Coverage Policy Manual
Policy #: 2016005
Category: Pharmacy
Initiated: February 2016
Last Review: February 2019
  Anti-PD-1 (programmed death receptor-1)Therapy (Pembrolizumab)(Nivolumab) (Durvalumab)

Description:
The programmed death 1 protein (PD1) is an immune checkpoint receptor expressed by activated T cells. PD-1 binds to its ligands Pd1-L1 and PD1-L2 which are expressed on tumor cells, causing immunosuppression and preventing the immune system from rejecting the tumor.
 
PD-1 inhibition has been studied in clinical trials in metastatic melanoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, head and neck cancer and urothelial cancer.
 
Regulatory Status
Pembrolizumab was originally approved under accelerated approval by the U.S. Food and Drug Administration on September 04, 2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor. In October 2015, approval was received for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA approved test and who have disease progression melanoma was revised to allow for unresectable or metastatic melanoma without the requirement of disease progression following ipilimumab and BRAF inhibitor treatment. On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
 
Nivolumab was originally approved in December 2014 by the U.S. Food and Drug Administration under an accelerated approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and if BRAF V600 mutation positive, a BRAF inhibitor. In September 2015, the FDA granted approval for the treatment of metastatic squamous non-small cell lung cancer in patients with progression on or after platinum-based chemotherapy as well as in combination with ipilimumab in patients with BRAF V600 wild-type melanoma. In November 2015, FDA approval was granted for the use as a single agent in the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. In January 2016, the FDA granted expansion of the indication as a single agent for the treatment of patients with BRAF V600 mutation positive, unresectable or metastatic melanoma to remove the restriction that such patients should have disease progression following ipilimumab and a BRAF inhibitor. Additionally, the approval expanded the indication for the combined use with ipilimumab for the treatment of patients with unresectable or metastatic melanoma to remove the restriction for the treatment of only patients with BRAF wild-type melanoma.
 
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.
 
A new “Warning and Precaution” was issued for complications of allogeneic HSCT after nivolumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions.  FDA has required the manufacturer to further study the safety of allogeneic HSCT after nivolumab.
 
On March 14, 2017, the U.S. Food and Drug Administration granted accelerated approval for pembrolizumab in the treatment of adult and pediatric patients with refractory cHL, or who have relapsed after 3 or more prior lines of therapy. Products approved under the accelerated approval regulations, 21 CFR 601.41, require further adequate and well-controlled studies/clinical trials to verify and describe clinical benefit. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials (FDA, 2017).
 
Duralumab (Imfinzi™) was FDA-approved in May 2017 for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.  (U.S. Food and Drug Administration 2017).
 
Coding
Effective January 01, 2019, there is a specific HCPCS code - J9173 for Durvalumab..

Policy/
Coverage:
 Effective November 2018
 
Pembrolizumab (Keytruda®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
 
  1. For the treatment of adults as a single agent with unresectable or metastatic melanoma:
a.  For first-line therapy in untreated disease or
b.  Following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor as subsequent therapy with documented disease progression on or after recent therapy.
2. For the treatment of patients with metastatic non-small cell lung cancer (NSCLC).
a.  In combination with carboplatin and either paclitaxel or nab-paclitaxel as a first-line treatment of patients with metastatic squamous NSCLC.
b.  In combination with pemetrexed and carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC, with no EGFR or ALK geromic tumor aberrations.
c.  As a single agent for the first-line treatment in adults whose tumors have high PD-L1 expression [Tumor Proportion Score  (TPS) >50%]  as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.                
d.  as a single agent in adults whose tumors express PD-L1 (TPS >1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy.  Patients with EGFR or ALK genomic tumor mutations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.  
3.  For the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
4.  For the treatment of patients with classical Hodgkin lymphoma that has resisted treatment or relapsed after three or    more prior lines of therapy with all of the following
a.  No  history  of allogeneic HSCT in the past 5 years, AND
b,  No documentation of active autoimmune disease, AND  
c.  No chronic ongoing infection, AND   
d.  ECOG performance status 0-1   
5.  For the treatment of patients with locally advanced or metastatic urothelial carcinoma
    • who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or in patients who are not eligible for any platinum containing chemotherapy regardless of PD-L1 status.
      who have disease progression during or following platinum-containing chemotherapy or within 12 months or neoadjuvant of adjuvant treatment with platinum-containing chemotherapy. (Effective February 2019)
6.  For the treatment of adult and pediatric patients with primary mediastinal large B-cell  lymphoma (PMBCL) that is refractory, or who have relapsed after 2 or more prior lines of therapy.
         Limitations of use: KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy. (Effective February 2019)
7.  For the treatment of patients with recurrent of metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS1) as determined by an FDA-approved test.
8.  For the treatment of patients with colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, that is microsatellite instability-high.
9.  For the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after two or more prior lines of therapy including
fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/new-targeted  therapy.
10. For the treatment of patients with hepatocellular carcinoma who have previously been treated with sorafenib.  (Effective December 2018)
11. For the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. (Effective February 2019)
 
 
Off Label
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030
 
Dosing
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of either 200mg every 3 weeks for adults or 2mg/kg (up to 200mg) every 3 weeks for pediatrics.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
    • For adults having received another PD-1 agent (i.e. nivolumab)
    • For any other indication than those listed above as meeting primary coverage criteria.
    • In combination with any other drug except as listed above.
 
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.  Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Nivolumab (Opdivo®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab meets member benefit certificate primary coverage criteria and is covered for the following indications:
  1. For the treatment of adults with melanoma with one of the following:
a.  with BRAF V600 wild-type metastatic or unresectable disease for  as a single agent
b.  with BRAF V600 mutation-positive metastatic or unresectable disease for  as a single agent
c.  with metastatic or unresectable disease in combination with ipilimumab
d.  with melanoma with lymph node involvement or metastatic disease following complete resection, as an adjuvant agent
2.  For the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
3.  For the treatment of adults with advanced renal cell carcinoma  and one of the following:
a.  who have received prior anti-angiogenic therapy (e.g. axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc).
b.  who are previously untreated and have intermediate or poor risk, in combination with ipilumab
4.  For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after one of the following:
a.  autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin
b.  3 or more lines of systemic therapy that includes autologous HCST
5. For the treatment of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy.
6. For the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
a.  have disease progression during or following platinum-containing chemotherapy
b.  Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
7.  For the treatment of adult and pediatric (12 years and older) patients with colorectal cancer that is microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, given as a single agent or in combination with ipilimumab
8.  For the treatment of patients with hepatocellular carcinoma who have previously been treated with sorafenib.
 
Off Label
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
Dosing Guidelines:
Dosing should be in accordance with FDA labeling:
 
With Ipilimumab
The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer OPDIVO as a single agent over 30 minutes, as either:
• 240 mg every 2 weeks or
• 480 mg every 4 weeks
 
As a single agent
Recommended dosing is either:
• 240 mg every 2 weeks or
• 480 mg every 4 weeks
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, nivolumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Durvalumab (Imfinzi®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Durvalumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for:
  1. Locally advanced or metastatic urothelial carcinoma in individuals:
    • who have disease progression during or following platinum-containing chemotherapy or
    • who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
 
2. Individuals with unresectable, Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. (Effective May 2018)
 
Off Label
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg weekly every 2 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
        • For patients having received another PD-1 agent (i.e. nivolumab, pembrolizumab) AND  
        • For any other indication than those listed above as meeting primary coverage criteria
 
For members with contracts without primary coverage criteria, durvalumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Effective July 2018
 
Pembrolizumab (Keytruda®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Pembrolizumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
    1. For the treatment of adults as a single agent with unresectable or metastatic melanoma:
a) for first-line therapy in untreated disease or
b) following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor as subsequent therapy with    documented disease progression on or after recent therapy.
2. For the treatment of patients with metastatic non-small cell lung cancer (NSCLC)
        1. when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy.
a.  with EGFR and/or ALK mutations who have had disease progression on FDA-approved therapy
b. when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test (e.g., greater than 50% of tumor cells express PD-1) and are negative for EGFR or ALK sensitizing mutations either as: (a) primary treatment OR (b) for treatment of disease progression on or after platinum-containing chemotherapy.
c. in combination with pemetrexed and carboplatin, as first-line treatment.
3.  For the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
4.  For the treatment of patients with classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy with all of the following
        1. No  history  of allogeneic HSCT in the past 5 years, AND
        2. No documentation of active autoimmune disease, AND  
        3. No chronic ongoing infection, AND   
        4. ECOG performance status 0-1   
    1. For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or in patients who are not eligible for any platinum containing chemotherapy regardless of PD-L1 status
    2. For the treatment of adult and pediatric patients with primary mediastinal large B-cell  lymphoma (PMBCL) that is refractory, or who have relapsed after 2 or more prior lines of therapy.
    3. For the treatment of patients with recurrent of metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS1) as determined by an FDA-approved test
    4. For the treatment of patients with colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, that is microsatellite instability-high.
    5. For the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors expres PD-L1 as determined by an FDA-approved test with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/new-targeted therapy.
    6. NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
        • For adults having received another PD-1 agent (i.e. nivolumab)
        • For any other indication than those listed above as meeting primary coverage criteria.
        • In combination with any other drug except as listed above.
 
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational.  Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Dosing
 
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of either 200mg every 3 weeks for adults or 2mg/kg (up to 200mg) every 3 weeks for pediatrics.
 
Nivolumab (Opdivo®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab meets member benefit certificate primary coverage criteria and is covered for the following indications:
    1. For the treatment of adults with melanoma with one of the following:
        1. with metastatic or unresectable disease for  as a single agent
        2. with metastatic or unresectable disease in combination with ipilimumab
        3. following complete resection, as an adjuvant agent
    2. For the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
    3. For the treatment of adults with advanced renal cell carcinoma  and one of the following:
        1. who have received prior anti-angiogenic therapy (e.g. axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc).
        2. who are previously untreated and have intermediate or poor risk, in combination with ipilumab
    4. For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after one of the following:
        1. autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin
        2. 3 or more lines of systemic therapy that includes autologous HCST
    5. For the treatment of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy.
    6. For the treatment of patients with locally advanced or metastatic urothelial carcinoma who:
        1. have disease progression during or following platinum-containing chemotherapy
        2. Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
    7. For the treatment of adult and pediatric (12 years and older) patients with colorectal cancer that is microsatellite instability high (MSI-H) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, given as a single agent or in combination with ipilimumab
    8. For the treatment of patients with hepatocellular carcinoma who have previously been treated with sorafenib.
    9. NCCN 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
 
Dosing Guidelines:
Dosing should be in accordance with FDA labeling:
 
With Ipilimumab
The recommended dose of OPDIVO is 1 mg/kg administered as an intravenous infusion over 30 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses. After completing 4 doses of the combination, administer OPDIVO as a single agent over 30 minutes, as either:
• 240 mg every 2 weeks or
• 480 mg every 4 weeks
 
As a single agent
Recommended dosing is either:
• 240 mg every 2 weeks or
• 480 mg every 4 weeks
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, nivolumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Durvalumab (Imfinzi®)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Durvalumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for:
  1. Locally advanced or metastatic urothelial carcinoma in individuals:
    • who have disease progression during or following platinum-containing chemotherapy or
    • who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
 
2. Individuals with unresectable, Stage III non-small cell lung cancer (NSCLC) whose  disease has not progressed following concurrent platinum-based  chemotherapy and radiation therapy. (Effective May 2018)
 
3. NCCN 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg weekly every 2 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
    • For patients having received another PD-1 agent (i.e. nivolumab, pembrolizumab) AND  
    • For any other indication than those listed above as meeting primary coverage criteria
 
For members with contracts without primary coverage criteria, durvalumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
EFFECTIVE JUNE 2018
 
Pembrolizumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of adults as a single agent with unresectable or metastatic melanoma:  a) for first-line therapy in untreated disease or b) following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor as subsequent therapy with documented disease progression on or after recent therapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic NSCLC with EGFR and/or ALK mutations who have had disease progression on FDA-approved therapy
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. (Effective October 2016)
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test (e.g., greater than 50% of tumor cells express PD-1) and are negative for EGFR or ALK sensitizing mutations either as: (a) primary treatment OR (b) for treatment of disease progression on or after platinum-containing chemotherapy. (Effective November 2016)
 
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy with:
        • No  history  of allogeneic HSCT in the past 5 years, AND
        • No documentation of active autoimmune disease, AND
        • No chronic ongoing infection, AND  
        • ECOG performance status 0-1  
(Effective June 2017).
 
Dosing Guidelines:
 
Melanoma:  Maximum FDA recommended dosing for pembrolizumab is 2 mg/kg   administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity
 
HNSCC and NSCLC: The recommended dosing for pembrolizumab is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks
 
Classical Hodgkin Lymphoma: The recommended dosing for pembrolizumab is: Adults 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks; Pediatrics 2 mg/kg (up to 200 mg) administered as an intravenous infusion over 30 minutes every 3 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. nivolumab)
        • For any other indication than those listed above as meeting primary coverage criteria.
 
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. nivolumab)
        • For any other indication than those listed above as meeting primary coverage criteria.
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Nivolumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 wild-type unresectable or metastatic melanoma.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma.
 
Nivolumab, in combination with ipilimumab, meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or metastatic melanoma.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with advanced renal cell carcinoma (with histologic confirmation of clear-cell component who have received prior anti-angiogenic therapy (e.g. axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc).
 
Nivolumab meets member benefit primary coverage criteria and is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma, in combination with ipilimumab (FDA approved indication). (Effective June 2018).
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin.  (Effective August 2016)
 
Nivolumab meets member benefit certificate primary coverage criteria for use as a single agent in treatment of platinum-refractory, recurrent squamous-cell carcinoma of the head and neck. (Effective November 2016)
 
Dosing Guidelines:
The maximum FDA approved dose of nivolumab  is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses.
 
The maximum FDA approved subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
 
The maximum FDA approved dose of nivolumab as a single agent is 3 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab does not meet member benefit certificate primary coverage criteria:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
        • For any other indication.
 
For members with contracts without primary coverage criteria, nivolumab is considered investigational:
 
    • In patients less than 18 years of age; OR
    • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
    • For any other indication.Investigational services are specific exclusions in most member benefit certificates of coverage.  
 
Durvalumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Durvalumab meets primary coverage criteria and is covered for the following:
 
    1. Locally advanced or metastatic urothelial carcinoma in individuals:
      • who have disease progression during or following platinum-containing chemotherapy or
      • who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
2. Urothelial carcinoma in individuals with: (Effective June 2018)
      • Cinical stage T4b or T2-4a, N1-3 disease or
      • Recurrence post cystectomy or
      • Metastatic disease as a single agent for subsequent systemic therapy post-platinum
3. Individuals with unresectable, Stage III non-small cell lung cancer (NSCLC) whose  disease has not progressed following concurrent platinum-based  chemotherapy and radiation therapy. (Effective May 2018)
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg weekly every 2 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is considered investigational for contracts without primary coverage criteria:
 
    • For patients having received another PD-1 agent (i.e. nivolumab, pembrolizumab) AND
    • For any other indication than those listed above as meeting primary coverage criteria
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO JUNE  2018
Pembrolizumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of adults as a single agent with unresectable or metastatic melanoma:  a) for first-line therapy in untreated disease or b) following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor as subsequent therapy with documented disease progression on or after recent therapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic NSCLC with EGFR and/or ALK mutations who have had disease progression on FDA-approved therapy
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. (Effective October 2016)
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test (e.g., greater than 50% of tumor cells express PD-1) and are negative for EGFR or ALK sensitizing mutations either as: (a) primary treatment OR (b) for treatment of disease progression on or after platinum-containing chemotherapy. (Effective November 2016)
 
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy with:
        • No  history  of allogeneic HSCT in the past 5 years, AND
        • No documentation of active autoimmune disease, AND
        • No chronic ongoing infection, AND  
        • ECOG performance status 0-1  (Effective June 2017).
 
Dosing Guidelines:
 
Melanoma:  Maximum FDA recommended dosing for pembrolizumab is 2 mg/kg   administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity
 
HNSCC and NSCLC: The recommended dosing for pembrolizumab is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks
 
Classical Hodgkin Lymphoma: The recommended dosing for pembrolizumab is: Adults 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks; Pediatrics 2 mg/kg (up to 200 mg) administered as an intravenous infusion over 30 minutes every 3 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. nivolumab)
        • For any other indication than those listed above as meeting primary coverage criteria.
 
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. nivolumab)
        • For any other indication than those listed above as meeting primary coverage criteria.
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Nivolumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or Metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 wild-type unresectable or metastatic melanoma.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma.
 
Nivolumab, in combination with ipilimumab, meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or metastatic melanoma.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with advanced renal cell carcinoma (with histologic confirmation of clear-cell component who have received prior anti-angiogenic therapy (e.g. axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc).
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin.  (Effective August 2016)
 
Nivolumab meets member benefit certificate primary coverage criteria for use as a single agent in treatment of platinum-refractory, recurrent squamous-cell carcinoma of the head and neck. (Effective November 2016)
 
Dosing Guidelines:
The maximum FDA approved dose of nivolumab  is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses
The maximum FDA approved subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
 
The maximum FDA approved dose of nivolumab as a single agent is 3 mg/kg administered as
an intravenous infusion over 60 minutes every 2 weeks until disease progression or
unacceptable toxicity.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab does not meet member benefit certificate primary coverage criteria:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
        • For any other indication.
 
For members with contracts without primary coverage criteria, nivolumab is considered investigational:
 
        • In patients less than 18 years of age; OR
        • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
        • For any other indication. Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Durvalumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Durvalumab meets primary coverage criteria and is covered for the following:
     1. Locally advanced or metastatic urothelial carcinoma in individuals:
          • who have disease progression during or following platinum-containing chemotherapy or  
          • who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
      
     2. Individuals with unresectable, Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based  chemotherapy and radiation therapy. (Effective May 2018)
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg weekly every 2 weeks
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is considered investigational for contracts without primary coverage criteria:
 
          • For patients having received another PD-1 agent (i.e. nivolumab, pembrolizumab) AND
          • For any other indication than those listed above as meeting primary coverage criteria
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
EFFECTIVE PRIOR TO MAY 2018
 
Pembrolizumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of adults as a single agent with unresectable or metastatic melanoma:  a) for first-line therapy in untreated disease or b) following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor as subsequent therapy with documented disease progression on or after recent therapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy.
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic NSCLC with EGFR and/or ALK mutations who have had disease progression on FDA-approved therapy
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. (Effective October 2016)
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) when used as a single agent in adults whose tumors express PD-L1 as determined by an FDA-approved test (e.g., greater than 50% of tumor cells express PD-1) and are negative for EGFR or ALK sensitizing mutations either as: (a) primary treatment OR (b) for treatment of disease progression on or after platinum-containing chemotherapy. (Effective November 2016)
 
 
Pembrolizumab meets member benefit certificate primary coverage criteria for the treatment of patients with classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy with:
    • No  history  of allogeneic HSCT in the past 5 years, AND
    • No documentation of active autoimmune disease, AND
    • No chronic ongoing infection, AND
    • ECOG performance status 0-1
(Effective June 2017).
 
Dosing Guidelines:
 
Melanoma:  Maximum FDA recommended dosing for pembrolizumab is 2 mg/kg   administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity
 
HNSCC and NSCLC: The recommended dosing for pembrolizumab is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks
 
Classical Hodgkin Lymphoma: The recommended dosing for pembrolizumab is: Adults 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks; Pediatrics 2 mg/kg (up to 200 mg) administered as an intravenous infusion over 30 minutes every 3 weeks.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Pembrolizumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
    • In patients less than 18 years of age; OR
    • For adults having received another PD-1 agent (i.e. nivolumab)
    • For any other indication than those listed above as meeting primary coverage criteria.
 
For members with contracts without primary coverage criteria, pembrolizumab is considered investigational:
 
    • In patients less than 18 years of age; OR
    • For adults having received another PD-1 agent (i.e. nivolumab)
    • For any other indication than those listed above as meeting primary coverage criteria.
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Nivolumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 wild-type unresectable or metastatic melanoma.
 
Nivolumab as a single agent meets member benefit certificate primary coverage criteria for the treatment of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma.
 
Nivolumab, in combination with ipilimumab, meets member benefit certificate primary coverage criteria for the treatment of adults with unresectable or metastatic melanoma.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab.
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of adults with advanced renal cell carcinoma (with histologic confirmation of clear-cell component who have received prior anti-angiogenic therapy (e.g. axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc).
 
Nivolumab meets member benefit certificate primary coverage criteria for the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin.  (Effective August 2016)
 
Nivolumab meets member benefit certificate primary coverage criteria for use as a single agent in treatment of platinum-refractory, recurrent squamous-cell carcinoma of the head and neck. (Effective November 2016)
 
Dosing Guidelines:
 
The maximum FDA approved dose of nivolumab  is 1 mg/kg administered as an intravenous infusion over 60 minutes, followed by ipilimumab on the same day, every 3 weeks for 4 doses. The maximum FDA approved subsequent dose of nivolumab, as a single agent, is 3 mg/kg as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
 
The maximum FDA approved dose of nivolumab as a single agent is 3 mg/kg administered as
an intravenous infusion over 60 minutes every 2 weeks until disease progression or
unacceptable toxicity.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Nivolumab does not meet member benefit certificate primary coverage criteria:
 
    • In patients less than 18 years of age; OR
    • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
    • For any other indication.
 
For members with contracts without primary coverage criteria, nivolumab is considered investigational:
 
    • In patients less than 18 years of age; OR
    • For adults having received another PD-1 agent (i.e. pembrolizumab); OR
    • For any other indication.
 
Investigational services are specific exclusions in most member benefit certificates of coverage.
 
Durvalumab
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Durvalumab meets primary coverage criteria and is covered for the following locally advanced or metastatic urothelial carcinoma in individuals:
 
    • who have disease progression during or following platinum-containing chemotherapy or
    • who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of less than 10mg/kg weekly every 2 weeks
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness and is considered investigational for contracts without primary coverage criteria:
 
    • For patients having received another PD-1 agent (i.e. nivolumab, pembrolizumab) AND
    • For any other indication than those listed above as meeting primary coverage criteria.
 

Rationale:
Pembrolizumab
 
FDA accelerated approval of pembrolizumab was based on open-label, multicenter expansion cohort of phase I trial of adults aged 18-88 years with unresectable or metastatic melanoma with disease progression within 24 weeks of their last dose of ipilimumab, and if BRAF V600 mutation positive, prior treatment with BRAF inhibitor (Robert, 2014). The trial randomly assigned 173 participants to receive pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) IV once every 3 weeks until disease progression or unacceptable toxicity, with median follow-up duration of 8 months. Additional inclusion criteria for the study included participants who had progressive, measurable, unresectable melanoma who previously received two or more doses of ipilimumab; with confirmed disease progression using immune-related response; adequate ECOG and organ function; and resolution of ipilimumab-related adverse events. Major study exclusion criteria were "previous treatment with a PD-1 or PD-L1 blocking agent, current systemic immunosuppressive therapy, and active infection or autoimmune disease." Participants were excluded from the study if there was evidence of central nervous system (CNS) progression within 8 weeks of previous treatment. The major efficacy endpoints that were confirmed included overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST v1.1) as assessed by a blinded independent review committee and duration of response (DOR). Both groups had an ORR of 26% with 21 of 81 participants in the 2 mg/kg group and 20 of 76 participants in the 10 mg/kg group (difference 0%, 95% confidence interval [CI], -14 to 13; p=0.96). Safety profiles were similar between groups with treatment well tolerated in this population. There were no drug-related deaths reported. Grade 3 or 4 adverse events occurred in 12% (n=20) of study participants; fatigue was the only drug-related grade 3 to 4 adverse event that occurred in more than 1 participant (n=5 [3%]). Drug-related serious adverse events were reported in 5% (n=8) of the population with 3% (n=6) discontinuing treatment as a result of a drug-related adverse event. Fatigue, pruritus, and rash were the most common drug-related adverse events of any grade reported. In summary Robert and colleagues conclude: “Our findings suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks could be an effective treatment option for patients with ipilimumab-refractory advanced melanoma, a population for whom there are few effective treatment options.”
 
In 2015, Robert and colleagues reported preliminary results from the KEYNOTE-006 trial, a phase III randomized, open-label, controlled study of 834 participants with histologically confirmed, unresectable stage III or IV melanoma with no more than one previous systemic therapy for advanced disease. The participants were randomly assigned in a 1:1:1 ratio to receive pembrolizumab 10mg/kg every 2 weeks or pembrolizumab 10 mg/kg every 3 weeks or 4 cycles of ipilimumab 3 mg/kg every 3 weeks. The study inclusion criteria included: Known BRAF V600 mutation status was required; previous BRAF inhibitor therapy was not required for patients with normal lactate dehydrogenase levels and no clinically significant tumor-related symptoms or evidence of rapidly progressive disease. Other key eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (on a 5-point scale, with higher scores indicating greater disability) and provision of a tumor sample adequate for assessing PD-L1 expression. Excluded from the study were patients who had received previous therapy with CTLA-4, PD-1, or PD-L1 inhibitors and those who had ocular melanoma, active brain metastases, or a history of serious autoimmune disease.
 
The estimated 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2% respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons).
 
The rate of Grade 3-5 adverse events were lower in the pembrolizumab group (13.3% and 10.1%) than in the ipilimumab group (19.9%). There were no drug-related deaths in the pembrolizumab group, one drug related death in the ipilimumab group, and common adverse events associated with the use of pembrolizumab were fatigue, diarrhea, rash and pruritus.
 
The author concluded that the "randomized study comparing two immune checkpoint inhibitors showed that pembrolizumab, as compared with ipilimumab, significantly prolonged progression-free and overall survival with fewer high-grade toxic events in patients with advanced melanoma."
 
The FDA expanded indication for use of pembrolizumab in individuals with metastatic NSCLC whose tumors express PD-L1 and have disease progression on or after platinum-containing chemotherapy is based on findings from the Phase I KEYNOTE-001 trial. The safety of pembrolizumab was studied in 550 participants with metastatic NSCLC. The most common side effects reported among study participants included dyspnea, cough, shortness of breath, fatigue, decreased appetite, and severe adverse events resulting from the immune system effect from pembrolizumab. The efficacy for pembrolizumab was demonstrated in a subgroup of 61 participants with pretreated PD-L1 positive advanced NSCLC as determined by the 22C3 pharmDx diagnostic test; the overall response rate for pembrolizumab (percentage of participants who experienced complete and partial shrinkage of their tumors) was 41% (n=25), with effect lasting between 2.1 and 9.1 months. Garon and colleagues (2015) reported findings from the KEYNOTE-1, authors conclude that "pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab".
 
Nivolumab
 
The advanced melanoma indication for nivolumab received accelerated biologics license application approval based on tumor response rate and durability of response in one open-label, Phase III trial of nivolumab in adults with unresectable or metastatic melanoma following progression on ipilimumab and, if BRAF V600 mutation‒positive, a BRAF inhibitor (dabrafenib or vemurafenib). An improvement in survival or disease-related symptoms has not yet been established. Phase III trials are to be submitted by end of 2016. CheckMate-372 was a randomized (2:1), open-label trial in which 370 patients with unresectable or metastatic melanoma received nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine or carboplatin plus paclitaxel. Primary end points were ORR, by independent radiology review committee, and overall survival (OS). Secondary end points included progression-free survival (PFS); PD-L1 expression; and health-related quality of life (HRQOL).
 
Efficacy was assessed in a single-arm, noncomparative, preplanned interim analysis in the first 120 patients who received nivolumab in Trial 1 and in whom the minimum duration of follow-up was 6 months. Data are unpublished and taken from the label. ORR in the efficacy subset was 32% (95% confidence interval [CI], 23 to 41), consisting of 4 complete responses and 34 partial responses in nivolumab-treated patients. Of the 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. There were objective responses in patients with and without BRAF V600 mutation‒positive melanoma. Data on quality of life were not reported at this time. Because of the uncontrolled, observational nature of the interim efficacy subset in the first 120 patients who received nivolumab in and in whom the minimum duration of follow-up was 6 months.
 
Warnings and precautions are generally related to the development of moderate-to-severe immune-mediated reactions in a small number of patients; this results in administration of corticosteroids and either withholding the drug (in the majority of cases) or discontinuation of the drug. Such reactions included immune-mediated pneumonitis (2.2%), colitis (2.2%), hepatitis (1.1%), nephritis or renal dysfunction (0.7%), hyperthyroidism (3%) or hypothyroidism (8%), or other immune-mediated events (<1%). Nivolumab was discontinued for adverse reactions in 9% of patients, while 26% of patients receiving nivolumab had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving nivolumab. The most frequent grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction was rash (> 20%).  
 
July 2016 Update
On May 17, 2016, the FDA granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma. The approval was based on two single-arm, multicenter trials of nivolumab in adults with relapsed or refractory cHL (FDA, 2016).  The trials enrolled patients regardless of PD-L1 expression status on Reed-Sternberg cells. The primary efficacy endpoint was objective response rate (ORR) as determined by an independent radiographic review committee.  Additional outcome measures included duration of response (DOR).
 
Efficacy was evaluated in 95 patients previously treated with autologous HSCT and post-transplantation brentuximab vedotin.  Patients had a median of 5 prior systemic regimens (range: 3, 15) and received a median of 17 doses of nivolumab (range: 3, 48). Single-agent nivolumab produced a 65% ORR (95% CI: 55%, 75%), with 58% partial remission and 7% complete remission.  The median time-to-response was 2.1 months (range: 0.7 to 5.7 months).  The estimated median DOR was 8.7 months.
 
Safety was evaluated in 263 patients with relapsed or refractory cHL.  Ninety-eight per cent of patients had received autologous HSCT.  Patients received a median of 10 doses of nivolumab (range: 1, 48) at the approved dose-schedule.  The most common (reported in at least 20%) adverse reactions of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea.  Additional common adverse reactions (reported in at least 10%) included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.
 
Other immune-mediated adverse reactions, occurring in 1% to 5% of patients, included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis.  Serious adverse reactions were reported in 21% of patients. The most common SAEs, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.
 
September 2016 Update
On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
 
The approval was based on demonstration of a durable objective response rate in a subgroup of patients in an international, multicenter, non-randomized, open-label, multi-cohort study. The subgroup included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy.
 
As a condition of the accelerate approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab.  Merck currently has an ongoing multicenter, randomized trial (NCT02252042) in patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy with a primary endpoint of overall survival.
 
2017 Update
 
The FDA granted accelerated approval to pembrolizumab for  the treatment of classical Hodgkin lymphoma that has resisted treatment or relapsed after three or more prior lines of therapy. The decision was based on tumor response rate as well as durability of response in a study of 210 patients. The label states, “Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials" (FDA, 2017). The label includes the following information:
 
“The efficacy of KEYTRUDA was investigated in 210 patients with relapsed or refractory cHL, enrolled in a multicenter, non-randomized, open-label study. Patients with active, non-infectious pneumonitis, an allogeneic HSCT within the past 5 years (or greater than 5 years but with symptoms of GVHD), active autoimmune disease, a medical condition that required immunosuppression, or an active infection requiring systemic therapy were ineligible for the trial. Patients received KEYTRUDA at a dose of 200 mg every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months in patients that did not progress. Disease assessment was performed every 12 weeks. The major efficacy outcome measures (ORR, CRR, and duration of response) were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria.
 
Among the 210 patients, the baseline characteristics were: median age of 35 years (range: 18 to 76), 9% age 65 or older; 54% male; 88% White; 49% had an ECOG performance status (PS) of 0 and 51% had an ECOG PS of 1. The median number of prior lines of therapy administered for the treatment of cHL was 4 (range 1 to 12). Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Sixty-one percent of patients had undergone prior auto-HSCT, 83% had received prior brentuximab and 36% of patients had prior radiation therapy”(FDA, 2017).  
 
According to the information included in the FDA approved label, an overall response rate (ORR) of 69% was achieved with 22% of patients receiving complete remission and 47% achieving partial remission. There was an 11.1 month response duration (FDA, 2017).    
 
AUGUST 2017 UPDATE
Durvulumab
The safety and efficacy of durvalumab for urothelial cancer has been evaluated in one multicenter open-label study, in which 182 patients with locally advanced or metastatic disease were enrolled. Patients had progressed on or after platinum-based therapy.  Patients with immunodeficiency, medical conditions that required immunosuppression (defined as greater than or equal to 10mg of prednisone or equivalent), severe autoimmune disease, untreated CNS metastatses, HIV, active TB, hepatitis B or hepatitis C were excluded.  Enrolled patients had a median age of 67, with 72% being male. Of the enrolled patients, 70% had received cisplatin, 30% had received carboplatin, and 35% had received two or more prior lines of therapy. Tumor assessments were subsequently performed. Of the 182 patients, 5 had a complete response and 26 had a partial response.
 
2018 Update
A literature search conducted through November 2018 did not reveal any new literature that would prompt a change in the coverage statement.
 
February 2019 Update
A multicenter, phase 2, non-controlled study was conducted with pembrolizumab (anti–PD-1) for adults with advanced Merkel-cell carcinoma who had received no previous systemic therapy. In this studay, a total of 26 patients received at least one dose of pembrolizumab. The objective response rate among the 25 patients with at least one evaluation during treatment was 56% (95% confidence interval [CI], 35 to 76); 4 patients had a complete response, and 10 had a partial response. With a median follow-up of 33 weeks (range, 7 to 53), relapses occurred in 2 of the 14 patients who had had a response (14%). The response duration ranged from at least 2.2 months to at least 9.7 months. The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86). A total of 17 of the 26 patients (65%) had virus-positive tumors. The response rate was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with virus-negative tumors (4 of 9 patients). Drug-related grade 3 or 4 adverse events occurred in 15% of the patients. (Nghiem, Paul T et al., 2016) In this study, first-line therapy with pembrolizumab in patients with advanced Merkel-cell carcinoma was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive tumors and those with virus-negative tumors. (Funded by the National Cancer Institute and Merck; ClinicalTrials.gov number, NCT02267603.) (Nghiem, Paul T et al., 2016).

CPT/HCPCS:
C9492Injection, durvalumab, 10 mg
J9173Injection, durvalumab, 10 mg
J9271Injection, pembrolizumab, 1 mg
J9299Injection, nivolumab, 1 mg
J9999Not otherwise classified, antineoplastic drugs

References: Armand P, Shipp MA, Ribrag V, et al.(2016) Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol. 2016 Jun 27. pii: JCO673467. [Epub ahead of print]

Borghaei H, Paz-Ares L, Horn L, et al.(2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;37:1627-1639.

Brahmer J, Reckamp KL, Baas P, et al.(2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135.

Durvalumab [Internet]. Tampa (FL): Elsevier. c2017- [cited 2017 May 16]. Available from: http://www.clinicalpharmacology.com

FDA. KEYTRUDA® (pembrolizumab) Prescribing Information. Availabe at http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s015lbl.pdf. Last accessed 23 March 2017.

Ferris RL., Blumenschein G., Fayette J., et al.(2016) Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 2016; 375:1856-1867.

Garon EB, Rizvi NA, Hui R, et al.(2015) Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med May 2015; 372:2018-2028.

Imfinzi® [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP.; 2017

Keytruda (prembrolizumab) prescribing information Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s045lbl.pdf. Last accessed 12/20/2018

Nghiem PT, Bhyatia S, Lipson EF, et al.(2016) PD-1 Blockade with Pembrolizumab in Advanced merkel-Cell Carcinoma N Engl J Med. 2016 Jun 30;374(26):2542-52. doi: 10.1056/NEJMoa1603702. Epub 2016 Apr 19.

Pembrolizumab (KEYTRUDA). Accessed at http://www.fda.gov/drugs/informationondrugs/approvedDrugs/ucm515627.htm.

Pembrolizumab (MK-3475) versus standard treatment for recurrent or metastatic head and neck cancer (MK-3475-040/KEYNOTE-040). NCT02252042. Accessed at https://clinicaltrials.gov/ct2/show/NCT02252042?term=KEYNOTE+040&rank=1.

Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.(2016) Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med 2016; 375:1823-1833.

Robert C, Ribas A, Wolchok JD, et al.(2014) Anti-programmed-death receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014 Sep 20;384(9948):1109-17.

Robert C, Schachter J, Long GV, et al, for the KEYNOTE-006 investigators.(2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–2532.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.