Medical Policy

 

Subject: Pembrolizumab (Keytruda®)
Document #: DRUG.00071 Publish Date:    11/15/2018
Status: Revised Last Review Date:    11/08/2018

Description/Scope

This document addresses the use of pembrolizumab (Keytruda, Merck Sharp & Dohme Corp, Whitehouse Station, NJ), a human programmed death receptor-1 (PD-1) blocking antibody, for the treatment of recurrent or metastatic cervical cancer; unresectable metachronous metastases or unresectable advanced or metastatic colorectal cancer; recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma; recurrent, unresectable or metastatic head and neck squamous cell carcinoma; relapsed or refractory Hodgkin lymphoma; resected, unresectable or metastatic melanoma (cutaneous or uveal); malignant pleural mesothelioma; recurrent or metastatic non-small cell lung cancer; metastatic or recurrent locoregional Merkel cell carcinoma; primary mediastinal large B-cell lymphoma; advanced small cell lung cancer; unresectable or metastatic solid tumor and locally advanced or metastatic urothelial carcinoma. Pembrolizumab is also being studied for use in other indications.

Note: Please see these documents for related topics:

Position Statement

Medically Necessary:

Cervical Cancer:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with recurrent or metastatic cervical cancer when all of the following criteria are met:
    1. Being used as a single agent; and
    2. Tumor with PD-L1 gene expression with Combined Positive Score (CPS) of greater than or equal to 1; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Colorectal Cancer:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with colorectal cancer when all the following criteria are met:
    1. Being used as a single agent; and
    2. Individual meets one of the following criteria:
      1. Primary treatment as a single agent for unresectable metachronous metastases (defective mismatch repair/high microsatellite instability [dMMR/MSIH] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
      2. Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (dMMR/MSIH only) following previous treatment with one of the following:
        1. Oxaliplatin-irinotecan and fluoropyrimidine-based therapy; or
        2. Oxaliplatin-irinotecan; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Gastric or Gastroesophageal Junction Adenocarcinoma:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma when the following criteria are met:
    1. Being used as a single agent; and
    2. Tumor with PD-L1 gene expression with CPS of greater than or equal to 1; and
    3. Has demonstrated disease progression on or after two or more prior lines of therapy including fluoropyrimidine and platinum-containing chemotherapy, if appropriate HER2/neu-targeted therapy; and
    4. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    5. Current ECOG performance status of 0-2; and
    6. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Head and Neck Squamous Cell Carcinoma (HNSCC):

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with recurrent, unresectable or metastatic HNSCC when all the following criteria are met:
    1. Being used as a single agent; and
    2. Has demonstrated disease progression on or after platinum-containing chemotherapy; and
    3. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Hodgkin Lymphoma:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with relapsed or refractory Hodgkin lymphoma except for those with lymphocyte-predominant Hodgkin lymphoma.

Malignant Pleural Mesothelioma:

  1. The use of pembrolizumab as a single agent is considered medically necessary for the treatment of individuals with malignant pleural mesothelioma when the following criteria are met:
    1. Being used as subsequent therapy; or
    2. Individual is ineligible for platinum-based chemotherapy, defined as having one or more of the following risk factors for platinum-based chemotherapy toxicity:
      1. ECOG performance status equal to 2;
      2. Glomerular filtration rate less than 60mL/min;
      3. Hearing loss (measured at audiometry) of 25dB at two contiguous frequencies;
      4. Grade 2 or greater peripheral neuropathy; and
    3. Current ECOG performance status of 0-2; and
    4. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Melanoma (Cutaneous and Uveal):

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with melanoma when all the following criteria are met:
    1. Being used as a single agent; and
    2. Presence of unresectable or metastatic melanoma; and
    3. Treatment meets one of the following criteria:
      1. Used as first-line therapy in untreated disease; or
      2. Used as second-line or subsequent therapy for documented disease progression while receiving or since completing most recent therapy; and
    4. Current ECOG performance status of 0-2; and
    5. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    6. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.
  2. The use of pembrolizumab  as a single agent is considered medically necessary for up to 12 months of adjuvant therapy for the treatment of individuals with melanoma when all of the following criteria are met:
    1. The individual has resected, high-risk stage III disease; and
    2. Current ECOG performance status of 0-2; and
    3. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    4. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Merkel Cell Carcinoma (MCC):

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with MCC when all the following criteria are met:
    1. Being used as a single agent; and
    2. Presence of metastatic or recurrent locoregional MCC determined to be not amenable to definitive surgery or radiation therapy; and
    3. Current ECOG performance status of 0-2; and
    4. Has not received treatment with another PD-1 agent (for example, nivolumab); and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Non-Hodgkin Lymphoma, Primary Mediastinal Large B-Cell Lymphoma:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with primary mediastinal large B-cell lymphoma when the following criteria are met:
    1. Being used as single agent; and
    2. Treatment meets one of the following:
      1. Used for refractory disease; or
      2. Used as subsequent therapy for disease relapse after receiving two or more prior lines of therapy; and
    3. Current ECOG performance status 0-2; and
    4. Has not received treatment with another  PD-1 agent (for example, nivolumab); and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Non-Small Cell Lung Cancer:

  1. The use of pembrolizumab is considered medically necessary for the first-line treatment of advanced (metastatic) non-small cell lung cancer (NSCLC) when all the following criteria are met:
    1. Being used as a single agent; and
    2. Cytologically confirmed stage IV NSCLC; and
    3. Tumor expresses PD-L1 gene on at least 50% of tumor cells; and
    4. No sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations in nonsquamous carcinoma; and
    5. Has not received another PD-1 agent (for example, nivolumab) and has not undergone previous systemic therapy for metastatic disease; and
    6. Current ECOG performance status of 0-2; and
    7. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.
  2. The use of pembrolizumab is considered medically necessary for the first-line treatment of advanced or metastatic nonsquamous NSCLC when all the following criteria are met:
    1. Being used in combination with pemetrexed and a platinum agent; and
    2. Cytologically confirmed stage IIIb or IV NSCLC; and
    3. No sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) translocations; and
    4. Has not received another PD-1 agent (for example, nivolumab) and has not undergone previous systemic therapy for metastatic disease; and
    5. Current ECOG performance status of 0-2; and
    6. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.
  3. The use of pembrolizumab is considered medically necessary for the first-line treatment of metastatic squamous NSCLC when all of the following criteria are met:
    1. Being used in combination with carboplatin plus paclitaxel or nab-paclitaxel; and
    2. Cytologically confirmed stage IV NSCLC; and
    3. Has not received another PD-1 agent (for example, nivolumab) and has not undergone previous systemic therapy for metastatic disease; and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.
  4. The use of pembrolizumab is considered medically necessary for continuation maintenance therapy of recurrent or metastatic nonsquamous NSCLC when all of the following criteria are met:
    1. Being used in combination with pemetrexed as continuation maintenance therapy, if given first-line as part of pembrolizumab/pemetrexed and platinum-based regimen; and
    2. Has achieved tumor response or stable disease following initial cytotoxic therapy; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.
  5. The use of pembrolizumab is considered medically necessary for continuation maintenance therapy of recurrent or metastatic squamous cell NSCLC when all of the following criteria are met:
    1. Being used as a single-agent as continuation maintenance therapy, if given first-line as part of pembrolizumab/carboplatin/paclitaxel regimen; and
    2. Has achieved tumor response or stable disease following initial cytotoxic therapy; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.
  6. The use of pembrolizumab is considered medically necessary for the treatment of metastatic NSCLC as a second or subsequent line of therapy when all the following criteria are met:
    1. Being used as a single agent; and
    2. Tumor with PD-L1 gene expression level greater than or equal to 1% with demonstrated disease progression on or after platinum-containing chemotherapy; and
    3. When anaplastic lymphoma kinase (ALK) or epidermal growth factor receptor (EGFR) genomic tumor aberrations are present, must have demonstrated disease progression on U.S. Food and Drug Administration (FDA) approved therapy for the aberrations prior to receiving pembrolizumab; and
    4. Has not received another PD-1 agent (for example, nivolumab); and
    5. Current ECOG performance status of 0-2; and
    6. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.

Small Cell Lung Cancer:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with small cell lung cancer as subsequent therapy when all of the following criteria are met:
    1. Being used as a single agent; and
    2. Treatment meets one of the following criteria:
      1. Demonstrated disease relapse within 6 months following complete or partial response or stable disease with initial treatment; or
      2. Primary progressive disease; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.

Solid Tumors:

  1. The use of pembrolizumab is considered medically necessary for the treatment of individuals with unresectable or metastatic solid tumors (dMMR/MSIH only) when all the following criteria are met:
    1. Being used as a single agent; and
    2. Demonstrated disease progression following prior treatment with no other satisfactory alternative treatment options; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Urothelial Carcinoma:

  1. The use of pembrolizumab is considered medically necessary for the treatment of locally advanced or metastatic urothelial carcinoma when all the following criteria are met:
    1. Being used as a single agent; and
    2. Treatment meets one of the following criteria:
      1. Individual not eligible for any platinum-containing chemotherapy,  and if cisplatin-ineligible, tumor expresses PD-L1 with CPS of greater than or equal to 10; or
      2. Has demonstrated disease progression on or after platinum-containing chemotherapy; or
      3. Has demonstrated disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; and
    3. Has not received another PD-1 agent (for example, nivolumab); and
    4. Current ECOG performance status of 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Investigational and Not Medically Necessary:

The use of pembrolizumab is considered investigational and not medically necessary when the above criteria are not met, including but not limited to any of the following:

  1. Treatment used as first-line therapy, except as described above;
  2. The reason for treatment is other than for a diagnosis with accompanied criteria noted above.
Rationale

Melanoma (Cutaneous and Uveal):

Metastatic melanoma is an aggressive disease. The median survival for individuals with stage IV melanoma is 6-10 months, and less than 5% of individuals survive beyond 5 years (Khan, 2006). It has been estimated that approximately 50% of cutaneous melanomas carry the mutated BRAF gene which keeps the protein production constantly activated and driving cell growth (Davies, 2002). Most of these mutations occur at amino acid position 600, the most common of which results in the V600E amino acid substitution (Arkenau, 2011). Despite recent advances with melanoma treatment, there remains a challenge since there are few effective treatment options for individuals who relapse or do not respond to ipilimumab or BRAF inhibitors.

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology on Melanoma (2018) address the challenges with treatment for stage IV melanoma:

The therapeutic landscape for metastatic melanoma is rapidly changing with the recent development of novel agents, which has demonstrated better efficacy than traditional chemotherapy. The first generation of novel targeted and immunotherapy agents (ie, vemurafenib, dabrafenib, ipilimumab) demonstrated significantly improved response rates and outcomes compared with conventional therapies. Subsequently, a number of ongoing or recently completed phase II and phase III trials testing new immunotherapies, targeted therapies, and combination regimens have yielded noteworthy results. A second generation of effective agents and combination regimens are now available for treatment of advanced unresectable or metastatic melanoma.

On September 4, 2014, pembrolizumab achieved accelerated approval and breakthrough therapy status by the FDA, because it provided an option for individuals with late-stage cancer who have been through several other therapies and yet still have disease progression. The FDA approved pembrolizumab (as a single agent) for the treatment of unresectable or metastatic melanoma and disease progression in individuals following ipilimumab (Yervoy intravenous [IV]; Bristol-Myers Squibb, Princeton, NJ) and, if BRAF V600 mutation positive, a BRAF inhibitor. BRAF inhibitors are dabrafenib (Tafinlar® oral; GlaxoSmithKline, Research Triangle Park, NC) or vemurafenib (Zelboraf® oral; Genentech, San Francisco, CA). On December 18, 2015, the FDA expanded the label for pembrolizumab in the treatment of unresectable or metastatic melanoma. The expanded use now includes the initial treatment of individuals with unresectable or metastatic melanoma. (Product Information Label, 2018)

The FDA accelerated approval of pembrolizumab was based on an open-label, multicenter expansion cohort of a 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.

The updated NCCN Drugs and Biologics Compendium and the NCCN clinical practice guideline (CPG) in oncology (2018) on melanoma include Category 2A off-label recommendations for use of pembrolizumab as a single agent in first-line, second-line or subsequent therapy for disease progression or following maximal clinical benefit from BRAF targeted therapy for individuals with a performance status of 0-2. The NCCN CPG states the following:

Pembrolizumab and nivolumab may cause immune-mediated adverse reactions. Grade 3-4 toxicities are less common than with ipilimumab, but require similar expertise in management. The most common adverse events (>20% of patients) include fatigue, rash, pruritus, cough, diarrhea, decreased appetite, constipation, and arthralgia. Depending on the severity of the reaction, pembrolizumab and nivolumab should be discontinued. For moderate to severe immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism anti-PD1 therapy should be discontinued and systemic steroids should be administered. For patients with preexistent hypophysitis due to ipilimumab, pembrolizumab or nivolumab may be administered if patients are on appropriate physiologic replacement endocrine therapy.

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 10 mg/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.

Study results reported:

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 authors 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.”

Recently, there has been increasing interest in the use of pembrolizumab for another form of metastatic uveal melanoma. In the recently updated NCCN Drug and Biologics Compendium and the NCCN Clinical Practice Guideline for uveal melanoma (2018), the NCCN panel offers off-label recommendations (category 2A) for use of pembrolizumab in the treatment of unresectable disease. The NCCN panel recommendation for use of pembrolizumab as a single agent is based on case series (Algazi, 2016; Kottschade, 2016) that evaluated pembrolizumab as a treatment option for uveal melanoma.

Eggermont and colleagues (2018) reported results from the KEYNOTE-054 study (NCT02362594), a randomized phase 3 trial designed to evaluate pembrolizumab versus placebo after completion of resection of high-risk stage III melanoma. Participants were randomized 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks (n=514) or placebo every 3 weeks (n=505) for a total of 18 doses or until disease progression or unacceptable toxic effect from treatment. The authors reported:

At a median follow-up of 15 months, pembrolizumab was associated with significantly longer recurrence-free survival than placebo in the overall intention-to treat population (1-year rate of recurrence-free survival, 75.4% (95% confidence interval [CI], 71.3 to 78.9] vs. 61.0% [95% CI, 56.5 to 65.1]; hazard ratio for recurrence or death, 0.57; 98.4% CI, 0.43 to 0.74; P<0.001) and in the subgroup of 853 patients with PD-L1-positive tumors (1-year rate of recurrence-free survival, 77.1% [95% CI; 72.7 to 80.9] in the pembrolizumab group and 62.6% [95% CI, 57.7 to 67.0] in the placebo group; hazard ratio, 0.54; 95% CI 0.42 to 0.69; P<0.001).

Adverse events (grade 3-5) were reported in 14.7% of participants in the pembrolizumab group and 3.4% of participants in the placebo group, in the pembrolizumab group there was one treatment-related death due to myositis reported. In summary, the authors concluded that: “as adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.”

NSCLC
On October 2, 2015, the FDA granted accelerated approval for pembrolizumab to treat individuals with advanced (metastatic) NSCLC whose disease has progressed after other treatment and with tumors that express a protein called PD-L1. On October 24, 2016 the FDA approved expanded use of pembrolizumab as first-line treatment of individuals with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score of 50% or more) with no EGFR or ALK genomic tumor aberrations in nonsquamous carcinoma. (Product Information Label, 2018)

The FDA expanded indication for use of pembrolizumab in individuals with metastatic NSCLC whose tumors express PD-L1 and who 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.”

The FDA approval of expanded use of pembrolizumab as a first-line treatment of individuals with advanced (metastatic) NSCLC was based on preliminary results from the KEYNOTE-024 study, an open-label, phase 3 trial. The study enrolled 305 participants with previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing EGFR mutations or ALK translocations to receive pembrolizumab (n=154) or platinum-based chemotherapy (n=151), investigator’s choice (Reck, 2016). The primary end point, “median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2 in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001).” The pembrolizumab groups rate of overall survival at 6 months was 80.2% versus 72.4% in the chemotherapy group “(hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005).” The pembrolizumab group had a response rate of 44.8%, higher than the 27.8% reported for the chemotherapy group. There were fewer treatment-related adverse events reported of any grade in the pembrolizumab group (73.4%) versus 90.0% in the chemotherapy group. The rate of Grade 3-5 adverse events were lower in the pembrolizumab group (26.6%) than in the chemotherapy group (53.3%). Reck and colleagues concluded that “in patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy.”

The updated NCCN Drugs and Biologics Compendium and the NCCN clinical practice guideline (CPG) in oncology (2018) on NSCLC offers recommendations for use of pembrolizumab for use as first-line therapy for PD-L1 positive NSCLC with PD-L1 expression positive (≥ 50%) and EGFR, ALK, ROS1 negative or unknown disease (Category 1) (Reck, 2016) The panel includes category 1 recommendations for use of pembrolizumab as a subsequent therapy for disease progression in individuals with NSCLC tumors with PD-L1 expression levels ≥ 1%, when pembrolizumab not previously given. The panel recommendations are based on preliminary results from one phase 1 study (KEYNOTE-001) and a phase 2/3 trial (KEYNOTE-010) that evaluated use of pembrolizumab as subsequent therapy for metastatic NSCLC. In the NCCN clinical practice guideline for NSCLC the panel defines continuation maintenance therapy as “the use of at least one of the agents that was given in the first-line regimen”. The NCCN panel includes category 1 recommendations for nonsquamous NSCLC continuation maintenance therapy for use of pembrolizumab in combination with pemetrexed if given first-line as part of pembrolizumab/carboplatin/pemetrexed or pembrolizumab/cisplatin/pemetrexed regimen. For squamous cell NSCLC the panel offers a category 2A recommendation for use of pembrolizumab as a single agent as continuation maintenance therapy, if given first-line as part of pembrolizumab/carboplatin/paclitaxel regimen.

On May 10, 2017, the FDA granted accelerated approval for use of pembrolizumab in combination with pemetrexed and carboplatin as first-line treatment of individuals with untreated metastatic nonsquamous NSCLC. This indication was approved under an accelerated process and is based upon unpublished data from the phase I/II KEYNOTE-021 trial (NCT02039674) (Cohort G1), an open-label, multicenter, multi-cohort study that evaluated tumor response and progression-free survival in 74 individuals with nonsquamous NSCLC. The FDA also included a contingency that continued approval may be based upon verification and description of clinical benefit in confirmatory trials. According to the Keytruda product label, “in Cohort G1 of KEYNOTE-021, there was a statistically significant improvement in ORR in patients randomized to Keytruda in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin alone.”  Langer and colleagues reported early findings from a phase 2 cohort of the multi-cohort KEYNOTE-021 open-label trial. (Langer, 2016; Product Information Label, 2018)

Paz-Ares and colleagues (2018) reported results from the KEYNOTE-407 (NCT02775435) study, a phase 3, double blind study that randomly assigned 559 participants with untreated metastatic, squamous NSCLC in a 1:1 fashion to receive pembrolizumab with chemotherapy (pembrolizumab-combination group) or saline placebo (placebo-combination group). All participants received carboplatin and either paclitaxel or nanoparticle albumin-bound (nab)-paclitaxel. Primary endpoint was OS and PFS. The authors observed that:

After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression.

In the pembrolizumab-combination group the median PFS was 6.4 months (95% CI, 6.2 to 8.3) and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Grade 3-5 adverse events occurred more frequently with participants in the pembrolizumab-combination group (69.8%) than in the placebo-combination group (68.2%). Adverse events that resulted in discontinuation of treatment were more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). In each of the trial groups there was one death, as a result of an immune-mediated adverse event (pneumonitis).

In conclusion, the addition of pembrolizumab to standard chemotherapy with carboplatin and either paclitaxel or nab-paclitaxel in patients with previously untreated metastatic, squamous NSCLC resulted in significantly longer overall survival and progression-free survival, a higher response rate, and a longer duration of response than chemotherapy alone, regardless of the level of PD-L1 expression.

Head and Neck Squamous Cell Carcinoma (HNSCC):
On August 5, 2016, Merck Sharp & Dohme Corp. was granted FDA approval for pembrolizumab for use in the treatment of individuals with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. The accelerated approval was based on data from the KEYNOTE-012 study, a multicenter, nonrandomized, open-label phase 1b study that evaluated safety in 192 participants with recurrent or metastatic HNSCC with ECOG performance status of 0 to 1. Efficacy was evaluated in 174 of the participants with disease progression on or after receiving platinum-containing chemotherapy (as induction, concurrent, or adjuvant therapy). Pembrolizumab was administered at 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or rapid disease progression that was symptomatic, requiring urgent intervention. Participants without disease progression received treatment with pembrolizumab for a period up to 24 months. The pembrolizumab (Keytruda) 2018 FDA Product Information label product label reported study response rates:

The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10mg/kg every 2 weeks or 200mg every 3 weeks) or HPV status.

The NCCN Drugs and Biologics Compendium and the NCCN CPG in oncology (2018) on head and neck cancer include Category 2A off-label recommendations for use of pembrolizumab as a treatment of recurrent, unresectable or metastatic disease HNSCC as a single agent for disease progression on or after platinum-containing chemotherapy based on panel consensus and preliminary findings reported from two phase Ib studies (Chow, 2016; Seiwert, 2016).

Classic Hodgkin Lymphoma:
In March 2017 the FDA granted expanded use of pembrolizumab in the treatment of adults or children with refractory classic Hodgkin lymphoma (cHL), or in the treatment of individuals who have relapsed after three or more prior lines of therapy. The National Comprehensive Cancer Network® (NCCN) Drugs and Biologics Compendium and the NCCN CPG for Hodgkin disease (2018) includes a 2A recommendation for off-label use of pembrolizumab as an additional therapy option when used as a single agent for individuals with relapsed or refractory cHL. The recommendation is based on uniform consensus and data from a phase Ib study (KEYNOTE-013) (abstract) (NCT01953692) of individuals with relapsed or refractory cHL treated with pembrolizumab after brentuximab vedotin failure; 67% of participants also failed prior autologous stem cell transplant (Moskowitz, 2014). There were no serious adverse events reported among participants. A total of 3 participants (20%) had a complete response (CR) at 12 weeks. “Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%. Four patients (27%) experienced PD, although all 4 experienced a decrease in their overall tumor burden.” The authors concluded that “pembrolizumab therapy appears to be safe, tolerable, and associated with clinical benefit in patients with heavily pretreated cHL.”

Merkel Cell Carcinoma:
Nghiem and colleagues (2016) reported preliminary results from a multicenter, phase 2, noncontrolled study of 26 adults with the rare condition advanced Merkel cell carcinoma, in which subjects received pembrolizumab as first-line therapy with a median follow-up of 33 weeks. Efficacy was evaluated in 25 participants that received one or more evaluations during treatment. Authors observed an ORR of 56% (95% CI, 35 to 76); 4 participants had a complete response rate and 10 had a partial response. “The rate of progression-free survival at 6 months was 67% (95% CI, 49 to 86)”. Grade 3 to 4 drug-related adverse events were observed in 15% of participants. Authors conclude that:

Although additional experience with longer follow-up and larger patient cohorts is needed, these early findings compare favorably with results for standard chemotherapy regimens for this tumor, for which retrospective studies show a median progression-free survival of approximately 3 months, with progressive disease developing in 90% of patients within 10 months.

In the NCCN Drugs and Biologics Compendium and the NCCN CPG in Oncology on Merkel cell carcinoma (2017), the panel included a category 2A recommendation for off-label use of pembrolizumab in the treatment of disseminated disease as clinical judgment dictates; the “preliminary data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockage compared with cytotoxic therapy.”

Colon Cancer:
In March 2018, the NCCN Drugs and Biologics Compendium and the NCCN CPG in Oncology on colon cancer and rectal cancer lists off-label use of pembrolizumab for individuals with unresectable metachronous metastases or unresectable advanced or metastatic colorectal cancer. The recommendations were based on 2A category of evidence and uniform consensus. The panel recommends use of:

Pembrolizumab or nivolumab as treatment options in patients with metastatic MMR-deficient colorectal cancer in second- or third-line therapy. Patients progressing on either of these drugs should not be offered the other. Additional clinical trials are ongoing to confirm the benefit of these drugs in this setting.

Small Cell Lung Cancer:
The updated NCCN Drugs and Biologics Compendium and the NCCN CPG in oncology (2018) on small cell lung cancer offers recommendations for use of pembrolizumab as a single agent as subsequent systemic therapy for individuals with disease relapse within 6 months following complete or partial response, or stable disease with initial treatment (category 2A). The panel also recommends use of pembrolizumab as a single agent for the treatment of primary progressive disease (category 2A). The recommendations are based on uniform consensus and unpublished data from the KEYNOTE-158 study (NCT02628067), a phase 2, multicenter, non-randomized, open-label, multicohort trial that used pembrolizumab in the treatment of advanced SCLC. Among the 107 participants enrolled with SCLC, 79% (n=85) had received one or more lines of therapy. Median follow-up was 10.1 months (range 0.5-17.5 months). Efficacy was based on ORR 18.7% (n=20) (95% CI, 11.8-27.4), Forty two (39%) of individuals had PD-L1-positive tumors and 50 (47%) had PD-L1-negative tumors. Overall, median duration of response (DOR) had not been reached; median OS was 9.1 months (95% CI, 3.9-10.4). Of the 107 participants enrolled in the study, 59% (n=63) had treatment-related adverse events, 4 led to discontinuation of therapy and 1 reported death, related to pneumonia. Chung and colleagues (2018) concluded that “pembrolizumab has shown promising antitumor activity and durable responses in advanced SCLC, especially in patients with PD-L1-positive tumors.”

Solid Tumors:
On May 23, 2017 the FDA granted accelerated approval for expanded use of pembrolizumab in adults or children for the treatment of unresectable or metastatic solid tumors (dMMR/MSIH only) (which can be found in biliary, bladder, breast, colorectal, endometrial, esophageal, gastric/gastroesophageal junction, pancreatic, prostate, renal cell, retroperitoneal adenocarcinoma, sarcoma, small cell lung, small intestine and thyroid) with disease progression following prior treatment and no other satisfactory alternative treatment options identified. The approval included coverage in treatment of individuals with unresectable or metastatic colorectal cancer (dMMR/MSIH only) with disease progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The FDA approval was based on tumor response rate and durability of response. The FDA also included a contingency that continued approval may be based upon verification and description of clinical benefit in confirmatory trials. (Product Information Label, 2018)

Recently the NCCN Drugs and Biologics Compendium and the NCCN CPG for bone cancer – Ewing sarcoma (2018) and osteosarcoma (2018) offer off-label category 2A recommendation for use of pembrolizumab when used as a single agent for unresectable or metastatic, MSI-H or dMMR tumors with disease progression with prior treatment or when the individual has no satisfactory alternative treatment options, in line with current FDA approval.

In the recent NCCN Drugs and Biologics compendium and the NCCN CPG for ovarian cancer (2018) the NCCN panel lists off-label category 2A recommendations for use of pembrolizumab as a single-agent therapy for persistent disease or recurrence if MSI-H or dMMR, based on preliminary analysis from the KEYNOTE-028 study which led to the FDA approval for treatment of unresectable or metastatic solid tumors (dMMR/MSI-H only).

Urothelial Carcinoma:
Merck Sharp & Dohme Corp. was granted regular FDA approval on May 18, 2017 for use of pembrolizumab in the treatment of individuals with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. On May 18, 2017 the FDA also granted accelerated approval for use of pembrolizumab in the treatment of individuals with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. The regular FDA approval for second-line indication was based on preliminary data from the KEYNOTE-045 trial, a multicenter, randomized, active-controlled trial in individuals with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Individuals were randomly assigned at a 1:1 ratio to the pembrolizumab group 200 mg every 3 weeks (n=270) or investigator’s choice of a chemotherapy regimen (paclitaxel [n=84], docetaxel [n=84], or vinflunine [n=87]) every 3 weeks (n=272). According to the FDA press release:

The trial demonstrated statistically significant improvements in overall survival (OS) and objective response rate (ORR) for participants assigned to pembrolizumab as compared to chemotherapy. Median OS was 10.3 and 7.4 months in the pembrolizumab and chemotherapy arms, respectively (HR 0.73; 95% CI: 0.59, 0.91, p=0.004). ORR was 21% for pembrolizumab and 11% for chemotherapy (p=0.002). No statistically significant difference in progression-free survival between the two arms was observed.

The accelerated approval for the first-line indication was based on data from KEYNOTE-052, a single-arm, open-label trial in 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. Patients received pembrolizumab 200 mg every 3 weeks. With a median follow-up time of 7.8 months, the ORR was 28.6% (95% CI 24, 34) and the median response duration was not reached (range 1.4+, 17.8+ months).

The most common adverse reactions reported for at least 20% of pembrolizumab-treated patients in either of the two trials included fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea, diarrhea, constipation, and rash. Discontinuation of pembrolizumab secondary to adverse reactions occurred in 8% of participants in KEYNOTE-045 and in 11% in KEYNOTE-052. Dose interruption of pembrolizumab occurred in approximately 20% of patients in either trial. Serious adverse reactions occurred in approximately 40% of pembrolizumab-treated patients. Immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, and endocrinopathies, were reported in the trials and were managed according to guidelines in Warnings and Precautions of the label.

In May 2018, the FDA issued a warning, based on data from the ongoing KEYNOTE-361 (NCT02853305) study, that individuals “with PD-L1 low status had decreased revival” compared to individuals “who received cisplatin-or carboplatin-based chemotherapy” (FDA, 2018). As a result, in July 2018 the FDA amended the prescribing label to restrict first-line use of pembrolizumab for the treatment of individuals with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing therapy and whose tumors expressed PD-L1 CPS ≥ 10, or in individuals who are not eligible for any platinum-containing chemotherapy regardless to PD-L1 status.

The recently updated NCCN Drug and Biologics Compendium and National Comprehensive Cancer Network Bladder Cancer Guidelines (2018) indicates that pembrolizumab may be used for first-line systemic therapy for locally advanced or metastatic disease for cisplatin-ineligible individuals who have tumors expressing PD-L1 (CPS ≥10) or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression (Category 2A recommendation). The NCCN panel offers a category 1 recommendation for use of pembrolizumab in the treatment of subsequent systemic therapy for locally advanced or metastatic disease.

Gastric or Gastroesophageal Junction Adenocarcinoma:
On September 22, 2017 Merck received accelerated approval for use of pembrolizumab in previously treated individuals with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumor expressed PD-L1 (Combined Positive Score [CPS]) greater than or equal to 1 with disease progression on or after two or more lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. The FDA approval was based on unpublished data from the KEYNOTE-059 (NCT02335411) trial, a phase 2, multicenter, non-randomized open-label multiple-cohort study that enrolled 259 participants with gastric and gastroesophageal junction adenocarcinoma with demonstrated disease progression on two prior systemic treatments for advanced disease.

Malignant Pleural Mesothelioma:
The recently updated NCCN CPG for malignant pleural mesothelioma (2018) includes a category 2A recommendation for use of pembrolizumab as subsequent systemic therapy for the treatment of malignant pleural mesothelioma, a highly aggressive cancer with poor prognosis and limited treatment options. The recommendation is based on preliminary results from the KEYNOTE-028 study, a non-randomized, open-label, phase 1b trial that evaluated the clinical safety and activity of pembrolizumab in individuals with malignant pleural mesothelioma. Alley and colleagues (2017) found that pembrolizumab appeared to be well tolerated and might confer anti-tumor activity in individuals with PD-L1 positive malignant pleural mesothelioma, further assessment of pembrolizumab in a phase 2 trials is ongoing.

Cervical Cancer:
Merck Sharp & Dohme Corp. was granted regular FDA approval on June 12, 2018 for use of pembrolizumab in the treatment of recurrent or metastatic cervical cancer, when tumor expressed PD-L1 CPS greater than or equal to 1 with disease progression. The FDA approval was based on unpublished data from the KEYNOTE-158 (NCT02628067) trial, a phase 2, multicenter, non-randomized, open-label, multicohort trial that enrolled 98 participants in Cohort E with recurrent or metastatic cervical cancer. Among the participants enrolled in Cohort E, 79% (n=77) had tumors that expressed PD-L1 with one or more lines of chemotherapy in the metastatic setting. Efficacy was based on ORR 14% (95% CI: 7.4, 24.1), including 2.6% complete response and 11.7% partial response rates. Of the 98 participants enrolled in the study, 39% had serious adverse reactions that included anemia, fistula, hemorrhage, and infections. (Product Information Label, 2018)

Non-Hodgkin Lymphoma, Primary Mediastinal Large B-Cell Lymphoma:
The FDA granted accelerated approval on June 13, 2018 for use of pembrolizumab in the treatment of pediatric and adults with refractory PMBCL, or who have relapsed after two or more prior lines of therapy. The FDA approval was based on unpublished dated from the KEYNOTE-170 trial (NCT02576990), a multicenter, open-label single-arm study that enrolled 53 participants who were treated with pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression, or for up to 24 months for participants who did not progress. The efficacy was based on ORR and duration of response; ORR was 45% (95% CI: 32, 60), including 11% complete responses and 34% partial responses. The median duration of response was not reached within the follow-up period (median 9.7 months). The median time to first objective response was 2.8 months (range 2.1 to 8.5 months). Serious adverse reactions were reported among 26% of participants and included arrhythmia, cardiac tamponade, myocardial infarction, pericardial effusion, and pericarditis. Pembrolizumab is not recommended for treatment of individuals with PMBCL who require urgent cytoreductive therapy. (Product Information Label, 2018)

Other Indications:
Pembrolizumab is currently being studied in clinical trials for a variety of other cancers. Pembrolizumab is also currently being studied in ongoing clinical trials for other uses including, but not limited to other malignancies and solid tumors. However for these off-label uses, currently there is insufficient published evidence to support the use of pembrolizumab for such conditions.

The NCCN Drugs and Biologics Compendia and the NCCN Clinical Practice Guideline for anal cancer (2018) offered a category 2A recommendation for the use of pembrolizumab as a single agent for subsequent treatment of metastatic squamous cell carcinoma of the anal canal as a treatment option. The NCCN Panel recommendation is based on unpublished preliminary results reported from the KEYNOTE-28 trial, a multi-cohort, phase 1b trial for PD-1 positive squamous cell carcinoma of the anal canal (Ott, 2015). Ott and colleagues (2015) concluded that further studies of PD-1 and PD-L1 inhibitors is warranted for treatment of squamous cell carcinoma of the anal canal. “The preliminary data support further study of pembrolizumab in this population.” Ott and colleagues (2017) reported findings from the KEYNOTE-028 trial; of the 25 participants enrolled, 64% (n=16) experienced treatment related adverse events, and of 24 participants with confirmed squamous cell carcinoma, 4 participants demonstrated a partial response. An “overall response rate of 17% (95% confidence interval [CI], 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%.” Ott and colleagues concluded that “these data support further study of pembrolizumab in this population.”

In the NCCN Drugs and Biologics Compendia and the NCCN Clinical Practice Guideline for B-Cell lymphomas (2018) the panel includes a category 2A recommendation for use of pembrolizumab in the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma based on preliminary unpublished results from the KEYNOTE-170 trial.

Based on the recent NCCN Drugs and Biologics Compendia and NCCN Clinical Practice Guideline for hepatobiliary cancer (2018) the NCCN panel included a category 2A recommendation for use of pembrolizumab as primary treatment of unresectable or metastatic disease hepatobiliary (extrahepatic, gallbladder and intrahepatic) adenocarcinoma (MSI-H only). The recommendation is based on unpublished preliminary results from the 1-PREDICT study (NCT0253467). In summary, the authors concluded that “there is limited clinical data to support pembrolizumab in this setting.”

The NCCN Drug and Biologics Compendia and the NCCN Clinical Practice Guideline for gestational trophoblastic neoplasia (2018) offer a category 2A recommendation for pembrolizumab as a single agent in the treatment of recurrent or progressive intermediate trophoblastic tumor following treatment with a platinum/etoposide-containing regimen and as a single agent for individuals with methotrexate-resistant high-risk disease. However, there is insufficient published evidence to support the use of pembrolizumab for such condition.

In the NCCN Clinical Practice Guideline for T-Cell Lymphomas (2018) the NCCN panel included a category 2A recommendation for extranodal NK/T-Cell lymphoma as a treatment option for pembrolizumab in relapsed or refractory disease following therapy in a clinical trial. The NCCN Panel concluded that use of pembrolizumab in “clinical trial is the preferred relapsed/refractory option in the absence of a clinical trial, pembrolizumab is an appropriate option.”

The recently updated NCCN Drugs and Biologics and NCCN Clinical Practice Guideline for testicular cancer (2018) offer a category 2A recommendation for use of pembrolizumab as a single agent as palliative treatment in individuals with MSI-H/dMMR tumors and progression after treatment with high dose chemotherapy or third-line therapy. The recommendation is based on a small phase II study (Le, 2015; Le 2017). In summary, the authors conclude that pembrolizumab may be a treatment option, however, they suggest participation in a clinical trial as the preferred treatment option.

Background/Overview

Cervical Cancer:
Cervical cancer is the fourth most common cancer among women worldwide. The National Cancer Institute (NCI) estimates 13.240 new cases in 2018 and 4170 deaths from cervical cancer in the United States. The majority of cases of cervical cancer are preventable by routine screening and treatment of precancerous lesions.

Colorectal Cancer:
Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. According to the American Cancer Society, there will be an estimated 97,220 new cases of colon cancer and 43,030 new cases of rectal cancer diagnosed in 2017. It is expected that 50,630 persons will die from colon and rectal cancer combined in 2018.

Esophageal, Gastric, and Gastroesophageal Junction Adenocarcinoma:
Gastric and esophageal cancers are rare. The NCI estimates 26,240 new cases and 10,800 deaths from gastric cancer in the United States in 2018. For esophageal cancer, the NCI estimates 17,290 new cases and 15,850 deaths will occur in 2018. Gastroesophageal junction adenocarcinoma, a form of cancer that is located in the region where the esophagus joins the stomach, is also rare, but equally lethal. Five-year survival rates for both cancers are relatively low for esophageal cancer and for gastric cancer. Treatments are aimed at extending OS, while also providing palliative and supportive care.

HNSCC:
Head and neck cancers account for nearly 3 percent (approximately 62,000 cases) of all cancers in the United States, and an estimated 13,000 deaths, with nearly 90% from the squamous cell variety. Head and neck cancer usually begins in the squamous cells that line moist, mucosal surfaces inside the head and neck (for example, inside the mouth, nose and throat), and is commonly referred to as squamous cell carcinoma of the head and neck. Head and neck cancers can also begin in the salivary glands, but these are much less common (NCI, 2018).

Hodgkin Lymphoma:
Hodgkin lymphoma is a type of malignancy which starts in the lymphocytes, a type of white blood cell that fights infection. Hodgkin lymphoma most commonly affects people between the ages of 15 and 40 and people older than age 55. In Hodgkin lymphoma, cells in the lymphatic system grow abnormally and may spread beyond the lymphatic system. As the disease progresses, it compromises the body's ability to fight infection. Many initial signs and symptoms may be similar to those of influenza, such as fever, fatigue and night sweats. Eventually, tumors develop. Hodgkin lymphoma is distinguished by the presence of abnormal Reed-Sternberg cells with the majority of cases expressing CD15 and CD30 on immunohistochemistry testing of tissue. In developed countries, classical Hodgkin lymphoma accounts for approximately 95% of all Hodgkin disease (ACS, 2018).

Malignant Mesothelioma:
Malignant mesothelioma is a rare cancer where malignant cells are found in the lining of the chest or abdominal cavity, occurs in approximately 2,500 individuals in the U.S annually. Malignant pleural mesothelioma is the most common type, difficult to treat because the majority of individuals have advanced disease at presentation. The NCCN CPG for malignant pleural mesothelioma (2018) reported the median overall survival for the disease to be approximately 1 year, with cure rare.

MCC:
MCC is an uncommon type of skin cancer, also known as neuroendocrine carcinoma with up to 97% of cases primarily in the epidermis of the skin. According to the ACS (2018) there are approximate 1500 cases diagnosed in the United States each year with more than 9 out of 10 individuals diagnosed older than 50 years of age. An overall 5-year survival rate for MCC was reported at nearly 60%.

Melanoma:
Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). In men, melanoma is often found on the trunk or the head and neck. In women, it often develops on the lower legs. Melanoma is rare in individuals with very dark skin. When it does develop in dark-skinned people, it tends to occur under the fingernails or toenails, or on the palms or soles. Occasionally, melanoma may arise in the lining of the brain (meninges), the digestive tract, lymph nodes, or other areas where melanocytes are found. People at high risk for developing melanoma include those with a personal or family history of the disease, fair complexions, and weakened immune systems.

The American Cancer Society (ACS) estimated that approximately 91,271 cases of melanoma (also referred to as malignant melanoma) will be diagnosed in the United States in 2017 (ACS, 2018). While melanoma accounts for only approximately 5% of skin cancer cases, it is estimated to be responsible for the vast majority of skin cancer deaths, with 9,320 deaths projected in 2017. BRAF gene mutations are seen most commonly in melanoma, occurring in approximately 50% of cutaneous melanomas. Mutations of the BRAF gene have been associated with shorter progression-free intervals and overall decreased survival. When discovered early, melanoma can usually be cured with surgery. Once metastasis occurs, the prognosis is usually poor. In the metastatic stage of melanoma (stage IV), the average survival rate is about 6 months with a 1-year mortality rate of 75%. Treatment of metastatic melanoma may include lymphadenectomy, immunotherapy, radiation therapy, chemotherapy or participation in a clinical trial.

NSCLC:
Lung cancer is the leading cause of death from cancer worldwide, with advanced NSCLC representing the majority (85%) of these cases. According to the National Cancer Institute, in 2018, an estimated 234,030 new cases of lung cancer will be diagnosed in the United States, and of these, approximately 154,050 deaths (65.8%) will occur because of the disease. It has been estimated that only 15.7% of all individuals with lung cancer will survive 5 years or more following diagnosis (NCI, 2018).

Urothelial Carcinoma:
Urothelial carcinoma is the most common type of bladder cancer. The ACS estimates that in 2018 there will be approximately 81,190 new cases of bladder cancer (incidence about four times higher in men than in women) and 16,870 deaths from bladder cancer (about 12,240 in men and 4630 in women) in the United States (ACS, 2018).

Pembrolizumab (Keytruda) 2018 FDA Product Information label includes the following warnings and precautions:
Warning: Immune-Mediated Adverse Reactions: Administer corticosteroids based on the severity of the reaction.

Additional precautions include:

Embryofetal toxicity: Keytruda may cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Information for use in specific populations includes:

Pregnancy Category D
Based on its mechanism of action, Keytruda may cause fetal harm when administered to a pregnant woman.

Nursing Mothers
It is not known whether Keytruda is excreted in human milk. No studies have been conducted to assess the impact of Keytruda on milk production or its presence in breast milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with Keytruda.

Pediatric Use
There is limited experience with Keytruda in pediatric patients.

Geriatric Use
Of 3991 patients with melanoma, NSCLC, HNSCC, cHL or urothelial carcinoma  who are treated with Keytruda in clinical studies, 46% were 65 years and over and 16% were 75 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

Females and Males of Reproductive Potential
Based on its mechanism of action, Keytruda may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Keytruda and for at least 4 months following the last dose of pembrolizumab.

Hepatic Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] less than or equal to ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST). Keytruda has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and an AST) or severe (TB greater than 3 times ULN and any AST).

Renal Impairment
Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with renal impairment.

Definitions

BRAF: The oncogene which directs production of a protein in the regulating MAP kinase / ERKs signaling pathway, which affects cell division, differentiation, and secretion. BRAF is also known as v-raf murine sarcoma viral oncogene homolog B1, and its protein as serine/threonine-protein kinase B-Raf.

ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

Line of therapy:

Melanoma: A type of cancer that begins in the melanocytes. Melanoma is also referred to as malignant melanoma and cutaneous melanoma.

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread beyond the local lymph nodes; also referred to as stage IV cancer.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Mutation: A permanent, transmissible change in genetic material.

Non-small cell lung cancer: A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

Phase I trial: A study to test a new drug or treatment in a small group of participants for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

Unresectable: Unable to be removed with surgery.

Coding

 The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J9271

Injection, pembrolizumab, 1 mg [Keytruda]

 

 

ICD-10 Diagnosis

 

 

C00.0-C76.8

Malignant neoplasms

 

C7B.00-C7B.8

Secondary neuroendocrine tumors

 

C77.0-C79.9

Secondary malignant neoplasms

 

C80.0-C80.2

Malignant neoplasm without specification of site

 

C81.10-C81.99

Hodgkin lymphoma (classical)

 

C85.20-C85.29

Mediastinal (thymic) large B-cell lymphoma

 

Z85.00-Z85.59

Personal history of malignant neoplasms

 

Z85.71

Personal history of Hodgkin lymphoma

 

Z85.810-Z85.9

Personal history of malignant neoplasms

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer. 2016; 122(21):3344-3353.
  2. Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomized, open-label, phase 1b trial. Lancet Oncol. 2017; 18:623-630.
  3. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011; 104(3):392-398.
  4. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockage with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016; 34(31):3733-3739.
  5. Bellmunt J, deWit R, Vaugh DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Eng J Med. 2017; 376(11):1015-1026.
  6. Chen R, Luigi Z, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017; 35:2125-2132.
  7. Chow LQ, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase lb KEYNOTE-012 expansion cohort. J Clin Oncol. 2016; pii:JCO681478.[Epub ahead of print]
  8. Chung HC, Lopez-Martin JA, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018; 36: Abstract 8506.
  9. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-954.
  10. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018; 378(19):1789-1801.
  11. Frenel JS, Le Tourneau C, Ott PA, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase 1b KEYNOTE-028 trial. J Clin Oncol. 2017. 35(36):4035-4041.
  12. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-819.
  13. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Eng J Med. 2018; 378(22):2078-2092.
  14. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372(21):2018-2028.
  15. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369(2):134-144.
  16. Khan MA, Andrews S, Ismail-Khan R, et al. Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database. Cancer Control. 2006; 13(3):211-217.
  17. Kottschade LA, McWilliams RR, Markovic, et al. The use of pembrolizumab for the treatment of metastatic uveal melanoma. Melanoma Res. 2016; 26(3):300-303.
  18. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refactory NK/T-cell lymphoma failing l-asparaginase. Blood. 2017; 129(17):2437-2442.
  19. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small cell lung cancer: a randomized, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet. 2016; 17:1497-1508.
  20. Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349):409-413.
  21. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372(26):2509-2520.
  22. Moskowitz CH, Ribrag V, Michot J-M, et al. PD-1 blockade with the monoclonal antibody pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: preliminary results form a phase 1b study (KEYNOTE-013). Blood. 2014; 124:Abstract 290. [Epub Ahead of Print]
  23. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016; 374(26):2542-2552.
  24. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative oncology Group. Am J Clin Oncol. 1982; 5(6):649-655.
  25. Ott PA, Pha-Paul SA, Munster P, et al. Pembrolizumab (MK-3475) for PD-L1 positive squamous cell carcinoma (SCC) of the anal canal: Preliminary safety and efficacy results from KEYNOTE-028. The European Cancer Congress 2015:2015:500. [Epub Ahead of Print]
  26. Ott PA, Pha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Am Oncol. 2017; 28(5):1036-1041.
  27. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Eng J Med. 2018; doi:10.1056/NEJMoa1810865. [Epub ahead of print]
  28. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Eng J Med. 2016; 375(19):1823-1833.
  29. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384(9948):1109-1117.
  30. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015; 372(26):2521-2532.
  31. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicenter, randomized, open-label phase 3 study (KEYNOTE-006). Lancet. 2017; 390:1853-1862.
  32. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicenter, phase 1b trial. Lancet Oncol. 2016; (7):956-965.
  33. Shahabi V, Whitney G, Hamid O, et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012; 61(5):733-737.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2018. Atlanta: American Cancer Society; 2018. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed on September 21, 2018.
  2. American Cancer Society. Key statistics for bladder cancer. Revised on January 5, 2017. Available at: https://www.cancer.org/cancer/bladder-cancer/about/key-statistics.html. Accessed on September 21, 2018.
  3. Hanna N, Johnson D, Temin S, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol Pract. 2017; 13(12):832-837.
  4. Keytruda [Product Information]. Whitehouse Station, NJ. Merck Sharp & Dohme Corp.; August 20, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s035lbl.pdf. Accessed on September 21, 2018.
  5. Merck Sharp & Dohme Corp. A trial of pembrolizumab (MK-3475) in participants with blood cancers (MK-3475-013) (KEYNOTE-013). NLM Identifier: NCT01953692. Last updated December 19, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01953692. Accessed on September 21, 2018.
  6. Merck Sharp & Dohme Corp. Study of pembrolizumab (MK-3475) compared to platinum-based chemotherapies in participants with metastatic non-small cell lung cancer (MK-3475-024/KEYNOTE-024). NLM Identifier: NCT02142738. Last updated March 16, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02142738?term=KEYNOTE-024&rank=1. Accessed on September 21, 2018.
  7. Merck Sharp & Dohme Corp. Study of pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-012/KEYNOTE-012). NLM Identifier: NCT01848834. Last updated March 14, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT01848834. Accessed on September 21, 2018.
  8. Merck Sharp & Dohme Corp. Study of pembrolizumab (MK-3475 in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158). NLM Identifier: NCT02628067. Last updated June 28, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02628067. Accessed on September 21, 2018.
  9. Merck Sharp & Dohme Corp. Study of pembrolizumab (MK-3475) in participants with progressive locally advanced or metastatic carcinoma, melanoma, or non-small cell lung carcinoma (P07990/MK-3475-001/KEYNOTE-001). NLM Identifier: NCT01295827. Last updated on September 13, 2018. Available at: http://clinicaltrials.gov/ct2/show/NCT01295827?term=01295827&rank=1. Accessed on September 21, 2018.
  10. National Cancer Institute. Common terminology criteria for adverse events. Version 4.03. June 2010. Available at: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed on September 21, 2018.
  11. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on September 21, 2018.
  12. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 21, 2018.
    • Anal Carcinoma (V.2.2018). Revised June 8, 2018.
    • B-Cell Lymphomas (V.4.2018). Revised May 15, 2018.
    • Bladder Cancer (V.5.2018). Revised July 3, 2018.
    • Central Nervous System Cancers. (V.1.2018) Revised March 20, 2018.
    • Colon Cancer (V.3.2018). Revised August 7, 2018.
    • Head and Neck Cancer (V.2.2018) Revised June 20, 2018.
    • Hodgkin lymphoma (V.3.2018) Revised April 16, 2018.
    • Malignant Pleural Mesothelioma (V.2.2018). Revised February 26, 2018.
    • Melanoma (Cutaneous) (V.3.2018) Revised July 12, 2018.
    • Merkel cell carcinoma (V.1.2019) Revised August 31, 2017.
    • Non-Small Cell Lung Cancer (V.6.2018) Revised August 17, 2018.
    • Ovarian Cancer (V.2.2018) Revised March 9, 2018.
    • Rectal Cancer (V.3.2018). Revised August 7, 2018.
    • Small Cell Lung Cancer (V.1.2019). Revised October 10, 2018.
    • T-Cell Lymphomas. (V.5.2018). Revised August 13, 2018.
    • Testicular Cancer (V.2.2018). Revised February 16, 2018.
    • Uveal Melanoma. (V.1.2018). Revised March 15. 2018.
  13. Pembrolizumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised June 20, 2018. Accessed on September 21, 2018.
  14. Pembrolizumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated September 19, 2018. Available at: http://www.micromedexsolutions.com. Accessed on September 21, 2018.
  15. U.S. Food and Drug Administration. Keytruda (pembrolizumab) or Tecentriq (atezolizumab): FDA alerts health care professionals and investigators: FDA statement - decreased survival in some patients in clinical trials associated with monotherapy. May 18, 2018. Available at: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm608253.htm. Accessed on September 21, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/docroot/home/index.asp. Accessed on September 21, 2018.
  2. Genetics Home Reference. BRAF. Reviewed September 26 2017. Available at: http://ghr.nlm.nih.gov/gene/BRAF. Accessed on September 21, 2018.
  3. National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/types/alphalist. Accessed on September 21, 2018.
    • Adult Hodgkin lymphoma (PDQ). Last modified August 15, 2018.
    • Bladder Cancer Treatment (PDQ). Last modified April 12, 2018.
    • Cervical Cancer Treatment (PDQ). Last modified January 30, 2018.
    • Colon Cancer Treatment (PDQ). Last modified August 16, 2018.
    • Esophageal Cancer Treatment (PDQ). Last modified September 7, 2018.
    • Gastric Cancer Treatment (PDQ). Last modified August 17, 2018.
    • Malignant Mesothelioma Treatment (PDQ). Last modified July 27, 2018.
    • Melanoma (PDQ). Last modified July 19, 2018.
    • Metastatic squamous neck cancer with occult primary treatment (PDQ). Last modified February 8, 2018.
    • Non-Small Cell Cancer Treatment (PDQ). Last modified August 31, 2018.
    • Rectal Cancer Treatment (PDQ). Last modified August 17, 2018.
    • Renal Cell (Kidney) Cancer Treatment (PDQ). Last modified April 5, 2018.
    • Small Cell Lung Cancer Treatment (PDQ). Last modified July 19, 2018.
  4. National Library of Medicine. Medical Encyclopedia: Non-Small Cell Lung cancer. Updated August 1, 2015. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Accessed on September 21, 2018.
Index

Advanced Small Cell Lung Cancer
Keytruda
Locally Advanced or Metastatic Urothelial Carcinoma
Malignant Pleural Mesothelioma
Metastatic Melanoma (Cutaneous and Uveal)
Metastatic Non-Small Cell Lung Cancer
Metastatic or Recurrent Locoregional Merkel Cell Carcinoma
Pembrolizumab
Recurrent, Unresectable or Metastatic Head and Neck Squamous Cell Carcinoma
Unresectable Melanoma
Unresectable or Metastatic Solid Tumor

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

11/08/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

10/31/2018

Hematology/Oncology Subcommittee review. Added MN statement for pembrolizumab for the first-line treatment of metastatic squamous NSCLC when criteria met. Added MN statement for pembrolizumab for treatment of small cell lung cancer as subsequent therapy when criteria met. Removed presence of human immunodeficiency virus (HIV), hepatitis B virus infection and hepatitis C virus infection from INV/NMN statement. Updated Description, Rationale, Background, Index, References and Websites sections.

Revised

07/26/2018

MPTAC review.

Revised

07/18/2018

Hematology/Oncology Subcommittee review. Added MN statement for use of pembrolizumab in treatment of recurrent or metastatic cervical cancer when criteria met. Added MN statement for use of pembrolizumab in treatment of primary mediastinal large B-cell lymphoma when criteria met. Added MN statement for use of pembrolizumab as adjuvant therapy for the treatment of melanoma when criteria met. Added MN statement for use of pembrolizumab as continuation maintenance therapy of recurrent or metastatic (squamous cell and nonsquamous) NSCLC when criteria met. Revised MN statement for urothelial carcinoma. Updated Description, Rationale, Background, Coding, Index, References and Websites sections.

Revised

05/03/2018

MPTAC review.

Revised

05/02/2018

Hematology/Oncology Subcommittee review. Clarified MN statement for melanoma to include cutaneous and uveal melanoma. Clarified MN criteria for use of pembrolizumab for the first-line treatment of advanced or metastatic nonsquamous NSCLC. Updated Description, Rationale, Background, Index, References and Websites sections.

Revised

11/02/2017

MPTAC review.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. Added MN statement for treatment of recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma when criteria met. Added MN statement for the treatment of malignant pleural mesothelioma when criteria met. The document header wording updated from “Current Effective Date” to “Publish Date”. Updated Rationale, Background, Index, References and Websites sections.

Revised

08/03/2017

MPTAC review.

Revised

07/10/2017

Hematology/Oncology Subcommittee review. Revised MN statement for use in treatment of colorectal cancer when criteria met. Added MN statement for use in treatment of unresectable or metastatic solid tumors when criteria met. Clarified first-line NSCLC MN criterion which addresses “no sensitizing (EGFR) mutations or ALK translocations” to apply to nonsquamous carcinoma only. Updated Description, Rationale, Coding, References, Websites and Index sections.

Revised

06/13/2017

MPTAC review.

Revised

06/07/2017

Hematology/Oncology Subcommittee review. Reformatted the medically necessary criteria. Added medically necessary statement for first-line treatment of metastatic non-squamous NSCLC when criteria met. Added medically necessary criteria for locally advanced and metastatic urothelial carcinoma when criteria met. Updated Description, Rationale, Background, Coding and Index sections.

Revised

05/04/2017

MPTAC review.

Revised

05/03/2017

Hematology/Oncology Subcommittee review. Reformatted the medically necessary criteria. Added medically necessary position for colorectal cancer when criteria met. Revised medically necessary criteria for HNSCC. Updated Rationale, Background, Coding, References and Websites sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Corrected grammatical error in NSCLC MN statement. Added MN criteria for first-line use in NSCLC. Revised MN statement and criteria for metastatic NSCLC “as a second or subsequent line of therapy”. Added MN criteria for HNSCC. Reformatted MN position statement section. Added MN criteria for MCC. Revised INV/NMN statement. Updated Description, Rationale, Background, Coding, Reference, Website and Index sections.

Revised

05/05/2016

MPTAC review.

Revised

05/04/2016

Hematology/Oncology Subcommittee review. Clarified MN criteria for melanoma and NSCLC. Added MN criteria for Hodgkin lymphoma. Revised INV/NMN statement to address reason for treatment for diagnosis other than Hodgkin lymphoma. Updated Description, Rationale, Background, Coding, References and Websites sections.

Revised

02/04/2016

MPTAC review.

Revised

01/11/2016

Hematology/Oncology Subcommittee review. Revised medically necessary criteria for the treatment of metastatic NSCLC. Updated Rationale, Background, References and Websites. Updated Coding section; removed HCPCS code C9027 deleted 12/31/2015.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Revised medically necessary criteria for use of pembrolizumab as treatment of unresectable or metastatic melanoma. Added medically necessary statement for use of pembrolizumab as treatment of metastatic non-small cell lung cancer (NSCLC) when criteria are met. Revised investigational and not medically necessary statement. Updated Description, Rationale, Background, Definitions, Index, References and Websites sections.  Updated Coding section to include 01/01/2016 HCPCS changes; also removed ICD-9 codes.

Revised

05/07/2015

MPTAC review.

Revised

05/06/2015

Hematology/Oncology Subcommittee review. Revised medically necessary criteria to include use of pembrolizumab first-line treatment of individuals with melanoma, clarified medically necessary criteria for second-line or subsequent therapy and investigational and not medically necessary criteria. Updated Description, Rationale, Definitions and References.

New

11/13/2014

MPTAC review.

New

11/12/2014

Hematology/Oncology Subcommittee review. Initial document development.