % (5/117) of patients receiving nivolumab (BMS, 2015).  Hyperthyroidism occurred in 1.7 % (2/117) of patients including 1 Grade 2 case.  The labeling recommends monitoring thyroid function prior to and periodically during treatment.  Hormone replacement therapy should be administered for hypothyroidism.  Medical management should be initiated for control of hyperthyroidism. 

The following clinically significant immune-mediated adverse reactions occurred in less than 2 % of nivolumab-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction and vasculitis (BMS, 2015).  Across clinical trials of nivolumab administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barre syndrome, and myasthenic syndrome.  Based on the severity of adverse reaction, nivolumab should be withheld, high-dose corticosteroids administered, and, if appropriate, hormone-replacement therapy should be administered. 

Based on its mechanism of action, nivolumab can cause fetal harm when administered to a pregnant woman (BMS, 2015).  The labeling recommends advising pregnant women of the potential risk to a fetus.  Females of reproductive potential should be advised to use effective contraception during treatment with nivolumab and for at least 5 days after the last dose of nivolumab. 

It is not known whether nivolumab is present in human milk (BMS, 2015).  The labeling states, because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nivolumab, women should be advised to discontinue breastfeeding during treatment. 

Nivolumab for squamous cell lung cancer is administered 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (BMS, 2015).

The FDA approved nivolumab injection for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy (BMS, 2015). The labeled indication states that patients with EGFR mutation or ALK translocation should have disease progression on appropriate targeted therapy prior to receiving nivolumab.

The FDA approval was based on the results of the CheckMate -057 trial, a Phase 3 trial which demonstrated superior OS benefit for nivolumab versus docetaxel in previously treated metastatic NSCLC (BMS, 2015). CheckMate -057 was a Phase 3, open-label, randomized clinical trial that evaluated nivolumab (3 mg/kg administered intravenously every two weeks) (n=292) versus docetaxel (75 mg/m2 administered intravenously every three weeks) (n=290), in patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. Appropriate targeted therapy may have been given to patients with known EGFR mutation or ALK translocation. This study included patients regardless of their PD-L1 expression status. The primary endpoint of this trial was OS.

The median OS was 12.2 months in the nivolumab arm (95% CI: 9.7, 15.0) and 9.4 months in the docetaxel arm (95% CI: 8.0, 10.7) (BMS, 2015). The hazard ratio (HR) was 0.73 (95% CI: 0.60, 0.89; p=0.0015), which translates to a 27% reduction in the risk of death with nivolumab compared to docetaxel. The prespecified interim analysis was conducted when 413 events were observed (93% of the planned number of events for final analysis). Additional secondary endpoints included investigator-assessed objective response rate (ORR) and progression-free survival (PFS). The ORR in the nivolumab arm was 19% (56/292; 4 complete responses, 52 partial responses) (95% CI: 15, 24) and 12% with docetaxel (36/290; 1 complete response, 35 partial responses) (95% CI: 9, 17) p=0.02. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Median PFS was 2.3 months in the nivolumab arm versus 4.2 months with docetaxel; HR=0.92 (95% CI:0.77, 1.11, p=0.39).

The manufacturer stated that the safety profile of nivolumab in CheckMate -057 was consistent with prior studies (BMS, 2015). Serious adverse reactions occurred in 47% of patients receiving nivolumab. The most frequent serious adverse reactions in at least 2% of patients receiving nivolumab were pneumonia, pulmonary embolism, dyspnea, pleural effusions and respiratory failure. Nivolumab was discontinued in 13% of patients and was delayed in 29% of patients for an adverse reaction. The most common adverse reactions (reported in ≥20% of patients) were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%) and constipation (23%).

In Checkmate 057, immune-mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients receiving nivolumab including five Grade 3, two Grade 2, and three Grade 1 cases (BMS, 2015). Diarrhea or colitis occurred in 17% (50/287) of patients receiving nivolumab. Immune-mediated colitis occurred in 2.4% (7/287) of patients including three Grade 3, two Grade 2, and two Grade 1 cases. One patient (0.3%) developed immune-mediated hepatitis.

In Checkmate 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated TSH occurred in 17% of patients receiving nivolumab (BMS, 2015). Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients. Immune-mediated rash occurred in 6% (17/287) of patients receiving nivolumab including 4 Grade 3 cases. Fatal limbic encephalitis occurred in one patient (0.3%) receiving nivolumab . Grade 2 infusion reactions occurred in 1% (3/287) of patients receiving nivolumab. .

In Checkmate 057, serious adverse reactions occurred in 47% of patients receiving nivolumab (BMS, 2015). The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) reported with nivolumab were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%).

Nivolumab for metastatic non-small cell lung cancer is administered 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks (BMS, 2015).

The National Comprehensive Cancer Network Drug and Biologics Compendium (2017) recommends the use of nivolumab in non-small cell lung cancer (adenocarcinoma (with mixed subtypes); squamous cell carcinoma; large cell carcinoma) as a preferred single agent (if pembrolizumab not previously given) as subsequent therapy for metastatic disease in patients with performance status 0-2, following progression on a first-line cytotoxic regimen, or for further progression on other systemic therapy.

The NCCN Panel (2015) recommends nivolumab as subsequent therapy for patients with metastatic nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy based upon data from the CheckMate-57 phase III randomized trial (Paz-Ares et al, 2015).  For patients receiving nivolumab, median OS was 12.2 months compared with 9.4 months for docetaxel (HR 0.73, 95 % CI: 0.59 to 0.89, p = 0.0015).  Fewer grade 3 to 5 adverse events were reported for nivolumab (10 %) when compared to docetaxel (54 %) in the CheckMate-057 trial. 

The NCCN Panel (2015) also recommends nivolumab as subsequent therapy for patients with metastatic squamous cell carcinoma who have progressed on or after platinum-based chemotherapy based on data from a phase III randomized trial (CheckMate-017) (Brahmer et a., 2015), the FDA approval, and results of a phase II trial (Rizvi et al, 2015).  In the CheckMate-017 trial, the median OS was 9.2 months with nivolumab compared with 6.0 months for docetaxel (Brahmer et al, 2015).  There were fewer grade 3 to 4 adverse events with nivolumab (7 %) when compared with docetaxel (55 %).

Colorectal Cancer

The NCCN Drug and Biologics Compendium (2017) recommends nivolumab for colorectal adenocarcinoma

• Primary treatment as a single agent for unresectable metachronous metastases (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
• Initial therapy as a single agent for patients with unresectable advanced or metastatic disease (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) who are not appropriate for intensive therapy
• Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (defective mismatch repair/high microsatellite instability [dMMR/MSI-H] only) following previous oxaliplatin- irinotecan- and/or fluoropyrimidine-based therapy.

The National Comprehensive Cancer Network's clinical practice guideline on "Colon cancer" (NCCN, 2017) states that "small bowel and appendiceal adenocarcinoma may be treated with systemic chemotherapy according to the NCCN Colon Cancer Guidelines."

Anal Cell Carcinoma

The NCCN Drugs & Biologics Compendium (NCCN, 2018) recommends nivolumab for second-line therapy as a single agent for metastatic disease.

Morris et al (2017) stated squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, this was a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. This was a single-arm, multicenter, phase 2 trial at ten academic centers in the USA. The study enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. The authors stated to their knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease.

Combined Ipilimumab and Nivolumab for Colorectal Cancer (dMMR/MSI-H)

On July 11, 2018, Bristol-Meyers Squibb announced the U.S. Food and Drug Administartion (FDA) approval of Opdivo (nivolumab) 3 mg/kg plus low-dose Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) for the treatment of patients 12 years and older with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan (BMS, 2018).

Approval for this indication has been granted under the FDA’s accelerated approval which was based on overall response rate (ORR) and duration of response (DOR) from the ongoing Phase 2, multicenter, non-randomized, multiple-parallel cohort, open-label CheckMate -142 trial, which demonstrated an ORR of 46% (95% CI: 35-58; n = 38/82). The CheckMate -142 trial enrolled MSI-H/dMMR mCRC patients who had received at least one prior line of therapy for metastatic disease, and efficacy was analyzed for both patients who had received prior treatment with a fluoropyrimidine, oxaliplatin and irinotecan (82 of the total 119 patients) as well as for all enrolled patients.

Among all enrolled patients, 49% (95% CI: 39-58; n = 58/119) responded to treatment with Opdivo + Yervoy; 4.2% (n = 5/119) experienced a complete response, while 45% (n = 53/119) experienced a partial response. Among the 58 responders, the median DOR was not reached (range: 1.9-23.2+ months); 83% of those patients had responses of six months or longer, and 19% had responses of 12 months or longer. In the combination cohort, 51 of 58 responders were ongoing at the time of database lock; 78% of these ongoing responders had not reached 12 months of follow-up from the date of onset of response. The application was granted Priority Review and Breakthrough Therapy Designation by the FDA. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials (BMS, 2018).

Overman et al. (2018) state nivolumab plus ipilimumab may provide clinical benefit in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). In the CheckMate-142 trial, 119 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Out of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% and disease control rate for ≥ 12 weeks was achieved in 80% of patients. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life.  The authors concluded that nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC. Evaluation of nivolumab plus ipilimumab as a firstline therapy (phase II) in patients with dMMR/MSI-H mCRC is ongoing.

The most frequent serious adverse reactions (greater than 2% of patients) were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. The most common adverse reactions (greater than 20% of patients) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%) (BMS, 2018).

Renal cell carcinoma

In a phase II clinical trial, Motzer et al (2015) evaluated the anti-tumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic RCC (mRCC).  Patients with clear-cell mRCC previously treated with agents targeting the VEGF pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks.  The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end-points included ORR, OS, and safety.  A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts; 118 patients (70 %) had received more than 1 prior systemic regimen.  Median PFS was 2.7, 4.0, and 4.2 months, respectively (p = 0.9).  Respective ORRs were 20 %, 22 %, and 20 %.  Median OS was 18.2 months (80 % confidence interval [CI]: 16.2 to 24.0 months), 25.5 months (80 % CI: 19.8 to 28.8 months), and 24.7 months (80 % CI: 15.3 to 26.0 months), respectively.  The most common treatment-related adverse event (AE) was fatigue (24 %, 22 %, and 35 %, respectively); 19 patients (11 %) experienced grade 3 to 4 treatment-related AEs.  The authors concluded that nivolumab demonstrated anti-tumor activity with a manageable safety profile across the 3 doses studied in mRCC.  No dose-response relationship was detected as measured by PFS.  These efficacy and safety results in mRCC support study in the phase III setting.

In a phase I clinical trial with expansion cohorts, McDermott et al (2015) reported clinical activity, survival, and long-term safety in patients with advanced RCC treated with nivolumab.  A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every 2 weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation.  Ten patients (29 %) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; 9 additional patients (27 %) demonstrated stable disease lasting greater than 24 weeks; 3 of 5 patients who stopped treatment while in response continued to respond for greater than or equal to 45 weeks.  Median OS in all patients (71 % with 2 to 5 prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71 %, 48 %, and 44 %, respectively.  Grade 3 to 4 treatment-related AEs occurred in 18 % of patients; all were reversible.  The authors concluded that patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation.  They stated that OS is encouraging, and toxicities were generally manageable.  Moreover, they stated that ongoing randomized clinical trials will further assess the impact of nivolumab on OS in patients with advanced RCC.

Motzer, et al. (2015) reported that, among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. A randomized, open-label, phase 3 study (Checkmate 025) compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. Investigators randomly assigned 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148).  The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). The investigators concluded that, among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. 

An accompanying editorial (Quinn & Lara, 2015) stated that nivolumab is the choice for patients who have disease progression while they are receiving VEGF-targeted therapy given the overall survival advantage it confers and its relatively good side-effect profile. However, "for all the success reported here, many questions remain." The editorialist stated that complete remissions remained "disappointingly elusive'; the complete remission rate was 1%." Although it is possible that complete remission with nivolumab may be unnecessary to achieve a long-term benefit, the lack of profound responses begs for selection or combination approaches that expand the benefit spectrum." In other tumors, PD-1 ligand 1 (PD-L1) expression, in tumor cells or infiltrating immune cells, is associated with benefit from PD-1 or PD-L1 inhibitors. Unfortunately, PD-L1 expression in renal-cell cancer tissue did not delineate the patients who were more likely to benefit. In addition, the most effective duration of therapy with nivolumab and whether the therapy should continue beyond progression remains unknown.

Dreicer, et al. (2015) commented that, nivolumab, by virtue of its clear survival benefit and favorable effects profile in Checkmate 025, is now the treatment of choice for patients with disease progression on VEGF-targeted therapy. He observed that, unlike other neoplasms, PD-L1 expression, although likely prognostic regarding disease biology, is not a predictive biomarker for the selection anti-PD1 directed therapy in advanced renal cancer.

Clinical trials are ongoing on the use of nivolumab for the treatment of other malignancies (e.g., Hodgkin's lymphoma and non-Hodgkin lymphoma) and solid tumors (e.g., bladder cancer, breast cancer, colon cancer, gastric cancer, glioblastoma, head and neck cancer, and pancreatic cancer). 

Taube and colleagues (2014) stated that immune-modulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies.  Identifying factors predicting clinical response could guide patient selection and therapeutic optimization.  Patients (n = 41) with melanoma, NSCLC, RCC, colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of nivolumab at one institution and had evaluable pre-treatment tumor specimens.  Immuno-architectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for inter-relationships and potential correlations with clinical outcomes.  Membranous PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC.  In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (p < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression.  Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes.  PD-L2, the second ligand for PD-1, was associated with PD-L1 expression.  Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients.  These correlations were stronger than borderline associations of PD-1 expression or the presence of intra-tumoral immune cell infiltrates with response.  The authors concluded that tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.

Ohaegbulam et al (2015) noted that PD-1 receptor and its ligands PD-L1 and PD-L2, members of the CD28 and B7 families, play critical roles in T cell co-inhibition and exhaustion.  Over-expression of PD-L1 and PD-1 on tumor cells and tumor-infiltrating lymphocytes, respectively, correlates with poor disease outcome in some human cancers.  Monoclonal antibodies (mAbs) blockading the PD-1/PD-L1 pathway have been developed for cancer immunotherapy via enhancing T cell functions.  Clinical trials with mAbs to PD-1 and PD-L1 have shown impressive response rates in patients, particularly for melanoma, NSCLC, RCC, and bladder cancer.  The authors concluded that further studies are needed to dissect the mechanisms of variable response rate, to identify biomarkers for clinical response, to develop small-molecule inhibitors, and to combine these treatments with other therapies.

Gunturi and McDermott (2015) noted that one mechanism by which tumor cells are thought to evade the host's immune system is by inducing negative signals that cause T-cell suppression.  An important interaction that results in this phenomenon is the one between PD-1 on the T cell and its ligand PD-L1 on the tumor cell.  PD-1 pathway blocking agents (e.g., nivolumab) are therefore capable of reversing T-cell suppression and ultimately induce anti-tumor responses.  These researchers summarized investigations related to the safety and efficacy of nivolumab in a variety of malignancies thus far, including advanced melanoma, NSCLC, and RCC.  The results have been promising with a large number of objective responses and favorable safety profiles inspiring several phase III trials in these settings.  More recent studies are exploring the role of this drug in the treatment of various other cancers.  Combination therapies involving nivolumab are also being studied and are yielding interesting results.  Finally, the role of tumor PD-L1 expression as a predictive biomarker remains to be ascertained.  Thus, with rational refinement through biomarker and combination clinical trials, nivolumab and other PD-1 blocking agents will likely lead to significant improvements in cancer therapeutics.

The NCCN Drug and Biologics Compendium (NCCN, 2017) recommends nivolumab in kidney cancer as a single agent for relapse or stage IV disease as preferred subsequent therapy for predominant clear cell histology, or as systemic therapy for non-clear cell histology.

In a phase III trial (CheckMate 214), the combination of ipilimumab plus nivolumab (N + I) resulted in significantly improved overall survival and response rates compared with sunitinib (S) in previously untreated intermediate- and poor-risk patients with advanced clear cell RCC. Escudier, et al.(2017) randomized adults with clear-cell mRCC to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg daily orally for 4 weeks (6-week cycles). Co-primary endpoints were overall response rate (ORR), progression-free survival (PFS) per independent committee (IRRC) and overall survival (OS) all in intermediate/poor risk patients. The investigators randomized 1096 patients. With approximately 17.5 month minimum follow-up, confirmed ORR in intermediate/poor risk patients was 41.6% (9.4% complete response [CR]) versus 26.5% (1.2% CR) for N+I versus S (P<0.0001); median duration of response was not reached (NR; 95% CI 21.82-NR) versus 18.2 months (95% CI 14.82-NR), respectively; median PFS was 11.6 versus 8.4 months (HR 0.82, P=0.0331), respectively. In all treated patients, drug-related adverse events occurred in 509/547 (93% any grade, 46% grade 3-4) with N+I versus 521/535 (97% any grade, 63% grade 3-5) with S, including 22% versus 12% with adverse events leading to discontinuation. Death occurred in 159 N+I patients (7 [1%] drug-related) and 202 S patients (4 [1%] drug-related). The authors concluded that this study showed higher ORR and longer PFS for N+I compared with S in intermediate/poor risk mRCC, particularly in patients with tumor PD-L1 expression ≥1%, with a manageable safety profile. These results support the use of N+I as a potential first-line treatment for these patients. Based upon the results of Checkmate 214, the European Association of Urology revised its guidelines to recommend this combination as first-line treatment. 

Breast cancer

Janakiram et al (2012) noted that co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T-lymphocyte activation and tolerance.  These pathways are attractive therapeutic targets for human cancers including breast cancer.  Gene polymorphisms of B7x (B7-H4/B7S1), PD-1 (CD279), and CTLA-4 (CD152) are associated with increased risk of developing breast cancer although the underlying mechanisms are unclear.  In human breast cancer microenvironment, up-regulation of co-inhibitory B7/CD28 members B7x, B7-H3 (CD276), and PD-L1 (B7-H1/CD274) on tumor cells as well as PD-1 and PD-L1 on tumor-infiltrating immune cells are emerging as immune evasion pathways.  Chemotherapy can affect the expression of these molecules, and therefore may dampen the immune response against breast cancer.  Immunotherapy targeting T-cell co-inhibition as monotherapy or combined with standard therapies are in early stages of clinical development, but hold great promise for treatment of human breast cancer.

Gastric cancer

Venerito et al (2014) noted that gastric cancer (GC) continues to be an important health threat as the third leading cause of cancer related death in both sexes worldwide.  In a recent analysis, the mortality trends for the time period from 1980 till 2011 were significantly downward in all countries, but the declines in the USA, EU and several other major countries were of low magnitude when compared with the past.  Furthermore, the relative contribution of cardia cancers compared with non-cardia cancers increased among countries with higher GC rates.  With respect to pre-neoplastic changes of the gastric mucosa, a large population-based study suggested that Helicobacter pylori (H. pylori) infection and anti-gastric parietal cell antibodies-mediated autoimmune response might, for the most part, be independent and follow distinct pathways rather than causally related pathways leading to chronic atrophic gastritis.  A large prospective, randomized, open-label Korean trial questioned the role of H. pylori eradication for the prevention of metachronous lesions after endoscopic resection of early GC.  A review of 1,258 Japanese cases undergoing curative endoscopic submucosa dissection for early GC showed that scheduled follow-up endoscopy is mandatory for detecting metachronous lesions at an early stage, where they can be treated by endoscopic resection.  Ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist, is the first biological treatment that provides survival benefits to patients with advanced GC in progress after first-line chemotherapy.  Rilotumumab is currently being evaluated in patients with advanced GC over-expressing the HGF/c-MET signaling pathway.  In the near future, ipilimumab and nivolumab, two immune-stimulatory monoclonal antibodies with anti-neoplastic effects, might offer new therapeutic options for patients with advanced GC.

Prostate cancer

Dong et al (2014) noted that sipuleucel-T (Provenge) became the first approved cancer vaccine (developed to enhance T-cell immunity against metastatic castration-resistant prostate cancer) 4 years ago.  Other prostate cancer vaccines, including a viral-based vaccine PROSTVAC-VF and a cellular vaccine GVAX, are in development.  Moreover, several clinical trials are investigating the role of immune check-point blockade in the treatment of prostate cancer.  Ipilimumab and nivolumab are potent T cell check-point inhibitors that reverse immunologic tolerance in multiple types of cancers.

Hodgkin's lymphoma

On May 17, 2016, the FDA granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin (Adcetris). 

NCCN Drug and Biologics Compendium (2017) recommend nivolumab for persons with classical Hodgkin lymphoma, in adults age 18 and older as additional therapy as a single agent for refractory disease if Deauville 4-5 or for relapsed disease in patients previously treated with brentuximab vedotin or for disease that has relapsed or progressed following high-dose therapy and autologous stem cell rescue (HDT/ASCR) and post-transplant  brentuximab vedotin, The NCCN Compendium also recommends nivolumab in classical Hodgkin lymphoma as palliative therapy as a single agent for older adults greater than 60 years of age if previously treated with brentuximab vedotin.

Ansell et al (2015) stated that pre-clinical studies suggested that Reed-Sternberg cells exploit the PD-1 pathway to evade immune detection.  In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling.  These investigators hypothesized that nivolumab could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.  In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects.  Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.  Of the 23 participants, 78 % were enrolled in the study after a relapse following autologous stem-cell transplantation and 78 % after a relapse following the receipt of brentuximab vedotin.  Drug-related AEs of any grade and of grade 3 occurred in 78 % and 22 % of patients, respectively.  An objective response was reported in 20 patients (87 %), including 17 % with a complete response (CR) and 70 % with a partial response (PR); the remaining 3 patients (13 %) had stable disease (SD).  The rate of PFS at 24 weeks was 86 %; 11 patients were continuing to participate in the study.  Reasons for discontinuation included: stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients).  Analyses of pre-treatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands.  Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.  The authors concluded that nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma.

Head and neck cancer

Swanson and Sinha (2015) noted that targeted immunotherapy promoting anti-tumor T-cell activity has shown improved survival and durable objective responses in advanced melanoma patients.  Data are mounting that concurrent use of ipilimumab and nivolumab has a more pronounced effect than either as monotherapy.  Pre-clinical data suggested these therapies would be beneficial in head and neck malignancies as well. 

The FDA approved nivolumab 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. The approval was based on results from the Phase 3, CheckMate -141 trial in which nivolumab demonstrated statistically significant overall survival versus the comparator arm (investigator’s choice of methotrexate, docetaxel or cetuximab), with a 30% reduction in the risk of death (HR=0.70 [95% CI: 0.53-0.92; p=0.0101]).1 The median OS was 7.5 months (95% CI: 5.5-9.1) for nivolumab compared to 5.1 months (95% CI: 4.0-6.0) for investigator’s choice.  

CheckMate -141 was a phase 3, open-label, randomized, trial evaluating nivolumab versus investigator’s choice of therapy in patients with recurrent or metastatic SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. Patients were included regardless of their HPV or PD-L1 status. Patients were randomized 2:1 to receive nivolumab 3 mg/kg intravenously over 60 minutes every two weeks (n=240), or investigator’s choice (n=121) of: methotrexate 40 to 60 mg/m2 intravenously weekly, docetaxel 30 to 40 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. The primary endpoint was overall survival. The trial’s secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Nivolumab demonstrated statistically significant superior overall survival with a 30% reduction in the risk of death (HR=0.70 [95% CI: 0.53-0.92; p=0.0101]), and a median OS of 7.5 months (95% CI: 5.5-9.1) for nivolumab compared to 5.1 months (95% CI: 4.0-6.0) for the investigator’s choice arm. 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.

In CheckMate -141, nivolumab was discontinued in 14% of patients and was delayed in 24% of patients for an adverse reaction. Serious adverse reactions occurred in 49% of patients receiving nivolumab. The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, aspiration pneumonia, respiratory failure, respiratory tract infection, and sepsis.

The NCCN Drug and Biologics Compendium (NCCN, 2019) recommends nivolumab for very advanced recurrent or persistent head and neck cancer as a single agent for non-nasopharyngeal cancer (Category 1) if disease progression on or after platinum-containing chemotherapy or for nasopharyngeal disease (Category 2B) if previously treated, recurrent or metastatic non-keratinizing disease.

• newly diagnosed T4b, any N, M0 disease, unresectable nodal disease with no metastases, or for patients who are unfit for surgery and performance status (PS) 3
• metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy (RT) and PS 0-2
• unresectable locoregional recurrence without prior RT and PS 3. 

Cervical Cancer

There are currently 2 clinical trials (one is a phase I/II; the other is a phase II) on the use of nivolumab for the treatment of cervical cancer.

A phase I/II study -- “A Study to Investigate the Safety and Efficacy of Nivolumab in Virus-associated Tumors (CheckMate358)” (NCT02488759) is not yet open for participant recruitment.  The purpose of this study to investigate the safety and efficacy of using nivolumab to treat subjects who have virus-associated tumors.  Certain viruses that infect human cells have been known to play a role in tumor formation and growth.  This study will investigate the effects of the study drug nivolumab in human subjects who have the following types of viral-associated tumors: Gastric Cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.  (Last verified June 2015). 

A phase II study -- “Nivolumab in Treating Patients with Persistent, Recurrent, or Metastatic Cervical Cancer” (NCT02257528) is currently recruiting participants.  This phase II trial studies the side effects and how well nivolumab works in treating patients with cervical cancer that has grown, come back, or spread to other places in the body.  Monoclonal antibodies, such as nivolumab, may block tumor growth in different ways by targeting certain cells.  (Last verified June 2015). 

UpToDate reviews on “Management of recurrent or metastatic cervical cancer’ (Wright, 2015), “Management of early stage cervical cancer” (De Los Santos and Straughn, 2015a), and “Management of locally advanced cervical cancer” (De Los Santos and Straughn, 2015b) do not mention nivolumab as a therapeutic option.

Furthermore, the National Comprehensive Cancer Network (NCCN)’s clinical practice guideline on “Cervical cancer” (Version 2.2015) does not mention nivolumab as a therapeutic option.

Also, NCCN’s Drugs & Biologics Compendium (2015) does not list cervical cancer as a recommend indication of nivolumab.

Sarcomas

Uehara et al (2015) stated that although multi-modal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years.  Immunotherapies have shown the effectiveness for several types of advanced tumors.  Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas.  Cytokine therapies with interleukin (IL)-2 or interferons (IFNs) have limited efficacy because of their cytotoxicities.  Liposomal muramyl tripeptide phosphatidyl-ethanolamine (L-MTP-PE), an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year OS of patients.  Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas.  Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms.  These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas.  The authors provided an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discussed their potential as adjuvant therapies in combination with conventional therapies.

Roberts et al (2015) noted that pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin.  Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma.  Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis.  New therapies for these patients are urgently needed.  Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma.  In the past, immunomodulatory agents such as IFN, IL-2, and L-MTP-PE have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit.  Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas.  Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to re-direct T cells using chimeric antigen receptors and bi-specific antibodies are rapidly evolving with potential for the treatment of sarcomas.  These investigators focused on recent pre-clinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immune-editing, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines.

D'Angelo et al (2018) stated atients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. The authors investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma. The authors did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths. The authors concluded that nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted. This study is ongoing although enrolment is closed (ClinicalTrials.gov number NCT02500797).

Furthermore, NCCN’s clinical practice guideline on” Soft tissue sarcoma” (Version 1.2015) does not mention nivolumab as a therapeutic option.

Sarcomatoid Carcinoma of the Lung

Per Wikipedia, approximately 98 % of lung cancers are carcinoma, a term for malignant neoplasms derived from cells of epithelial lineage, and/or that exhibit cytological or tissue architectural features characteristically found in epithelial cells.  Under WHO-2004, lung carcinomas are divided into 8 major taxa:

• Squamous cell carcinoma
• Small cell carcinoma
• Adenocarcinoma
• Large cell carcinoma
• Adenosquamous carcinoma
• Sarcomatoid carcinoma
• Carcinoid tumor
• Salivary gland-like carcinoma

Sarcomatoid carcinomas are unique among lung carcinomas in that, although they are considered carcinomas, they contain cytological and tissue architectural features that are usually characteristic of sarcoma.

Small Cell Lung Cancer

On August 16, 2018, the Food and Drug Administration granted accelerated approval to nivolumab (Opdivo, Bristol-Myers Squibb Company Inc.) for patients with metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. Approval was based on demonstration of a durable overall response rate (ORR) in a subgroup of patients from CheckMate-032 (NCT01928394), a multicenter, open-label trial in patients with metastatic solid tumors. This subgroup comprised 109 patients with metastatic SCLC, with disease progression after platinum-based therapy and at least one other prior line of therapy, regardless of tumor PD-L1 status. All patients received nivolumab 3 mg/kg by intravenous infusion over 60 minutes every 2 weeks. The major efficacy outcome measures were overall response rate (ORR) and duration of response according to RECIST v1.1 as assessed by blinded independent central review. The ORR was 12% (95% CI: 6.5, 19.5). Responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of the 13 responding patients. PD-L1 tumor status did not appear to be predictive of response.

Safety data was evaluated in 245 patients with metastatic SCLC with disease progression following platinum-based chemotherapy and received at least one dose of nivolumab at a dose of 3 mg/kg every 2 weeks. The most common (≥20%) adverse reactions in CheckMate-032 were fatigue, decreased appetite, musculoskeletal pain, dyspnea, nausea, diarrhea, constipation and cough. Nivolumab was discontinued for adverse reactions in 10% of patients and 25% of patients had at least one dose withheld for an adverse reaction. Serious adverse reactions occurred in 45% of patients. The most frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, pneumonitis, pleural effusion, and dehydration.

The recommended dose and schedule of nivolumab for this indication is 240 mg every 2 weeks over 30 min.

The NCCN Drug and Biologics Compendium (Version 2.2018) lists nivolumab for small cell lung cancer as subsequent systemic therapy for patients with performance status 0-2 as a single agent or in combination with ipilimumab for relapse within 6 months following complete or partial response or stable disease with initial treatment, or for primary progressive disease.

Antonia, et al. (2016) assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with small cell lung cancer (SCLC) who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicenter, multi-arm, open-label trial was conducted at 23 sites (academic centers and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. The investigators stated that these data support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomized controlled trials in SCLC.

Malignant Pleural Mesothelioma

The NCCN Drugs & Biologics Compendium (NCCN, 2017) recommends nivolumab for malignant pleural mesothelioma as subsequent systemic therapy as a single agent or in combination with ipilimumab.

Scherpereel, et al. (2017) reported on a multicenter randomized non comparative phase 2 trial of nivolumab and ipilimumab for malignant pleural mesothelioma. Eligible patients were over 18 years of age, performance status (PS) 0-1, histologically proven malignant pleural mesothelioma (MPM) relapsing after 1 or 2 prior lines including pemetrexed/platinum doublet, measurable disease. Randomized patients (1:1) received nivolumab 3 mg/kg every two weeks, or nivolumab 3 mg/kg every two weeks plus ipilimumab 1 mg/kg every 6 weeks, until progression or unacceptable toxicity. Primary endpoint was disease control rate (DCR) at 12 weeks with a blinded independent central review (BICR). 114 patients were to be randomized (with 108 eligible), with one-step Fleming procedure, H0 P<20% versus H1 P>40%, with 95% power, 5% one-sided a-risk: greater than or equal to 17 failure-free patients had to be observed at 12 weeks in either arm, to conclude to the activity of the corresponding regimen. From March to August 2016, 125 patients were enrolled in 21 centers. Eighty percent of study subjects were males, median age of subjects was  71.8 years (range 32.5-88.1). 62.4% were performance status 1, 83.2% had epithelioid cancers, 69.6% had one previous line of therapy, 70% of patients received 3 or more cycles of either treatment. Twelve weeks-DCR assessed by BICR in the first 108 eligible patients was 42.6% [95% CI: 29.4-55.8%] with nivolumab (n=23/54), and 51.9% [95% CI: 38.5%-65.2%] with nivolumab plus ipilimumab (n=28/54). Overall response rate (ORR) was 16.7% [95% CI: 6.7%-26.6%] with nivolumab (n=9/54), and 25.9% [95% CI: 14.2%-37.6%] with nivolumab plus ipilimumab (n=14/54). All grade/G3-4 toxicities were slightly increased in the combination nivolumab plus ipilimumab arm (86.9%/16.4%) versus nivolumab alone (77.8%/9.5%). Three treatment-related deaths were observed in the combination nivolumab/ipilimumab arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). The investigators concluded that both nivolumab and nivolumab plus ipilimumab arms reached their endpoint in 2nd/3rd-line MPM pts, suggesting that immunotherapy may provide new options for these patients.

Urothelial Carcinoma

The NCCN Drugs and Biologics Compendium (2017) recommends nivolumab for the following urothelial carcinomas:

• Bladder cancer - Used as a single agent for clinical stage T4b or T2-4a, N1-3 disease, or for recurrence post cystectomy, or for metastatic disease as subsequent systemic therapy
• Primary Carcinoma of the Urethra - Used as a single agent as subsequent systemic therapy for recurrent or metastatic disease. Chemotherapy regimen based on histology. 
• Upper GU Tract Tumors - Used as a single agent as subsequent systemic therapy for metastatic disease.
• Urothelial Carcinoma of the Prostate - Used as a single agent as subsequent systemic therapy for metastatic disease.

Hepatocellular carcinoma

On September 22, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (Opdivo) for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.

FDA-approval was based on a 154-patient subgroup (median age 63 years; range 19-81 years) of CHECKMATE-040 (NCT 01658878), a multicenter, open-label trial conducted in patients with hepatocellular carcinoma (HCC) and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib. In addition to including patients without active hepatitis viral infection, the trial enrolled patients with either active HBV (31%) or HCV (21%) but not those with active co-infection with HBV and HCV or with hepatitis D virus infection. Patients received nivolumab 3 mg/kg by intravenous infusion every 2 weeks. The confirmed overall response rate, as assessed by blinded independent central review using RECIST 1.1, was 14.3% (95% CI: 9.2, 20.8), with 3 complete responses and 19 partial responses. Response duration ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or longer and 55% had responses lasting 12 months or longer (FDA, 2017).

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

About 2% to 10% of patients with CLL/SLL will develop histologic transformation (i.e, Richter's transformation) to diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma during the course of their disease and treatment. The NCCN guidelines state that based upon lower-level evidence, there is NCCN consensus that the use of nivolumab with or without ibrutinib for treatment of histologic (Richter's) transformation to diffuse large B-cell lymphoma (clonally related or unknown clonal status) in patients with del(17p)/TP53 mutation or who are chemotherapy refractory and unable to receive chemoimmunotherapy is appropriate (NCCN Category 2B).

Gestational Trophoblastic Neoplasia

The NCCN guidelines state PD1-/PD-L1 inhibitors (e.g., nivolumab) has shown to have some activity in treating resistant gestational trophoblastic neoplasia. The NCCN compendia lists single-agent therapy with nivolumab for recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum/etoposide-containing regimen  or for methotrexate-resistant high-risk disease. 

Veras et al (2017) stated one of the major immune checkpoints responsible for immune evasion in cancer cells is the interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1). As human trophoblastic cells display many of the features of malignant cells such as the ability to invade normal tissue including blood vessels and are apparently not eradicated by the host immune system, we undertook the present study to determine whether PD-L1 was upregulated in different types of trophoblastic cells during normal pregnancy and in gestational trophoblastic diseases. Immunohistochemistry using an anti-PD-L1-specific antibody demonstrated that in early and term normal placentas, PD-L1 was highly expressed in syncytiotrophoblast and to a much lower extent in intermediate trophoblastic cells located in the chorion laeve and implantation site. PD-L1 immunoreactivity was undetectable in cytotrophoblastic cells. This staining pattern in normal placenta was recapitulated in various types of gestational trophoblastic disease. PD-L1 was highly expressed by syncytiotrophoblast in complete moles and choriocarcinomas. The intermediate trophoblastic neoplasms, placental site trophoblastic tumors, and epithelioid trophoblastic tumors showed variable PD-L1 immunoreactivity but at a lower intensity than in the neoplastic syncytiotrophoblast in choriocarcinoma. In addition, we observed PD-1-positive lymphocytes located within the implantation site and in trophoblastic tumors. In summary, this study describes a novel mechanism for trophoblastic cells to create a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblast and in intermediate trophoblast. Trophoblastic tumors may also use PD-L1 expression to evade the host immune response thereby promoting their survival.

Appendix

Nivolumab is available as Opdivo injection as 40 mg/4 mL (10 mg/mL), 100 mg/10 mL (10 mg/mL), and 240 mg/24 mL (10 mg/mL), solution in a single-dose vial.

The FDA-approved labeling of Opdivo recommends the following dosages administered as an intravenous infusion over 30 minutes until disease progression or unacceptable toxicity

• Metastatic non-small cell lung cancer

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

• Unresectable or metastatic melanoma
   

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

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

• Adjuvant Treatment of Melanoma
   

  • Opdivo 240 mg every 2 weeks or 480 mg every 4 weeks for a maximum of 1 year.

• Advanced Renal cell carcinoma

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

  • Opdivo 3 mg/kg administered intravenously over 30 minutes followed by Yervoy 1 mg/kg administered intravenously over 30 minutes on the same day, every 3 weeks for a maximum of 4 doses, then nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks, administered intravenously over 30 minutes.
     

• Classic Hodgkin's lymphoma

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

• Recurrent or metastatic squamous cell carcinoma of the head and neck

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

• Locally advanced or metastatic urothelial carcinoma

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

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

  • Opdivo 240 mg every 2 weeks.

  • Opdivo with Yervoy (ipilimumab) : Opdivo 3 mg/kg administered as an I.V. infusion over 30 minutes, followed by ipilimumab 1 mg/kg adminisered as an I.V. infusion over 30 minutes, on the same day, every 3 weeks for 4 doses,  After completing 4 doses of the combination, administer Opdivo 240 mg as a single agent every 2 weeks as an I.V. infusion over 30 minutes until disease progression or unacceptable toxicity.
    
    

• Hepatocellular carcinoma

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

• Small cell lung cancer

  • Opdivo 240 mg every 2 weeks.

Dose Modifications

There are no recommended dose modifications for hypothyroidism or hyperthyroidism.

Withhold Opdivo (nivolumab) for any of the following:

• Grade 2 pneumonitis
• Grade 2 or 3 colitis
• Grade 2 or 3 hypophysitis
• Grade 2 adrenal insufficiency
• Grade 3 hyperglycemia in type 1 diabetes
• Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or Toxic Epidermal Necrolysis (TEN) 
• New onset moderate or severe neurologic signs and symptoms of encephalitis
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 5 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN in Hepatitis/non-HCC
• AST/ALT is within normal limits at baseline and increases to more than 3 and up to 5 times the ULN or if AST/ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times the ULN or if AST/ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times the ULN in Hepatitis/HCC
• Creatinine greater than 1.5 and up to 6 times ULN 
• Any other severe or Grade 3 treatment-related adverse reactions

Resume Opdivo (nivolumab) in patients whose adverse reactions recover to Grade 0-1.

Permanently discontinue Opdivo (nivolumab) for any of the following:

• Any life-threatening or Grade 4 adverse reaction
• Grade 3 colitis when administered with ipilimumab
• Grade 4 hyperglycemia in type 1 diabetes
• Grade 4 hypophysitis
• Grade 3 or 4 adrenal insufficiency
• Grade 4 rash or confirmed SJS or TEN
• Grade 3 or 4 pneumonitis
• Grade 4 colitis
• Immune-mediated encephalitis
• AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN in Hepatitis/non-HCC
• AST or ALT increases to more than 10 times the ULN or total bilirubin increases to more than 3 times the ULN in Hepatitis/HCC
• Creatinine greater than 6 times ULN
• Any severe or Grade 3 treatment-related adverse reaction that recurs
• Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks
• Persistent Grade 2 or 3 treatment-related adverse reactions that do not recover to Grade 0-1 within 12 weeks after last dose of Opdivo (nivolumab)
• Grade 3 myocarditis
  
  

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Nivolumab:
Other CPT codes related to the CPB:
81210	BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
96413	Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
HCPCS codes covered if selection criteria are met:
J9299	Injection, nivolumab, 1 mg
Other HCPCS codes related to the CPB:
Ibrutinib - no specific code :
C9257	Injection, bevacizumab, 0.25 mg
J9035	Injection, bevacizumab, 10 mg
J9042	Injection, brentuximab vedotin, 1 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9206	Injection, irinotecan, 20 mg
J9228	Injection, ipilimumab, 1 mg
J9263	Injection, oxaliplatin, 0.5 mg
Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
ICD-10 codes covered if selection criteria are met:
C00.0 - C05.1, C06.0 - C06.9, C09.0 - C09.9, C10.3, C11.0 - C11.9, C12, C13.0 - C13.9, C30.0, C31.0 - C31.9, C32.0-C32.9	Malignant neoplasms of lip, tongue, gum, floor of mouth, palate, other and unspecified parts of mouth, posterior was of oropharynx, nasopharynx, pyriform sinus, hypopharynx, nasal cavity, accessary sinuses, larynx
C17.0 - C17.9	Malignant neoplasm of small intestine
C18.0 - C20	Malignant neoplasm of colon and rectum
C21.0 - C21.8	Malignant neoplasm of anus and anal canal [adenocarcinoma]
C22.0 - C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C33 - C34.92	Malignant neoplasm of trachea, bronchus and lung
C4A.0 - C4A.9	Merkel cell carcinoma
C43.0 - C43.9	Malignant melanoma of skin
C44.520	Squamous cell carcinoma of anal skin
C45.0	Mesothelioma of pleura
C61	Malignant neoplasm of prostate
C64.1 - C64.9	Malignant neoplasm of kidney, except pelvis
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter
C67.0 - C67.9	Malignant neoplasm of bladder
C68.0	Malignant neoplasm of urethra
C69.30 - C69.32	Malignant neoplasm of choroid [uveal melanoma]
C77.0 - C77.9	Secondary and unspecified malignant neoplasm of lymph nodes
C79.31 - C79.32	Secondary malignant neoplasm of brain and cerebral meninges
C81.10 - C81.79	Hodgkin lymphoma [adults age 18 and older only]
C83.00 - C83.09	Small cell B-cell lymphoma [small lymphocytic lymphoma]
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type [small lymphocytic lymphoma]
D37.01 - D37.02, D37.05 - D37.09, D38.0, D38.5 - D38.6	Neoplasm of uncertain behavior of lip, oral cavity, pharynx, larynx, respiratory organs
Z85.820	Personal history of malignant melanoma of skin
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C16.0 - C16.9	Malignant neoplasm of stomach
C22.0	Liver cell carcinoma
C25.0 - C25.9	Malignant neoplasm of pancreas
C41.0 - C41.9, C44.00 - C46.9	Malignant neoplasm of bone of skull and face
C50.011 - C50.929	Malignant neoplasm of breast
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C56.1 - C56.9	Malignant neoplasm of ovary
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C76.0	Malignant neoplasm of head, face, and neck
C82.00 - C91.92	Malignant neoplasm of lymphoid, hematopoietic and related tissue [non-Hodgkin's lymphoma]

The above policy is based on the following references: