Medical Policies - Prescription Drugs


Checkpoint-Blocking/Inhibitor Antibody Treatment for Select Cancers

Number:RX502.033

Effective Date:10-15-2017

Coverage:

This medical policy has become INACTIVE as of 4/30/2018.  Refer to the following current medical policies for dates of service 5/1/2018 and after:

  • RX502.053, Ipilimumab (Yervoy),
  • RX502.054, Pembrolizumab (Keytruda),
  • RX502.055, Nivolumab (Opdivo), or
  • RX502.056, Atezolizumab (Tecentriq).

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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical Guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical Guidelines, or active Phase III clinical trials supporting the requested regimen.

Ipilimumab (Yervoy™)

Yervoy™ may be considered medically necessary in adults and children (12 years and older) for the following indications:

Melanoma:

o Single agent first-line therapy or in combination with Opdivo® for brain metastases if active against primary melanoma tumor for recurrent disease.

o Single agent therapy for brain metastases if active against primary melanoma tumor for recurrent stable systemic disease.

o Single agent as adjuvant treatment of patients with:

1. Stage III sentinel lymph node positive metastasis >1 mm following a complete lymph node dissection/resection;

2. Stage III disease with clinically positive lymph node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection/resection; or

3. Following complete lymph node dissection/resection and/or complete resection of nodal recurrence.

o Single agent first-line therapy in combination with Opdivo® for treatment of a histological diagnosis of Stage III or Stage IV unresectable or metastatic melanoma.

o Single agent or in combination with Opdivo® as second-line or subsequent therapy for disease progression of a histological diagnosis of Stage III or Stage IV unresectable or metastatic melanoma (if Yervoy™ not previously used). The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent or in combination with Opdivo® following maximum clinical benefit from BRAF (serine/threonine-specific protein kinase gene) targeted therapy for unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent or in combination with Opdivo® as re-induction therapy when the patient has experienced disease control and has no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation for unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

Small-cell lung cancer (SCLC):

o Subsequent systemic therapy, in combination only with Opdivo® when SCLC has relapsed within 6 months following a complete/partial response/stable disease with initial treatment or primary progressive disease. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

Malignant Pleural Mesothelioma (MPM):

o Subsequent systemic therapy, in combination only with Opdivo® for MPM. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

NOTE 1: Refer to the Description section for detailed information on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

Yervoy™ is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

Autoimmune diseases requiring treatment with immunosuppressants,

Bladder cancer or urothelial carcinoma,

Breast cancer,

Cervical cancer,

Chronic myeloid leukemia,

Colorectal cancer,

Gastric cancer,

Glioblastoma,

Hodgkin lymphoma,

Non-Hodgkin lymphoma,

Non-small-cell lung cancer,

Ovarian cancer,

Pancreatic cancer,

Prostate cancer,

Renal cell carcinoma, including metastatic,

Salivary tumor,

Sarcomas,

Solid organ tumors,

Stage I or Stage II melanoma, and

Use in combination therapy with another checkpoint inhibitor agent, unless addressed above with Opdivo®.

Pembrolizumab (Keytruda®)

Keytruda® may be considered medically necessary for the following indications:

Melanoma:

o Single agent first-line therapy for unresectable or metastatic melanoma.

o Single agent second-line or subsequent therapy (see NOTE 2) for disease progression of unresectable or metastatic melanoma, if anti PD-1 (programmed cell death protein 1) monotherapy is not previously used. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent after maximum clinical benefit from BRAF (serine/threonine-specific protein kinase gene) targeted therapy of unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent as a re-induction therapy for patients with unresectable or metastatic melanoma who experience disease control and have no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation. The patient must meet the 0-2 ECOG performance scale (see NOTE 1)

Non-Small-Cell Lung Cancer (NSCLC):

o Single agent first-line treatment of metastatic NSCLC when tumors have high PD-L1 (programmed death receptor-1 ligand) expression (Tumor Proportion Score [TPS] ≥50%) as determined by a U.S. Food and Drug Administration (FDA)-approved test (see NOTE 3), with no EGFR or ALK genomic tumor aberrations (see NOTE 4). The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent subsequent therapy for metastatic squamous NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by a FDA-approved test (see NOTE 3) and progression on or after platinum-based chemotherapy (see NOTE 5). The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o In combination with pemetrexed (Alimta®) and carboplatin (Paraplatin®) therapy for the treatment of metastatic nonsquamous NSCLC, when the patient meets the 0-1 ECOG performance scale (see NOTE 1), as:

1. First-line therapy for EGFR, ALK, ROS1, BRAF (see NOTE 4), and PD-L1 negative or unknown mutation;

2. First-line or subsequent therapy for BRAF V600E-mutation positive tumors;

3. Subsequent therapy for sensitizing EGFR mutation positive tumors (see NOTE 4) and prior erlotinib (Tarceva®), afatinib (Gilotrif®), gefitinib (Iressa®), or osimertinib (Tagrisso®) therapy;

4. Subsequent therapy for ALK rearrangement positive tumors and prior crizotinib, ceritinib (Zykadia®), alectinib (Alecensa®), or brigatinib (Alunbrig®) therapy;

5. Subsequent therapy for ROS1 rearrangement positive tumors (see NOTE 4) and prior crizotinib (Xalkori®) therapy; or

6. Subsequent therapy for PD-L1 expression positive (≥50%) tumors and EGFR, ALK, ROS1, and BRAF negative or unknown mutation (see NOTE 4).

Malignant Pleural Mesothelioma (MPM):

o Single agent subsequent systemic therapy for MPM. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

Head and Neck Squamous Cell Cancer (HNSCC):

o Single agent first-line therapy for non-nasopharyngeal HNSCC if progression on or after platinum-containing chemotherapy in the following indications:

1. Newly diagnosed T4b, any N, M0 disease (see NOTE 6 for TNM information), unresectable nodal disease with no metastases, or for patients who are ineligible for surgery and meets the 3 on the ECOG performance scale (see NOTE 1);

2. Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy. The patient must meet the 0-2 ECOG performance scale (see NOTE 1); or

3. Unresectable locoregional recurrence without prior radiation therapy. The patient must meet 3 on the ECOG performance scale (see NOTE 1).

Hodgkin Lymphoma (HL):

o Single agent subsequent therapy for refractory/relapsed classical HL for adult and pediatric patients or patients who have been treated previously with brentuximab vedotin (Adcetris™).

o Single agent as palliative therapy for refractory/relapsed classical HL when patients are ≥ 60 years of age.

Bladder Cancer (Urothelial Carcinoma):

o Single agent first-line therapy for locally advanced bladder cancer (clinical Stage T4b or T2-4a, N1-3 disease, or for recurrence post-cystectomy, or for metastatic disease (or recurrent disease), when patient is not eligible for cisplatin (Platinol®) chemotherapy.

o Single agent subsequent systemic therapy for locally advanced bladder cancer (clinical Stage T4b or T2-4a, N1-3 disease, or for recurrence post-cystectomy, or for metastatic disease (or recurrent disease) with progression on or after platinum-containing chemotherapy OR within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Merkel Cell Carcinoma (MCC):

o Single agent for treatment of distant metastases from MCC or disseminated recurrence with or without surgery or radiation therapy.

Keytruda® may be considered medically necessary for adult and pediatric patients, with unresectable or metastatic, microsatellite instability-high (MIS-H) OR mismatch repair deficient (dMMR) for the following indications:

Solid Tumors:

o Single agent second-line treatment of solid tumors that have progressed following prior treatment and satisfactory alternative options are not available.

Colorectal Cancer (CRC):

o Single agent as initial therapy for CRC in patients who are not appropriate for intensive therapy.

o Single agent treatment of unresectable metachronous CRC metastases and previous adjuvant FOLFOX/fluoropyrimidine (such as, fluorouracil [Adrucil®], oxaliplatin [Eloxatin®], and irinotecan [Campto®]) OR CapeOX (such as capecitabine [Xeloda®] and oxaliplatin [Eloxatin®]) within the past 12 months.

o Single agent subsequent therapy, if Keytruda® OR Opdivo® not previously given for CRC, following previous treatment with oxaliplatin (Eloxatin®), irinotecan (Campto®), and/or fluoropyrimidine (fluorouracil [Adrucil®])-based therapy.

NOTE 2: For some cancers, second-line treatments using checkpoint inhibitors may be administered for disease progression utilizing a different checkpoint inhibitor which was used as first-line therapy. For example, Keytruda® may be given for disease progression following treatment with Yervoy™, as second-line therapy for melanoma.

NOTE 3: Prior to administration of this agent, the FDA is requiring PD-L1 testing (e.g., using the “IHC 22C3 pharmDx Kit”).

NOTE 4: First-line therapy for nonsquamous NSCLC using Keytruda®: Those patients should not have EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase) genomic tumor aberrations, ROS1 (proto-oncogene tyrosine-protein kinase or receptor tyrosine kinase gene), or BRAF (serine/threonine-specific protein kinase gene).

NOTE 5: Second-line therapy for nonsquamous NSCLC using Keytruda: Those patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies for these aberrations prior to receiving Keytruda®.

NOTE 6: TNM (T = primary tumor; N = regional lymph nodes; M = distant metastasis) refers to staging classification of some cancers, particularly when the tumor reaches beyond the initial site of the cancer itself. More information on staging can be found in the Description of this medical policy.

Keytruda® is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

Breast cancer,

Gastric cancer, including gastroesophageal junction adenocarcinoma,

Glioblastoma,

Mediastinal B-cell lymphoma,

Multiple myeloma,

Myelodysplastic syndrome,

Mycosis fungoides,

Non-Hodgkin lymphoma,

Ovarian cancer,

Pancreatic cancer,

Prostate cancer,

Renal cell cancer,

Salivary tumor,

Sarcomas,

Sézary syndrome,

Small-cell lung cancer,

Solid organ tumors as a first-line treatment,

Squamous cell cancer, excluding head and neck cancer,

Stage I or Stage II melanoma, and

Use in combination therapy with another checkpoint inhibitor agent.

Nivolumab (Opdivo®)

Opdivo® may be considered medically necessary for the following indications:

Melanoma:

o Single agent first-line therapy for unresectable or metastatic melanoma.

o Single agent second-line or subsequent therapy (see NOTE 2) for unresectable or metastatic melanoma disease progression, if anti-PD-1 monotherapy not previously used. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent or in combination with Yervoy™ as first-line therapy (see NOTE 7) of unresectable or metastatic melanoma, when patient has the BRAF V600 wild-type (see NOTE 4).

o Single agent first-line followed by Opdivo® in combination with Yervoy™ as subsequent therapy (see NOTE 7) of unresectable or metastatic melanoma, when patient has the BRAF V600 wild-type (see NOTE 4) with disease progression (only if Opdivo® OR Keytruda® not previously used).

o Single agent or in combination with Yervoy™ as first-line therapy (see NOTE 7) of unresectable or metastatic melanoma, when patient has the BRAF V600 mutation-positive with disease progression following treatment with a BRAF inhibitor (see NOTE 4) (such as vemurafenib [Zelboraf®] or dabrafenib [Tafinlar®]).

o Single agent after maximum clinical benefit from BRAF targeted therapy (see NOTE 4) of unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Single agent as a re-induction therapy for patients with unresectable or metastatic melanoma who experience disease control and have no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o In combination with Yervoy™ for treatment of brain metastases if active against primary melanoma tumor for recurrent disease.

Small-Cell Lung Cancer (SCLC):

o Subsequent systemic therapy as a single agent OR in combination with Yervoy™ when metastatic SCLC with relapsed disease within 6 months following a complete/partial response/stable disease with initial treatment or primary progressive disease. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

Non-Small-Cell Lung Cancer (NSCLC):

o Single agent second-line subsequent therapy for metastatic (squamous and nonsquamous [see NOTE 8]) NSCLC and progression on or after platinum-based chemotherapy and if Keytruda® OR Tecentriq™ not previously given, when the patient meets the 0-2 ECOG performance scale (see NOTE 1).

Malignant Pleural Mesothelioma (MPM):

o Single agent subsequent systemic therapy for MPM. The patient must meet the 0-2 ECOG performance scale (see NOTE 1).

o Subsequent systemic therapy, in combination only with Yervoy™ for MPM.

Renal Cell Carcinoma (RCC):

o Single agent therapy for advanced Stage IV, relapsed, or metastatic RCC clear-cell histology who have received prior antiangiogenic therapy.

o Single agent therapy for advanced Stage IV, relapsed, or metastatic RCC non-clear-cell histology.

Hodgkin Lymphoma (HL):

o Additional single agent treatment for refractory/relapsed classical HL when the patient has been treated previously with brentuximab vedotin (Adcetris™) or following high-dose chemotherapy followed by autologous hematopoietic stem-cell transplant and post-transplantation therapy with brentuximab vedotin (Adcetris™).

o Single agent as palliative therapy for refractory/relapsed classical HL when patients are ≥ 60 years of age, if patient has been treated previously with brentuximab vedotin (Adcetris™).

Head and Neck Squamous Cell Cancer (HNSCC):

o Single agent first-line therapy for non-nasopharyngeal HNSCC if progression on or after platinum-containing chemotherapy in the following indications:

1. Newly diagnosed T4b, any N, M0 disease (see NOTE 6 for TNM information), unresectable nodal disease with no metastases, or for patients who are ineligible for surgery and meets 3 on the ECOG performance scale (see NOTE 1);

2. Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy. The patient must meet the 0-2 ECOG performance scale (see NOTE 1); or

3. Unresectable locoregional recurrence without prior radiation therapy. The patient must meet 3 on the ECOG performance scale (see NOTE 1).

Bladder Cancer (Urothelial Carcinoma):

o Single agent for locally advanced bladder cancer (clinical Stage T4b or T2-4a, N1-3 disease, or for recurrence post-cystectomy, during or after platinum-containing chemotherapy OR disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.

o Single agent subsequent systemic therapy for locally advanced metastatic disease (or metastatic recurrent disease) progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.

Opdivo® may be considered medically necessary for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MIS-H) OR mismatch repair deficient (dMMR) for the following indication:

Colorectal Cancer (CRC):

o Single agent as initial therapy for CRC in patients who are not appropriate for intensive therapy.

o Single agent treatment of CRC when following adjuvant treatment with FOLFOX/fluoropyrimidine (such as, fluorouracil [Adrucil®] and oxaliplatin [Eloxatin®]), OR CapeOX (such as capecitabine [Xeloda®] and oxaliplatin [Eloxatin®]) within the past 12 months.

o Single agent subsequent therapy if Opdivo® or Keytruda® not previously given and following previous treatment with oxaliplatin (Eloxatin®), irinotecan (Campto®), and/or fluoropyrimidine (fluorouracil [Adrucil®])-based therapy.

NOTE 7: Opdivo® may be given for disease progression following treatment with Yervoy™.

NOTE 8: Second-line therapy for nonsquamous NSCLC using Opdivo®: Those patients with EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) genomic tumor aberrations should have disease progression on FDA-approved therapies, e.g., docetaxel (Taxotere®) for these aberrations prior to receiving Opdivo®.

Opdivo® is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

Breast cancer,

Cervical cancer,

Gastric cancer,

Glioblastoma,

Hepatocellular carcinoma,

Merkel cell cancer,

Multiple myeloma,

Myelodysplastic syndrome,

Mycosis fungoides,

Non-Hodgkin lymphoma,

Ovarian cancer,

Sarcomas,

Sézary syndrome,

Solid organ tumors,

Squamous cell cancer,

Stage I or Stage II melanoma,

Use in combination therapy with another checkpoint inhibitor agent, unless addressed above with Yervoy®.

Atezolizumab (Tecentriq™)

Tecentriq™ may be considered medically necessary for the following indications:

Non-Small-Cell Lung Cancer (NSCLC):

o Single agent subsequent therapy for metastatic (squamous and non-squamous [see NOTE 9]) NSCLC who have disease progression during or after platinum-based chemotherapy and if Keytruda® OR Opdivo® not previously given, when the patient meets the 0-2 ECOG performance scale (see NOTE 1).

Bladder Cancer (Urothelial Carcinoma):

o Single agent first-line therapy for locally advanced or metastatic bladder cancer (clinical Stage T4b or T2-4a, N1-3 disease, or for recurrence post-cystectomy, or for metastatic disease when patient is not eligible for cisplatin-containing chemotherapy.

o Single agent subsequent systemic therapy for locally advanced bladder cancer (clinical Stage T4b or T2-4a, N1-3 disease, or for recurrence post-cystectomy, or for metastatic disease progression on or after platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant chemotherapy.

NOTE 9: Second-line therapy for nonsquamous NSCLC using Tecentriq™: Those patients with EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) genomic tumor aberrations should have disease progression on FDA-approved therapies, e.g., docetaxel (Taxotere®) for these aberrations prior to receiving Tecentriq™.

Tecentriq™ is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

• Acute myeloid leukemia,

• Autoimmune diseases requiring treatment with immunosuppressants,

• Breast cancer,

• Cervical cancer,

• Chronic myeloid leukemia,

• Colorectal cancer,

• Gastric cancer,

• Glioblastoma,

• Head and neck cancer,

• Hodgkin lymphoma,

• Melanoma,

• Non-Hodgkin lymphoma,

• Ovarian cancer,

• Pancreatic cancer,

• Prostate cancer,

• Renal cell carcinoma, including metastatic,

• Salivary tumor,

• Sarcomas,

• Small-cell lung cancer,

• Solid organ tumors,

• Stage I or Stage II melanoma, and

• Use in combination therapy with another checkpoint inhibitor agent.

NOTE 10: Some checkpoint inhibitors may have been granted orphan drug designation by the FDA for specific indications. Refer to the FDA approved labeling for more information.

Description:

According to the American Cancer Society, the crucial part of the immune system is its ability to distinguish between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells while leaving the normal cells alone. To accomplish this, the immune system uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system, being hidden or masked. However, a new class of drugs targets these “checkpoints” and hold a lot of promise as anti-cancer treatments or therapies. (1)

Programmed cell death protein 1 (PD-1), is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T-cell inflammatory activity. PD-1 is an immune checkpoint or a checkpoint protein on theses immune cells identified as T-cells. PD-1 guards against autoimmunity through a dual mechanism of promoting programmed cell death in antigen specific T-cells in lymph nodes while simultaneously reducing programmed cell death in regulatory T-cells (anti-inflammatory, suppressive T-cells). PD-1 acts as a type of “off-switch” that helps to keep the T-cells from attacking other normal cells within the body.

When PD-1 binds to ligands, such as PD-L1, it basically tells the T-cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them evade immune attack.

Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. Cytotoxic T-lymphocyte-associated protein (CTL-4), also known as CD152 (cluster of differentiation 152), is a protein receptor on some T-cells that, functioning as an immune checkpoint, down-regulates immune responses or as a type of “off-switch” to keep the immune system in check.

Microsatellite (MS) Instability-High (MSI-H) Solid Tumors

According to the National Institutes of Health, MSI is a biomarker occurring in certain types of cancers when cells are unable to repair DNA (a molecule that contains the cell’s genetic code) sequencing errors that then proliferate with future cell division, a genetic instability. (2) This flawed replication may lead to a cancer. Essentially, a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different than the number of repeats that was in the DNA when it was inherited. The cause of MSI may be a defect in the ability to repair mistakes, similar to a “spellcheck” function identifying the error and removing, made when the DNA is copied in the cell. The proteins correcting the DNA error are known as mismatch repair (MMR). When the MMR can’t repair the error, this activity is known as dMMR (mismatch repair deficient). This is primarily a sporadic, or nonheritable, event. When this repair system is faulty, microsatellites in the DNA develop short nucleotide repeats that lead to frame-shift mutations. MSI is genetic instability in short nucleotide repeats (microsatellites) due to a high mutation rate as a result of abnormal DNA mismatch repair, a hypermutation of uncorrected DNA replication. When there are 2 or more markers, the tumor is classified as MSI-High (MSI-H). Other MSI errors can be stratified to MSI-Low (MSI-L) or MS-Stable (MSS). MSI may result in cancer development in the following solid organs: colon, gastric, endometrium, ovarian, hepatobiliary tract, urinary tract, brain, and skin. MSI is most prevalent as the cause of colon cancers.

Overall, this new class of drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small-cell lung cancer (NSCLC), kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma (HL), and Merkel-cell carcinoma (MCC). They are also being studied for use against many other types of cancer.

This policy addresses the blockade of co-inhibitory molecules, checkpoint antibodies or inhibitors, such as CTLA-4, PD-1, PD-L1, and MSI-H, among others; studies are continuing for another T-cell down regulator or immune checkpoint receptor, known as LAG-3 (lymphocyte-activation gene 3).

Tumor Staging

Cancer staging is the process of determining the extent to which a cancer has developed by spreading. Contemporary practice is to assign a number from I to IV to a cancer, with I being an isolated cancer and IV being a cancer which has spread to the limit of what the assessment measures as shown in Table 1. The cancer Stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized). Staging is useful for the determination of which checkpoint inhibitor would be used for a select tumor indication.

Table 1. Overall Staging Definitions (3)

Stage

Characteristics

I

Tumor has not spread and can be surgically excised.

II

Tumor has not spread, but is larger and possibly with greater penetration or depth to the surrounding area(s).

III

Tumor has spread to the lymph nodes of any thickness and unresectable.

IV

There are metastases to other regions of the body, irrespective of the tumor size or depth.

For some tumors, the most clinical useful staging may be accessed by the tumor, node, and metastasis (TNM) classification or staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. (3) The AJCC TNM system classifies cancers by:

T – The size and extent of primary tumor,

N – The involvement of regional lymph nodes, and

M – The presence or absence of distant metastases.

Additional numbering and lettering may be assigned to any of the TNM categories to more accurately describe the pathological stage (e.g., cT3N1M0 or pT2N0). There is a TNM staging algorithm for cancers of virtually every anatomic site and histology, with the primary exception of pediatric cancers, brain tumors, and hematological malignancies. TNM is useful for treatment considerations, including the use of checkpoint inhibitors.

Melanoma

Melanoma is the most common serious form of skin cancer. (4) If recognized and treated early, it is almost always curable. Approximately 84% of melanomas are diagnosed at a localized Stage with 5-year survival of 98%. However, melanoma is more likely than other skin tumors to metastasize. Five-year survival for patients with regional metastasis is 62%, and for patients with distant metastasis 15%. Staging for a melanoma tumor is based on the overall staging classifications discussed earlier, with expansion of Stages II and III to indicate the if ulceration has occurred and size of the lesion(s), its penetration and thickness. (4)

Small-Cell Lung Cancer (SCLC)

Neuroendocrine tumors account for approximately 20% of lung cancers, with roughly 14% as SCLC. (5) According to the National Comprehensive Cancer Network (NCCN), an estimated 31,000 new cases of SCLC were diagnosed in 2015 in the United States (U.S.). Nearly all of these new cases are attributed to cigarette smoking. Although the number of lung cancers are decreasing overall, the incidence in women is increasing and the male-to-female incidence ratio is nearly equal. SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Staging for lung cancer, both SCLC and NSCLC, uses the TNM classification discussed earlier. (5) Staging is based on non-invasive assessments (radiological) and/or invasive (surgical) techniques.

Non-Small-Cell Lung Cancer (NSCLC)

According to the NCCN, lung cancer is the leading cause of cancer deaths in the U.S. (6) In 2015, an estimated 221,200 new cases of lung and bronchial cancer will be diagnosed, with 158,040 deaths estimated resulting from this disease. With the progress being made for screening, minimally invasive techniques for diagnosis and management, only 16.8% of all patients with lung cancer will survive to 5 years or more following the initial diagnosis. NSCLC is the most common form of lung cancer. It includes three sub-types: adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma. Therefore, the literature confirms that nonsquamous NSCLC is considered to include adenocarcinoma and large-cell carcinoma. The difference between squamous and nonsquamous NSCLC is a key distinction for some U.S. Food and Drug Administration (FDA) approved checkpoint-blocking antibody agents. Staging for NSCLC utilizes the same staging as SCLC, as described above. (6)

Malignant Pleural Mesothelioma (MPM)

Mesothelioma is a rare cancer that is estimated to occur in approximately 2500 individuals within the U.S. annually. (7) The most common type of mesothelioma is MPM. In addition to the lung, MPM can be found in other areas of the body, but those are extremely rare and difficult to treat, as the disease is advanced at the time of initial diagnosis. Median survival is approximately 1 year, and cure is very rare. According to the NCCN Guidelines for MPM, the incidence of MPM is leveling off in the U.S. as a result of the decline of asbestos use since the 1970s; however, the U.S. still leads with the number of cases and deaths worldwide. Staging for MSM uses the basic TNM classification described above, with enhancements from the International Mesothelioma Interest Group (IMIG) with focus on MPM. (7)

Head and Neck Squamous Cell Cancers (HNSCC)

The NCCN Guidelines for HNSCCs address tumors arising in the lip, oral cavity, pharynx, larynx, and paranasal sinuses. (8) In 2014, it is estimated that about 55,070 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur, which account for about 3% of new cancer cases in the U.S. An estimated 12,000 deaths from HNSCCs will occur during the same time period. Squamous cell carcinoma or a variant is the histologic type in more than 90% of these tumors. Alcohol and tobacco abuse are common etiologic factors in cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Human papillomavirus (HPV) infection is now well accepted as a risk factor for the development of squamous cancers of the oropharynx, particularly cancers of the lingual and palatine tonsils and base of the tongue. The overall incidence of HPV-positive HNSCCs is increasing in the U.S. Staging for HNSCC cancers uses the basic TNM classification described above, with changes particularly to primary tumor descriptions for moderately advanced local disease (T4a) and very advanced local disease (T4b). (8)

Hodgkin Lymphoma (HL)

HL is an uncommon malignancy involving lymph nodes and the lymphatic system. (9) Most patients are diagnosed between 15 and 30 years of age, followed by another peak in adults aged 55 years or older. The NCCN reports for 2015, over 9000 patients will be diagnosed with classical HL (cHL) in the U.S., with over 1100 patients dying from the same disease. The World Health Organization (WHO) Classification divides HL into 2 main types: cHL and nodular lymphocyte-predominant HL (NLPHL). In Western countries, cHL accounts for 95% and NLPH accounts for 5% of all HL. Staging for HL is based on the Ann Arbor staging system, according to the NCCN. Each Stage is divided into A and B categories. “A” indicates that no systemic symptoms are present and “B” is assigned to patient with unexplained weight loss of >10% of their body weight, unexplained fevers, or drenching night sweats. Patients with HL are usually classified into 3 groups: early-Stage favorable (Stage I-II with no unfavorable factors); early-Stage unfavorable (Stage I-II with any of the unfavorable factors such as large mediastinal adenopathy; >2-3 nodal sites of disease; B symptoms; extranodal involvement; or significantly elevated erythrocyte sedimentation rate ≥50) and advanced-Stage disease (Stage III-IV). (9)

Renal Cell Carcinoma (RCC)

RCC is the most common type of kidney cancer, which accounts for 3% of all adult malignancies, with a steadily increasing rate of about 2.5% annually. (10) Most people who have RCC are older, usually between the ages of 50 to 70 years of age. Approximately 90% of renal tumors are RCC, and approximately 80% of these are clear-cell histology. Generally, RCC begins as one tumor in the tubules of a single kidney, sometimes there are 2 or more tumors in 1 kidney or even diagnosed in both kidneys. RCC may be known as hypernephroma or renal cell adenocarcinoma. Cancer that originates in the ureters or in the renal pelvis is not considered as RCC. Although most adults are diagnosed with localized tumors, approximately one-third of patients present with metastatic disease. Staging for RCC uses the TNM classification described above, focused on the kidney. (10)

Bladder Cancer (Urothelial Carcinoma)

According to the NCCN, bladder cancer is the sixth most common cancer and is 3 times more prevalent in men than in women in the U.S. (11) In 2015 alone, approximately 74,000 new cases have been diagnosed in the U.S. Urothelial carcinoma, also known as transitional cell carcinoma (TCC) is the most common type of bladder cancer. Bladder cancers are rarely diagnosed in individuals younger than 40 years old, with a median age of 65 years. Bladder cancer is divided into 3 categories: non-muscle-invasive tumors, muscle-invasive tumors, and metastatic lesions. Bladder preservation is key throughout prognosis, management and therapeutic aims by providers. Staging of bladder cancer uses the TNM classification described above, focused on the bladder. (11)

Merkel Cell Carcinoma (MCC)

MCC, also known as primary cutaneous neuroendocrine carcinoma of the skin, is a rare type of skin cancer that usually appears as a flesh-colored or bluish-red nodule. (12) MCC tends to grow quickly and metastasizes to other areas of the body, with most recurrences after 2 years following initial diagnosis of the primary tumor. While the disease is 30 times rarer than melanoma (an estimated 0.24 cases per 100,000 persons in the U.S.), patient death occurs 1 in 3 patients compared with 1 in 6 for melanoma. MCC most often arises on sun-exposed areas in fair-skinned individuals over age 50. Its name comes from the similarity of these cancer cells to normal Merkel cells in the skin that are thought to be associated with touch sensation. Staging of MCC uses the TNM classification described above, focused on the skin. (12)

Colorectal Cancer (CRC)

The NCCN Guidelines for colon cancer stated that CRC is the fourth most frequently diagnosed cancer and second leading cause of cancer death in the U.S. (13, 14) In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 patients will die of colon and rectal cancer combined. The incidence of CRC has decreased at a rate of 3% per year between 2003 and 2012. In addition, the mortality from CRC has decreased by almost 35% from 1990 to 2007, and is currently down by about 50% from peak mortality rates. Each year, there are over 500,000 CRC cases worldwide. Based on findings, reported by Popet et al., from over 7000 patients stratified for MSI-H, MSI-L, or MSS colon cancers, those with MSI-H had a more positive prognosis by 15% to MSI-L or MSS tumors. (15) Colorectal tumors with MSI are found in the right colon, associated with poor differentiated tissue, high mucinogens, tumor infiltrating lymphocytes, and a presence of a Crohn's-like host response. MSI-H tumors contributing to CRC exhibit less metastasis than another derived CRC. This is demonstrated by previous research showing that MSI-H tumors are more representative in Stage II rather than Stage III cancer. Staging of CRC uses the TNM classification described above, focused on the colon and rectum. (13-16)

Eastern Cooperative Oncology Group (ECOG) Performance Scale

Assessment of the patient’s daily living abilities, also known as the patient’s performance status, including their ability to take care of themselves, daily activity, and physical ability, such as walking, working, etc., is required for a new treatment method, as well continued or repeated therapy. (17) One such measurement tool is the ECOG Performance Scale, developed in 1982. The following Table 2 displays the grade levels and performance scale descriptions.

Table 2. Eastern Cooperative Oncology Group (ECOG) Performance Scale (17)

Grade

ECOG Performance Status

0

Fully active, able to carry on all pre-disease performance without restriction.

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.

2

Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours.

3

Capable of only limited self-care; confined to bed or chair more than 50% of waking hours.

4

Completely disabled; cannot carry on any self-care; totally confined to bed or chair.

5

Dead.

Regulatory Status

Ipilimumab (Yervoy™):

Yervoy™, manufactured by Bristol-Myers Squibb Co., Princeton, N.J., received its initial FDA approval on March 25, 2011. (18) The initial approval was for the treatment option for unresectable or metastatic melanoma. Since then, the FDA has approved expanded labeled indications, to include the adjuvant treatment of patients at risk for Stage III melanoma recurrence, including following lymph node resection and SCLC. (18)

Yervoy™ is a PD-1 checkpoint inhibitor in addition to actively attaching to the CTLA-4 to boost the body’s immune response against cancer cells. Yervoy™ was given orphan drug designation upon its initial FDA approval in 2011 for pediatric patients. (18)

Pembrolizumab (Keytruda®):

Keytruda®, manufactured by Merck Sharp & Dohme Co., Whitehouse Station, N.J., received its initial FDA approval on September 4, 2014. (19) The initial approval was for the treatment of advanced, unresectable or metastatic melanoma, as a PD-1 checkpoint inhibitor.

Since then, the FDA has approved expanded labeled indications, to include the treatment of metastatic NSCLC when the tumor has expressed the PD-L1 determined by an FDA-approved test and the treatment of recurrent or metastatic HNSCC. (19) Additional FDA-approved indications include cHL, urothelial carcinoma, and MSI-H solid tumors. Keytruda® was given orphan drug designation upon its FDA approvals for treatment of primary mediastinal B-cell lymphoma, Stage IIb-IV malignant melanoma, Hodgkin lymphoma, gastric cancer (including gastroesophageal junction adenocarcinoma), multiple myeloma, nasopharyngeal carcinoma, Merkel cell carcinoma, hepatocellular carcinoma, follicular lymphoma, or esophageal carcinoma. The FDA-approved label included a limitation of use for pediatric patients with MSI-H central nervous system cancer, as safety and effectiveness have not been established in this population. (19)

Nivolumab (Opdivo®):

Opdivo®, manufactured by Bristol-Myers Squibb Co., Princeton, N.J., received its initial FDA approval on December 22, 2014. (20) This approval was for the treatment of advanced, unresectable or metastatic melanoma. Since then, the FDA has approved expanded labeled indications, to include the treatment of:

1) BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma;

2) Treatment of metastatic non-squamous NSCLC when the tumor has expressed the PD-L1 determined by an FDA-approved test (along with the FDA allowance for the treatment of patients with epidermal growth factor receptor [EGFR]) or anaplastic lymphoma kinase [AL]) genomic tumor aberrations when disease has progressed on prior FDA-approved treatments);

3) Treatment of advanced RCC who have received prior anti-angiogenic therapy;

4) Treatment of cHL that has relapsed or progressed after autologous hematopoietic stem-cell transplantation and post-transplantation brentuximab vedotin; and

5) The combination therapy with Yervoy™ for treatment of unresectable or metastatic melanoma. (20)

NOTE 11: Before each dose, patients are assessed for signs and symptoms of enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy. Clinical chemistry tests may be done prior to administration of any of the checkpoint-blocking or monoclonal antibodies, including liver function testing and thyroid function tests, among others.

In November 2016, the FDA approved Opdivo® for the treatment of recurrent or metastatic HNSCC with disease progression on or after a platinum-based chemotherapy. (20) According to the NCCN, this type of carcinoma is “very advanced or recurrent/persistent.” (8) In February 2017, the FDA approved Opdivo® for the treatment of “locally advanced or metastatic urothelial carcinoma with disease progression or after platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.” (20) As a PD-1 checkpoint inhibitor®, Opdivo® was given orphan drug designation upon its FDA approvals for treatment of gastric cancer and gastroesophageal junction cancer, hepatocellular carcinoma, SCLC, glioblastoma, esophageal cancer, Hodgkin lymphoma, Stage IIb-IV malignant melanoma, and combination therapy with Yervoy™ to treat Stage IIb-IV melanoma or gastric cancer and gastroesophageal junction cancer. (20)

Atezolizumab (Tecentriq™):

Tecentriq™, manufactured by Genentech, Inc., South San Francisco, CA, received its initial FDA approval on May 18, 2016. (21) This approval was for the treatment of patients with locally advanced or metastatic urothelial carcinoma. Tecentriq™ is a PD-L1 blocking antibody.

In November 2016, the FDA approved Tecentriq™ for the treatment of metastatic NSCLC who have disease progression during or after a platinum-based chemotherapy. (21) On April 21, 2017, the FDA approved Tecentriq™ for the treatment of locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. (21) Tecentriq™ was given orphan drug designation upon its FDA approvals for treatment of SCLC and of Stage IIb, IIc, III, and IV melanoma. (21)

NOTE 12: The FDA may have approved a checkpoint inhibitor indication or condition under the accelerated approval based on tumor response rate and durability of response. Continued FDA approval for any checkpoint inhibitor indication may be contingent upon verification and description of the clinical benefit in the confirmatory trials. (18-21) This applies to any of the checkpoint inhibitor drugs addressed in this medical policy. According to a 2013 ECRI Health Technology Forecast, checkpoint inhibitor agents are in clinical trials for treating other cancers (e.g., breast, pancreas, bladder, castrate-resistant prostate) as a single agent or in combination therapy with various agents, such as bevacizumab (Avastin®). (22) Therefore, for checkpoint inhibitors to treat specific cancers still in clinical trials, the FDA may frequently and rapidly approve these agents before confirmatory trials have been presented and reviewed by the FDA.

Rationale:

The medical policy originated in 2012 and continues to be based on the following:

The National Comprehensive Cancer Network (NCCN) Guidelines and Drugs & Biologics Compendium (4-14, 23-26);

The U.S. Food and Drug Administration (FDA)-approved labeling of checkpoint-blocking inhibitors/antibody treatments (18-21, 27); and

The Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Specialty Pharmacy Reports. (28-30).

A search of Medline, and the NCCN Guidelines and Drugs & Biologics Compendium, and the FDA-approved labeling was conducted through August 15, 2017. Each drug treatment will be summarized individually below with a focus on recommended use, including off-label indications, from the NCCN Drugs & Biologics Compendium.

Ipilimumab (Yervoy™)

In May 2011, BCBSA TEC released the Specialty Pharmacy Combined Capacity (SPCC) Report #6-2011 (28) concurrently to the release of the FDA-approved labeling of ipilimumab (Yervoy™). (18) At that time, Yervoy™ was the sole pharmaceutical listed on this medical policy. The 2017 NCCN Drugs & Biologics Compendium maintained recommendations for the use of Yervoy™ for specific melanoma diagnoses and small-cell lung cancer (SCLC), and added malignant pleural mesothelioma (MPM). (23)

Melanoma and Metastases to the Brain

Yervoy™’s FDA-approval was based upon a recent pivotal Phase 3, double-blind international study that randomized 676 patients with unresectable or metastatic melanoma, including metastases to the brain. (31) Hodi et al. reported all patients in the study had stopped responding to other FDA-approved or commonly used treatments of melanoma, such as aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. (31) The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. According to the FDA, “The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy™ alone, Yervoy™ plus an experimental tumor (peptide) vaccine called gp100, or the vaccine alone. (31) Those who received the combination of Yervoy™ plus the vaccine or Yervoy™ alone lived an average of about 10-months, while those who received only the experimental vaccine lived an average of 6.5-months.” The assessment of the tumor response was conducted at week 12 and 24, and every 3-months thereafter. The published study revealed the estimated overall survival at 1-year was 46% in the Yervoy™ arm, 44% in the Yervoy™ and vaccine arm, and 25% in the vaccine alone arm. At 2-years, the overall survival was 24% in the Yervoy™ arm, 22% in the Yervoy™ and vaccine arm, and 14% in the vaccine alone arm.

In October 2015, the FDA expanded the approved label for the adjuvant treatment of patients who are at risk of developing recurrence of Stage III melanoma after surgery as adjuvant therapy. This change was based upon a double-blind, Phase 3 trial reported by Eggermont et al. (32) The study purpose was to determine if Yervoy™ would be effective in the prevention or delay recurrence of Stage III melanoma, prolonging survival following complete resection by a full lymphadenectomy within 12-weeks prior to the study 1:1 randomization of 951 patients. ClinicalTrials.gov included trial parameters and results for this interventional study. (33) Staging was based according to the American Joint Committee on Cancer 2002 classification of Stage IIIA >1 mm nodal involvement, Stage IIIB with 1 to 3 involved lymph nodes, and Stage IIIC having ≥ 4 involved lymph nodes, which is found in the NCCN guidelines. (4) According to the FDA, patients were randomized to receive Yervoy™ 10 mg/kg (N=475) or placebo as an intravenous infusion (N=476) every 3-weeks for 4 doses, followed by Yervoy™ 10 mg/kg or placebo every 12-weeks from week 24 to week 156 (3 years) or until documented disease recurrence or unacceptable toxicity. (18) The outcomes were measured as recurrence-free survival from the time of randomization and the date of first recurrence (local, regional, or distant metastasis) or death. (This trial has yet to be published in a peer-reviewed journal.) The recurrence-free survival is shown on Table 3.

Table 3. Efficacy Results of Phase III Double Blind Randomized Trial (18)

Recurrence-Free Survival

Yervoy™

N=475

Placebo

N=476

Number of Events, N (%)

234 (49%)

294 (62%)

Recurrence

220

289

Death

14

5

Median (months)

26

17

(95% CI)

(19, 39)

(13, 22)

Hazard Ratio

0.75

(95% CI)

(0.64, 0.09)

p-value (stratified long-ranka)

P<0.002

Table Key:

N: number;

CI: confidence interval;

a: stratified by disease Stage.

Of the deaths during the trial, 5 (1%) were due to drug-related adverse events. (18) The balance was the result of colitis, myocarditis, and multi-organ failure with Guillain-Barre. The authors concluded that adjuvant Yervoy™ utilization for completely resected high-risk Stage III melanoma significantly improved recurrence-free survival. The adverse events profile was consistent when treated for advanced melanoma.

Small-Cell Lung Cancer (SCLC)

In 2017, the NCCN added treatment of relapsed SCLC with a combination of Yervoy™ and Opdivo®, which was based on a recent Phase 1/2 study published by Antonia, et al. (5, 24, 34) The patients received either Opdivo® alone or Opdivo® with Yervoy™. This was a multi-center, multi-arm, open-trial for patients 18-years of age or older. Patients had disease progression after at least 1 prior platinum-containing regimen. Two hundred sixteen patients were enrolled and treated, 98 patients receiving Opdivo® alone and 118 divided into 3 groups of various escalating doses of both agents. Response rates were 10% (10 of 98) for the Opdivo® alone, 19% (14 of 61) for Opdivo® with Yervoy™ (dose escalating for Yervoy™), and 19% (10 of 54) Opdivo® with Yervoy™ (dose escalating for Opdivo®). The NCCN panel did note that the response rate did not correlate with the PD-L1 expression. The study authors concluded that Opdivo® monotherapy and Opdivo® with Yervoy™ combined therapy showed anti-tumor activity with durable responses and manageable safety profiles in previously treated SCLC patients.

Malignant Pleural Mesothelioma (MPM)

The NCCN based their recommendation on the French IFCT-1501 MAPS2 (Intergroupe Francophone de Cancérologie Thoracique [French Cooperative Thoracic Intergroup]-1501 malignant pleural mesothelioma patients) randomized Phase 2 trial, which is still ongoing according to ClinicalTrials.gov, published by Scherpereel et al., in 2017. (35, 36) This Phase 2 trial was a multi-center randomized, non-comparative study evaluating Opdivo® monotherapy and Opdivo® plus Yervoy™ combination therapy in patients with previously treated recurrent MPM. The premise was to determine if anti-PD-L1 therapy is effective compared to a combination of anti-PD-L1 and anti-cytotoxic T-lymphocyte-associated protein (CTL-4) agents.

From March to August 2016, 125 patients were enrolled in 21 centers in France. (35, 36) Eligible patients, previously treated by 1 or 2 systemic chemotherapy lines, were randomized into 2 treatment groups: patients received Opdivo® (3 mg/kg every 2-weeks) or Opdivo® (3 mg/kg every 2-weeks) combined with Yervoy™ (1 mg/kg every 6-weeks) until progression or unacceptable toxicity. The primary endpoint is disease control rate. Secondary endpoints include number of participants with treatment-related adverse events, progression-free survival, overall survival, quality of life, evaluation of predictive value of tumor PD-L1 score and prognostic value of biomarkers.

Per Scherpereel et al., to date, there is no treatment recommended for MPM patients progressing after first-line pemetrexed-platinum doublet therapy. (35, 36) Second-line therapy, disease control rate is <30%, with all chemotherapy agents. Following 12-weeks in the IFCT-1501 MAPS trial, the first 108 patients were assessed, 42.6% were treated with Opdivo® alone and 51.9% with Opdivo® plus Yervoy™. The overall response rate was 16.7% with Opdivo® alone and 25.9% with Opdivo® plus Yervoy™. Slightly increased toxicities were found with the combination therapy versus the monotherapy. Three treatment related deaths happened in the combination arm, in addition to other serious adverse events. With that, the authors suggest that immunotherapy may provide new options for MPM.

Ongoing and Unpublished Clinical Trials: Yervoy™

Currently, there are 322 ongoing recruiting/active and/or unpublished completed trials, listed in ClinicalTrials.gov, focused on Yervoy™, with or without other pharmaceutical preparations to treat numerous conditions, including those which are FDA approved, e.g., prostatic cancer, breast cancer, solid organ tumors, urothelial cancer, non-small cell lung cancer, myelodysplastic syndromes, acute myeloid leukemia, head and neck cancers, glioblastoma and gliosarcoma, Merkel cell carcinoma, pancreatic cancer, post hematopoietic stem-cell transplantation (HSCT), etc. Some of the studies listed in ClinicalTrials.gov include Yervoy™ in combination with radiation therapy or radiosurgery, including stereotactic body radiation therapy.

Professional Guidelines and Position Statements: Yervoy™

National Comprehensive Cancer Network (NCCN) – Melanoma

The 2017 NCCN Guidelines and Drugs & Biologics Compendium continue to designate Yervoy™ as a Category I recommendation for Stage III melanoma disease with clinically positive lymph node(s) and close monitoring for adverse effect. (4, 18) The 2017 NCCN Drugs & Biologics Compendium recommends Yervoy™ as a Category 2A for Stage III sentinel lymph node positive metastases >1 mm and for the treatment of unresectable or metastatic melanoma (including brain metastases when the primary tumor is melanoma).

NCCN – Small-Cell Lung Cancer (SCLC)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for SCLC. (5, 18) The indications included subsequent systemic therapy with Yervoy™ for patients with ECOG performance status 0-2 when in combination with Opdivo®.

NCCN – Malignant Pleural Mesothelioma (MPM)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for MPM when combined with Opdivo® as subsequent systemic therapy. (7, 18)

Pembrolizumab (Keytruda®)

Late in 2014, pembrolizumab (Keytruda®) was added to the medical policy due to a FDA approval for use in the treatment of patients with unresectable or metastatic melanoma. On October 2, 2015, the FDA expanded the label for Keytruda® for the treatment of non-small cell lung cancer (NSCLC). (19) The FDA approved the use of Keytruda® for the treatment of head and neck squamous cell cancers (HNSCC) on August 6, 2016. (19) In 2017, the NCCN panel updated their Drugs & Biologics Compendium for Keytruda®, adding new indications for Merkel cell carcinoma (MCC), malignant pleural mesothelioma (MPM), and microsatellite instability-high (MSI-H) or mismatched repair deficient (dMMR) colorectal cancer (CRC). (24)

Melanoma

Per the FDA label, the accelerated FDA-approval of Keytruda® was based upon tumor response rate and durability of response. (19) Further studies have been requested by the FDA to continue the approval, “contingent upon verification and description of clinical benefits in the confirmatory trials.” The clinical trial the FDA based their decision was from Robert et al. in 2014. (37) An open-label, international, multi-center expansion cohort of a Phase 1 trial of 173 patients. Patients were randomized. The patients received either 2 mg/kg (N=89) or 10mg/kg (N=84) of Keytruda® during a median follow-up of 9-months. The assessment of tumor size was done every 12-weeks. The authors’ conclusion was the following: “The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3-weeks might be an effective treatment in patients for who there are few effective treatment options.”

Non-Small Cell Lung Cancer (NSCLC)

The FDA required the same confirmatory studies following the expanded label approval for NSCLC. The clinical trial the FDA based the recent approval on was from an investigation of a sub-group of 280 patients enrolled in a multi-center, open-label multi-cohort, activity-estimating study, known as Trial 1 (KEYNOTE-001). (19) The cohort consisted of patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations and any evidence of PD-L1 (PD-1 ligand) expression by a clinical trial immunohistochemistry assay. Patients with autoimmune disease, a medical condition that required immunosuppression, or who had received more than 30 Gy of thoracic radiation within the prior 26-weeks, were ineligible.

A prospectively defined sub-group was retrospectively analyzed using an analytically validated test for PD-L1 expression tumor proportion score (TPS). This retrospectively identified sub-group of 61 patients accounts for 22% of the 280 patients in the cohort cited above. Patients included in this sub-group had a PD-L1 expression TPS of greater than or equal to 50% tumor cells as determined by the PD-L1 “IHC 22C3 pharmDx Kit”. Patients received Keytruda® 10 mg/kg every 2 (n=27) or 3 (n=34) weeks until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Assessment of tumor status was performed every 9-weeks for the major efficacy outcome and duration of response.

Among the 61 patients with a TPS greater than or equal to 50%, the baseline characteristics were: median age 60-years (34% age 65 or older); 61% male; 79% Caucasian; and 34% and 64% with an ECOG (Eastern Cooperative Oncology Group) performance status 0 and 1, respectively. Disease characteristics were squamous (21%) and nonsquamous (75%); Merkel cell (98%); brain metastases (11%); 1 (26%), 2 (30%), or 3 or more (44%) prior therapies; and the incidence of genomic aberrations was EGFR (10%) or ALK (0%).

Efficacy results are summarized in Table 4. Note that the objective response rate and duration of response were similar regardless of schedule (every 2-weeks or every 3-weeks) and thus the data below are pooled.

Table 4. Efficacy Results Endpoint of 61 Patients (19)

Overall Response Rate

Percentage

Overall Response Rate %, (95% Confidence Interval)

41%

Complete Response

0%

Partial Response

41%

Among the 25 responding patients, 21 (84%) patients had ongoing responses at the final analysis of overall response rate; 11 (44%) patients had ongoing responses of 6-months or longer.

In a separate subgroup of 25 patients with limited follow-up with PD-L1 expression, TPS greater than or equal to 50% receiving Keytruda® at a dose of 2 mg/kg every 3-weeks in Trial 1, activity was also observed.

In 2015, Garon et al. reported on a Phase 1 study of 495 patients, to assess the PD-L1, which is associated with the likelihood of the clinical benefit when treating with Keytruda®. (38) The “training group” or “validation group” was given varied doses at either 2- or 3-weeks, similar to the study discussed above, with assessment at 9 weeks. Common side effects were equivocal to both groups, with no clear difference when tracking the dose or frequency. Among all patients, the objective response rate was 19.4% with median response duration of 12.5-months. The authors’ conclusions were Keytruda® had an acceptable side effect profile, and Keytruda® showed antitumor activity in patients with NSCLC.

Malignant Pleural Mesothelioma (MPM)

Alley et al. conveyed the findings of the KEYNOTE-028 trial, which assessed the clinical safety and activity following administration of Keytruda® to treat MPM. (39) This multi-center, non-randomized, open-label Phase 1b trial enrolled 25 patients who had been previously treated with other chemotherapy agents. Key eligibility criteria included measurable disease, failure of standard therapy, and ECOG performance scale 0-1. Early results revealed 5 (20%) patients had a partial response, for an objective response rate of 20%, and 13 (52%) of 25 had stable disease. The median response duration is 12 months. The remaining patients in the study had to cease treatment due to adverse events or patients are still in the treatment phase of the study. While the authors concluded the use of Keytruda® to treat MPM warrants further investigation, the NCCN has included treatment with Keytruda® for patients with MPM. (7, 24, 39)

Head and Neck Squamous Cell Cancers (HNSCC)

The FDA approval for Keytruda® was based upon a multi-center, nonrandomized, open-label, multi-cohort study (known as Trial 4) that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC, or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. (7)

Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG performance scale ≥2 were ineligible. Patients received Keytruda® 10 mg/kg every 2-weeks (n=53) or 200 mg every 3-weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4-weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with Keytruda® could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8-weeks.

The major efficacy outcome measures were objective response rate according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1 [40]), as assessed by blinded independent central review, and duration of response. number of prior lines of therapy administered for the treatment of HNSCC was 2. The objective response rate was 16% (95% CI [Confidence Interval]: 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 objective response rate and duration of response were similar irrespective of dosage regimen (10 mg/kg every 2-weeks or 200 mg every 3-weeks) or human papilloma virus (HPV) status.

The outcomes of Trial 4 confirmed an earlier safety and efficacy study published by Seiwert et al. in July 2016, with 60 patients with PD-L1-positive for HNSCC. (41) The authors concluded that Keytruda® was well tolerated and demonstrated clinically meaningful anti-tumor activity in recurrent or metastatic squamous cell carcinoma of the HNSCC, supporting further study of Keytruda® as an anti-cancer therapy available for advanced HNSCCs.

Hodgkin Lymphoma (Classical, cHL)

The FDA based their approval on a study of 210 patients (3 cohorts) with relapsed or refractory cHL enrolled in a multi-center, non-randomized, open-label study, KEYNOTE-087 from Chen et al. (42) Endpoint was either unacceptable toxicity, or documented disease progression, or for up to 24 months in patients that did not progress. 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. The efficacy of treatment is shown on Table 5.

Table 5. Efficacy Results of KEYNOTE-087 (42)

Endpoint

KEYNOTE-087

(based on median follow-up time of 9.4 months)

Objective Response Rate (95% CI)

69% (62, 75)

Complete Remission Rate

22%

Partial Remission Rate

47%

Duration of Response (median in months) Range

11.1 (0.0+, 11.1)*

Table Key:

CI: confidence interval;

+: denotes ongoing;

*: based on patients (number = 145) with a response by independent review.

Bladder Cancer (Urothelial Carcinoma)

The FDA approval for Keytruda® was based on the results of a multi-center, open-label, single-arm trial of 370 patients with locally advanced or metastatic urothelial carcinoma (by histology) who were not eligible for cisplatin-containing chemotherapy. (19) (This KEYNOTE-052 trial has yet to be published in a peer-reviewed journal.) The median follow-up time for the 370 patients treated was 7.8 months (range of 0.1 to 20 months. The efficacy results are found in Table 6.

Table 6. Efficacy Results in the KEYNOTE-052 Trial (19)

Endpoint

Keytruda®

200 mg every 3 weeks

Number of Patients = 370

Objective Response Rate (95% CI)

29% (24, 34)

Complete Remission Rate

7%

Partial Remission Rate

22%

Duration of Response (median in months) Range

NR

(1.4+, 17.8+)

Table Key:

mg: milligram;

CI: confidence interval;

NR: not reached;

+: denotes ongoing.

An additional study was published in 2017 by Bellmunt et al. reporting the efficacy of Keytruda® in the KEYNOTE-045 trial, an active-controlled trial in patients with locally advanced or metastatic urothelial carcinoma bladder cancer with disease progression on or after platinum-containing chemotherapy. (43) Patients were randomized to receive Keytruda® or the investigator’s choice of one preselected drugs, such as paclitaxel, docetaxel, or vinflunine. Fifteen percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant chemotherapy. Twenty-one percent had received 2 or more prior systemic regimens for metastatic disease. And, 76% of patients had received prior platinum chemotherapy treatments.

Table 7 summarizes the key efficacy measures for KEYNOTE-045, demonstrating the statistically significant improvements in overall survival and objective response rate for patients that were randomized. The median follow-up times for this trial was 9.0 months (range 0.2 to 20.8 months).

Table 7. Efficacy Results in the KEYNOTE-045 Trial (43)

Endpoints

Keytruda®

200 mg every 3 weeks

Number of Patients = 270

Chemotherapy

Number of Patients = 270

Overall Survival

Deaths (%)

155 (57%)

179 (66%)

Median in months (95% CI)

10.3 (8.0, 11.8)

7.4 (6.1, 8.3)

Hazard ratio (95% CI)

0.73 (0.59, 0.91)

p-value (stratified long-rank)

0.004

Progression-free Survival

Events (%)

218 (81%)

219 (81%)

Median, months (95% CI)

2.1 (2.0, 2.2)

3.3 (2.3, 3.5)

Hazard ratio (95% CI)

0.98 (0.81, 1.19)

p-value (stratified long-rank)

0.833

Objective Response Rate

(95% CI)

21% (16, 27)

11% (8, 16)

Complete response rate

7%

3%

Partial response rate

14%

8%)

p-value (stratified long-rank)

0.002

Median duration of response in months (range)

NR

(1.6+, 15.6+)

4.3

(1.4+, 15.4+)

Table Key:

mg: milligram;

CI: confidence interval;

NR: not reached;

+: denotes ongoing.

Merkel Cell Carcinoma (MCC)

In the 2017 NCCN Drugs & Biologics Compendium, the recommendation is first-line treatment of distant metastases from MCC or disseminated recurrence with or without surgery or radiation therapy. (12) This inclusion was based on a 2016 study published by Nghiem et al. (44) This multi-center, Phase 2, noncontrolled study of 26 adult patients who had no prior systemic therapy were given a dose of 2 mg/kg every 3-weeks of Keytruda®. The primary endpoint was the objective response rate, with the efficacy being correlated with tumor viral status. The 26 study patients were given at least 1 dose of Keytruda® and 25 patients were evaluated at least once during the treatment. The objective response rate for the 25 was 56% (95% CI, 35 to 76. Four patients had a complete response, and 10 had a partial response. The median follow-up was 33-weeks. The rate of progression free survival at 6-months was 67% (95% CI, 49 to 86). The authors concluded first-line treatment with this anti-PD-1 systemic treatment showed an acceptable objective response rate for patients diagnosed with advanced MCC.

Microsatellite Instability-High (MSI-H) Colorectal Cancer (CRC) and Solid Organ Tumors

The efficacy of Keytruda® was evaluated and presented to the FDA for approval. (19) Patients with MSI-H or dMMR solid tumors were enrolled in 1 of 5 uncontrolled, open-label, multi-cohort, multi-center, single-arm trials. Patients received either Keytruda® 200 mg every 3-weeks (group A) or 10 mg/kg every 2-weeks (group B) for a maximum 24-months. A total of 149 patients were included in 1 of the trials. Eighty-four percent of patients with metastatic CRC and 53% of patients with other solid tumors received 2 or more prior lines of therapy before administration of Keytruda®. Table 8 provides an overview of the 5 clinical trials used for the FDA approval. (This trial has yet to be published in a peer-reviewed journal.)

Table 8. Microsatellite Instability-High (MSI-H) CRC and Other Solid Organ Tumors Clinical Trials (19)

Study

Diagnosis

No. of Patients

MSI-H or dMMR Testing

Group

Prior Therapy Regimens

Published

KEYNOTE-016

NCT01876511

CRC and other tumors

28 CRC

30 Non-CRC

Local PCR or IHC

B

CRC: ≥2

Non-CRC: ≥1

Unpublished

KEYNOTE-164

NCT02460198

CRC

61

Local PCR or IHC

A

1

Unpublished

KEYNOTE-012

NCT01848864

PD-L1 positive for gastric, bladder, or triple negative breast cancer

6

Central PCR

B

≥1

Plimack ER, et al.

2017 (45)

Larkins E, et al.

2017 (46)

Muro K, et al.

2016 (47)

Nanda R, et al.

2016 (48)

KEYNOTE-028

NCT02054806

PD-L1 positive for esophageal, biliary, breast, endometrial, or CRC

5

Central PCR

B

≥1

Ott PA, et al. 2017 (49-51)

KEYNOTE-158

NCT02628067

MSI-H/dMMR Non-CRC

Rare Tumor Non-CRC Cohorts

19

Local PCR or IHC

Central PCR for Rare Tumor Non-CRC Cohorts

A

≥1

Unpublished

   

149

       

Table Key:

NCT: National Clinical Trial;

No: number

MSI-H: microsatellite instability-high;

dMMR: mismatch repair deficient;

CRC: colorectal cancer;

PCR: polymerase chain reaction;

IHC: immunohistochemistry;

Group A: Keytruda® 200 mg every 3 weeks;

Group B: Keytruda® 10 mg/kg every 2 weeks;

PD-L1: programmed cell death protein ligands 1.

Table 9 summarizes the key efficacy measures for all 5 KEYNOTE studies, demonstrating overall objective response rate evaluated by blinded independent central radiologists’ review according to RECIST v1.1 (40) and duration of response. Table 10 shows the response for each tumor type from all 5 trials, and includes non-CRC tumors evaluated.

Table 9. Efficacy Results for Patients with MSI-H/dMMR Cancer (19)

Endpoint

Number = 149

Objective Response Rate (95% CI)

39.6% (31.7, 47.9)

Complete Remission Rate

7.4

Partial Remission Rate

32.2

Duration of Response (median in months) Range

NR (1.6+, 22.7+)

Percent with duration ≥6 months

78%

Table Key:

MSI-H: microsatellite instability-high;

dMMR: mismatch repair deficient;

CI: confidence interval;

NR: not reached;

+: denotes ongoing.

Table 10. Treatment with Keytruda® Response by Solid Organ Tumor Type (19)

Indication

N

Objective Response Rate

Duration of Response Range (months)

n (%)

95% CI

CRC

90

32 (36%)

(26%, 46%)

(1.6+, 22.7+)

Non-CRC

59

27 (46%)

(33%, 59%)

(1.9+, 22.1+)

Endometrial Cancer

14

5 (36%)

(13%, 65%)

(4.2+, 17.3+)

Biliary Cancer

11

3 (27%)

(6%, 61%)

(11.6+, 19.6+)

Gastric or Gastric-Esophageal junction cancer

9

5 (56%)

(21%, 86%)

(5.8+, 22.1+)

Pancreatic Cancer

6

5 (83%)

(36%, 100%)

(2.6+, 9.2+)

Small Intestine Cancer

8

3 (38%)

(9%, 76%)

(1.9+, 9.1+)

Breast Cancer

2

PR, PR

 

(7.6, 15.9)

Prostate Cancer

2

PR, SD

 

9.8+

Bladder Cancer

1

NE

   

Esophageal Cancer

1

PR

 

18.2+

Sarcoma

1

PD

   

Thyroid Cancer

1

NE

   

Retroperitoneal Adenocarcinoma

1

PR

 

7.5+

Small-Cell Lung Cancer

1

CR

 

8.9+

Renal Cell Cancer

1

PD

   

Table Key:

N/n: number;

CI: confidence interval;

CRC: colorectal cancer;

+: denotes ongoing.

CR: complete response;

PR: partial response;

SD: stable disease;

PD: progressive disease;

NE: not evaluable.

Ongoing and Unpublished Clinical Trials: Keytruda®

Currently, there are 453 ongoing recruiting/active and/or unpublished completed trials, listed in ClinicalTrials.gov, focused on Keytruda®, with or without other pharmaceutical preparations to treat numerous conditions, including those which are FDA approved, e.g., prostatic cancer, breast cancer, solid organ tumors, urothelial cancer, non-small cell lung cancer, myelodysplastic syndromes, acute myeloid leukemia, head and neck cancers, glioblastoma and gliosarcoma, Merkel cell carcinoma, pancreatic cancer, post hematopoietic stem-cell transplantation (HSCT), etc. Some of the studies listed in ClinicalTrials.gov include Keytruda® in combination with radiation therapy or radiosurgery, including stereotactic radiation therapy.

Professional Guidelines and Position Statements: Keytruda®

National Comprehensive Cancer Network (NCCN) – Melanoma

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category I recommendation for first-line treatment of unresectable or metastatic melanoma. (4, 24) The 2017 NCCN Drugs & Biologics Compendium recommends Keytruda® as a Category 2A for second-line, subsequent or re-induction therapy to treat unresectable or metastatic disease, for patients with ECOG performance status 0-2.

NCCN – Non-Small-Cell Lung Cancer (NSCLC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 1 recommendation to treat recurrence or metastatic NSCLC (6, 24):

When PD-L1 expression-positive is ≥50%;

When the tumors are nonsquamous cell histology for patient with ECOG performance scale 0-1;

When PD-L1 expression levels ≥1% in metastatic disease for patients with ECOG performance scale 0-2 as subsequent therapy.

NCCN – Malignant Pleural Mesothelioma (MPM)

The 2017 NCCN added treatment with Keytruda® as a Category 2A recommendation for MPM for subsequent systemic treatment. (7, 24)

NCCN – Head and Neck Squamous Cell Cancer(HNSCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 2A recommendation as a single agent for non-nasopharyngeal HNSCC if disease progression on or after platinum containing chemotherapy, which include newly diagnosed or metastatic disease. (8, 24)

NCCN – Hodgkin Lymphoma (classical HL)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 2A recommendation for patients ≥18 years for refractory cHL following prior chemotherapy or as palliative therapy for older adult patients >60 years of age with relapsed or refractory disease. (9, 24)

NCCN – Bladder Cancer (Urothelial Carcinoma)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 1 recommendation for the treatment, as a first-line or subsequent therapy, of locally advanced, metastatic, or recurrence post-cystectomy bladder cancer, a histology of urothelial carcinoma. (11, 24) Additionally, the NCCN has as a 2A recommendation for the treatment using Keytruda® of urothelial carcinoma found in the urethra, upper genitourinary tract, and prostate.

NCCN – Merkel Cell Carcinoma MCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 2A recommendation for the treatment distant metastatic disease or disseminated recurrence of MCC, with or without surgery or radiation therapy. (12, 24)

NCCN – Colorectal Cancer (CRC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Keytruda® as a Category 2A recommendation for the following CRC treatments: (13, 14, 24)

Primary therapy for unresectable metachronous metastases following prior specific adjuvant treatment within last 12-months,

Initial therapy for unresectable advanced or metastatic disease when not appropriate for intensive therapy(s), and

Subsequent therapy for unresectable advance or metastatic disease following prior specific treatment.

Nivolumab (Opdivo®)

The FDA approved nivolumab (Opdivo®) in December 2014 followed by an expanded approval to treat NSCLC in March 2015; and, the NCCN panel updated their Guidelines on the treatment of melanoma in January 2015 and NSCLC in March 2015. (20) These changes lead to inclusion of Opdivo® to the medical policy. Recent FDA approved changes in 2017, expanded utilization of Opdivo® to treat urothelial carcinoma, malignant pleural mesothelioma (MPM), and microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC. (20)

Melanoma

The FDA approval for treatment of unresectable or metastatic melanoma using Opdivo® or the investigator’s chemotherapy selection was based upon a multi-center, open-label randomized Phase 3 trial of patients following treatment with Yervoy™ and BRAF inhibitors. (20, 52) Weber et al. performed tumor assessments at 9-weeks after the randomization then every 6-weeks for the first year, and every 12-weeks thereafter. (53) Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo® and in whom the minimum duration of follow-up was 6-months. The major efficacy outcome measured the objective response rate using the RECIST v1.1 (40) and duration of response. The objective response rate was 32% (95% CI: 23, 41), consisting of 4 complete responses and 34 partial responses in the Opdivo®-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 response of 6-months or longer. (53)

Although not included in the 2016 NCCN Guidelines or by the FDA, Robert et al. reported Opdivo® studied in patients previously untreated without the BRAF mutation, as this treatment option had not been tested in a Phase 3 controlled study (CHECKMATE-066). (52) Four hundred eighteen patients with advanced melanoma without BRAF mutation were randomly assigned to either Opdivo® or dacarbazine. The primary endpoint was overall survival. At 1-year, the overall rate of survival was 72.9% (95% CI: 65.5, 78.9) in the Opdivo® group compared to 42.1% (95% CI: 33.0, 50.9) in the dacarbazine group. The median progression free survival was 5.1-months in the Opdivo® group versus 2.2-months in the dacarbazine group. The objective response rate was 40.0% (95% CI, 33.3, 47.0) for the Opdivo® group compared to the 13.9% (95% CI: 9.5, 19.4) in the dacarbazine group. The conclusion by the authors was Opdivo® was associated with significant improvements in overall survival and progression-free survival among those patients previously untreated.

Table 11 provides the efficacy results from the CHECKMATE-066 Phase 3 trial, which demonstrated the statistically significant improvement of the overall survival for the Opdivo® arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events. (20, 52)

Table 11. Efficacy Results (20, 52)

Endpoints

Opdivo® (n=210)

Dacarbazine (n=208)

Overall Survival (OS)

Events (%)

50 (24)

96 (46)

Median, months (95% CI)

Not reached

10.8 (9.3, 12.1)

Hazard ratio (95% CI)

0.42 (0.30, 0.60)

p-value

<0.0001a

Progression-free Survival (PFS)

Events (%)

108 (51)

163 (78)

Median, months (95% CI)

5.1 (3.5, 10.8)

2.2 (2.1, 2.4)

Hazard ratio (95% CI)

0.43 (0.34, 0.56)

p-value

<0.0001a

Objective Response Rate (ORR)

34%

9%

(95% CI)

(28, 41)

(5, 13)

Complete response rate

4%

1%

Partial response rate

30%

8%

Table Key:

n: number;

CI: confidence interval;

a: p-value is compared with the allocated alpha of 0.0021 for this interim analysis.

The authors claim that at the time of the analysis, 88% (63/72) of the Opdivo® treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. (52) The trial had been stopped early as the evidence was showing the overall survival was superior in the Opdivo® arm when compared to the control/dacarbazine arm. As a result, the patients were unblinded; those patients in the control arm were then allowed to receive Opdivo®. Results of those patients have not been published as yet. (20) However, this study was the basis for the November 2015 FDA-approval and label change.

Small-Cell Lung Cancer (SCLC)

In 2017, the NCCN added treatment of relapsed SCLC with a combination of Yervoy™ and Opdivo®, which was based on a recent Phase 1/2 study published by Antonia, et al., discussed earlier in this Rationale. (34)

Non-Small Cell Lung Cancer (NSCLC)

A second trial (CHECKMATE-063) presented to the American Society of Clinical Oncology late in 2014 by Penrod et al. was utilized by the FDA as part of their priority review program to expand approval to include squamous NSCLC. (20, 54) The expanded approval was completed 3-months prior to the initial goal date by both the FDA and manufacturer as a combined early submission and review late in December 2014. The CHECKMATE-063 was randomized (Opdivo® group versus docetaxel; 1:1), open-label study enrolling 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. (54) This study included patients regardless of the PD-L1 status. The first tumor assessments were conducted at 9-weeks after randomization and continued every 6-weeks thereafter. The outcome was evaluated using RECIST v1.1. (40) At approximately 11-months of follow-up, the objective response rate was 15% (95% CI: 8.7, 22.21). The estimated 1-year survival was 41% (95% CI: 6.05, 10.91). Historically the expected 1-year survival rate for third-line squamous NSCLC patients is approximately 5.5% to 18%, which is based upon prior studies. (54)

The third trial discussed on the FDA approved label was the study used by the NCCN to make their recommendation of adding Opdivo® as an added treatment option for patients with NSCLC. (6) Rizvi et al. completed a single-arm trial for 117 patients that had progressed after having received a platinum-based therapy and at least 1 additional systemic treatment regimen, some of which had as many as 4 prior treatments. (55) This study included patient regardless of their PD-L1 status. As with the previous discussed above, the objective response rate was based upon RECIST v1.1 (41), which as 15% (95% CI: 9, 22), all were partial responses. The median time to onset of response was 3.3-months. Duration of response ranged from 1.9+ to 11.5+ months for 13 of 17 patients; 10 of these 17 patients had durable response of 6-months or longer. The authors concluded that the data supported the use of Opdivo® for first-line and second-line treatment is effective for squamous NSCLC.

The October 2015 FDA-approval of Keytruda® preceded the expansion of Opdivo® to treat patients diagnosed with non-squamous NSCLC, as Opdivo® also targets the cellular pathway known as PD-1/PD-L1. (20) This change was based upon a randomized, open-label, international Phase 3 study reported on by Borghaei, et al. (56) Patients diagnosed with non-squamous NSCLC that had progressed during or after platinum-based chemotherapy. The 2 arm 1:1 study assigned the 582 patients to either Opdivo® at a dose of 3 mg/kg every 2-weeks (N=292) or docetaxel at a dose of 75 mg/m2 every 3-weeks (N=290). According to the FDA, appropriate prior target therapy for patients with known sensitizing EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) translocation were allowed. (20) Table 12 demonstrates the statistically significant improvements in overall survival for the Opdivo® arm.

Table 12. Efficacy Results of Overall Survival and Progression Free Survival Improvements Opdivo® versus Docetaxel (20, 56)

Endpoints

Opdivo® (N=292)

Docetaxel (N=290)

Overall Survival

Deaths (%)

190 (65%)

223 (77%)

Median (months)

12.2

9.4

(95% CI)

(9.7, 15.0)

(8.0, 10.7)

p-valuea,b

0.0015

Hazard ratio

0.73

(95% CI)c

(0.60, 0.89)

Objective Response Rate

56 (19%)

36 (12%)

(95% CI)

(15, 24)

(9, 17)

p-valued

0.02

Complete response

4 (1.4%)

1 (0.3%)

Partial response

52 (18%)

35 (12%)

Median duration of response (months)

17

6

Progression-Free Survival

Disease progression of death (%)

234 (80%)

245 (84%)

Median (months)

2.3

 

p-valuea

0.39

Hazard ratio

0.92

(95% CI)

(0.77, 1.11)

Table Key:

N: number;

CI: confidence interval;

a: based on stratified log-rank test;

b: p-value is compared with 0.0408 of the allocated alpha for this interim analysis;

c: based on a stratified proportional hazards model;

d: based on the stratified Cochran-Mantel-Haenszel test.

As shown above in Table 12, the median overall survival for those treated with Opdivo® was 12.2 months. At 1-year for the same study arm, 51%, followed by 39% at 18-months. The same intervals for the docetaxel arm were 9.4-months, 39 % at 1-year, with 23% at the 18-month evaluation. The study authors concluded that among patients with advanced non-squamous NSCLC that had progressed during or after platinum-based chemotherapy, the overall survival was longer when treated with Opdivo® than with docetaxel. (56)

Malignant Pleural Mesothelioma (MPM)

In 2017, the NCCN added treatment of MPM with a combination of Opdivo® and Yervoy™, which was based on the recent ongoing French IFCT-1501 MAPS2 (Intergroupe Francophone de Cancérologie Thoracique [French Cooperative Thoracic Intergroup]-1501 malignant pleural mesothelioma patients) randomized Phase 2 trial published by Scherpereel et al., discussed earlier in this Rationale. (35, 36)

Renal Cell Carcinoma (RCC)

The FDA based their approval of Opdivo® to treat advanced RCC following prior treatment with anti-angiogenic therapy on an open-label study from Motzer et al., the CHECKMATE-025 trial (20, 57) A total of 821 patients were randomized (1:1 ratio) to receive Opdivo® or everolimus for advanced clear-cell RCC, despite prior treatment with 1 or 2 regimens of anti-angiogenic therapy, such as vascular endothelial growth factors. The patients had to have a Karnofsky performance score of 70%. The first tumor assessment was done at 8-weeks following randomization and continued every 8-weeks thereafter for the first year. Following 1-year, assessments were done every 12-weeks until disease progression or treatment discontinuation, whichever occurred later.

The major efficacy outcome measure was overall survival, which for this study was 25.0-months (95% CI, 21.8 to not estimable). (20, 57) Table 13 provides the efficacy results from this open-label trial, which includes the confirmed objective response rates. The trial demonstrated a statistically significant improvement in overall survival for patients treated with Opdivo®.

Table 13. Efficacy Results (20, 57)

Endpoints

Opdivo® (n=410)

Everolimus (n=411)

Overall Survival

 

Events (%)

183 (45)

215 (52)

Median, months (95% CI)

25.0 (21.7, NE)

19.6 (17.6, 23.1)

Hazard ratio (95% CI)

0.73 (0.60, 0.89)

p-value

<0.0018a

Confirmed Objective Response Rate

(95% CI)

21.5% (17.6, 25.8)

3.9% (2.2. 6.2)

Median duration of response in months (95% CI)

23.0 (12.0, NE)

13.7 (8.3, 21.9)

Median time to onset of confirmed response in months (min, max)

3.0 (1.4, 13.0)

3.7 (1.5, 11.2)

Table Key:

n: number;

CI: confidence interval;

NE: not estimable;

min: minimum;

max: maximum;

a: p-value is obtained from a two-sided log-rank test stratified by Memorial Sloan Kettering Cancer Center risk group, number of prior antiangiogenic therapies, and regions.

The authors concluded that among patients previously treated for advanced RCC, overall survival was longer and fewer more significant adverse events occurred with Opdivo® than with everolimus. There was no cross-over from the everolimus group to the Opdivo® group.

Hodgkin Lymphoma (HL)

The FDA based approval of Opdivo® on 2 studies assessing classical HL (cHL). (20) Opdivo® was evaluated as a single agent in patients with cHL following the failure of autologous HSCT and post-transplantation brentuximab vedotin. The first trial was a single-arm, open-label, multi-center, multi cohort of cHL. (20) (This trial has yet to be published in a peer-reviewed journal.) The second trial was not a single-arm, but rather a dose escalation study. (20, 58)

According to the FDA, both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN (upper limit of normal), creatinine clearance less than 40 mL/min, prior allogeneic HSCT, or chest irradiation within 24-weeks. (20) In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received 3 mg/kg of Opdivo® administered intravenously over 60-minutes every 2-weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted. Efficacy was evaluated by objective response rate as determined by an independent radiographic review committee. Additional outcome measures included duration of response. Efficacy was evaluated in 95 patients in both trials combined who had received brentuximab vedotin after failure of autologous HSCT. The median age was 37 years (range: 18 to 72). The majority were male (64%) and white (87%). Patients had received a median of 5 prior systemic regimens (range: 3 to 15).

Results are shown in Table 14. Patients received a median of 17 doses of Opdivo® (range 3 to 48), with a median duration of therapy of 8.3-months (range 1.9 to 24 months). (20)

Table 14. Efficacy in cHL after Autologous HSCT with Adcetris® (20)

Endpoints

Both Trials (n = 95 patients)

Objective Response Rate, n (%) a (95% CI)

62 (65%) (55, 75)

Complete Remission Rate (95% CI)

7 (7%) (3, 15)

Partial Remission Rate (95% CI)

55 (58%) (47, 68)

Median Duration of Response (months) (95% CI) Range

8.7 (6.8, NE) 0.0+, 23.1+

Median Time to Response (months) Range

2.1 0.7, 5.7

Table Key:

n: number.

CI: confidence interval.

NE: not evaluated

a: Per 2007 revised International Working Group criteria.

Head and Neck Squamous Cell Cancers (HNSCC)

The FDA approval for Opdivo® was based upon on an open-label clinical trial of 361 patients with metastatic or recurrent HNSCC who had experienced disease progression during or within 6 months of receiving platinum-based therapy. (20) While not published as of August 17, 2017, trial 9 was randomized (2:1), 240 patients were given Opdivo® and 121 patients were given the investigators’ choice (45% received docetaxel, 43% received methotrexate, and 12% received cetuximab). The first tumor assessments were conducted 9-weeks after randomization and continued every 6-weeks thereafter. The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were progression-free survival and objective response rate.

Outcomes summary for HNSCC treatment with Opdivo® displays survival results in Table 15.

Table 15. Overall Survival of Trial 9 (20)

Endpoint

Opdivo®

Number of patients = 240

Investigator’s Choice

Number of patients = 121

Overall Survival (OS)

   

Deaths (%)

133 (55%)

85 (70%)

Median (months) (95% CI)

7.5 (5.5, 9.1)

5.1 (4.0, 6.0)

Hazard ratio (95% CI)a

0.70 (0.53, 0.92)

p-valueb,c

0.0101

Table Key:

CI: Confidence Interval;

a: Based on stratified proportional hazards model;

b: Based on stratified log-rank test;

c: p-value is compared with 0.0227 of the allocated alpha for this interim analysis.

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the study population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative HNSCC, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PDL1 positive HNSCC, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio (HR) for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.- and 5.8-months for the Opdivo® and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7- and 4.6-months for the Opdivo® and chemotherapy arms, respectively, in the PD-L1 positive HNSCC subgroup.

Bladder Cancer (Urothelial Carcinoma)

The clinical trial used for the FDA-approval was documented in the FDA-approved label. (20) The study, described below from the FDA-approved label, has yet to be published.

In Trial 10, 270 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12-months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen were treated with Opdivo®.(20) Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received an intravenous infusion of 3 mg/kg of Opdivo® every 2-weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8-weeks for the first 48 weeks and every 12-weeks thereafter. Major efficacy outcome measures included confirmed objective response rate as assessed by independent radiographic review committee using RECIST v1.1 (41) and duration of response.

The median age was 66 years (range 38 to 90), 78% were male, 86% of patients were white. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.

Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients, were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed objective response rate in all patients and the two PD-L1 subgroups are summarized in Table 16. (20) Median time to response was 1.9-months (range; 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the objective response rate was 23.4% (95% CI: 14.5%, 34.4%).

Table 16. Efficacy of Trial 10 (20)

Endpoints

All Patients

PD-L1 <1%

PD-L1 ≥1%

N=270

N=146

N=124

Confirmed Objective Response Rate,

n (%) (95% CI)

53 (19.6%) (15.1, 24.9)

22 (15.1%) (9.7, 21.9)

31 (25.0%) (17.7, 33.6)

Complete Response Rate

7 (2.6%)

1 (0.7%)

6 (4.8%)

Partial Response Rate

46 (17.0%)

21 (14.4%)

25 (20.2%)

Median Duration of Responsea (months) (range)

10.3

(1.9+, 12.0+)

7.6

(3.7, 12.0+)

NE

(1.9+, 12.0+)

Table Key:

PD-L1: Programmed death receptor-1 ligand;

N/n: number;

CI: confidence interval;

NE: not estimable;

a: Estimated from the Kaplan-Meier Curve.

Microsatellite Instability-High (MSI-H) Colorectal Cancer (CRC)

The efficacy of Opdivo® was evaluated for CRC and presented to the FDA for approval. (20, 59) Patients diagnosed with MSI-H or dMMR metastatic CRC who had disease progression during, after, or were intolerant to, prior treatment with 1 of several agents. The CHECKMATE-142 trial was published by Overman et al. in 2017, as an open-label, multi-center, Phase 2 study. (20, 60) The 74 adult patients had received 3 or more prior treatments before receiving Opdivo®. Opdivo® was given every 2-weeks until disease progression, death, unacceptable toxic effect, or withdrawal from the study. At the median follow up of 12-months, 51 patients had disease control for 12-weeks or longer. Table 17 provides the efficacy results of the CHECKMATE-142 trial. (20, 60)

Table 17. Efficacy of the CHECKMATE-142 Trial (20, 60)

Endpoint

All Patients

(Number = 74)

Prior Treatment

(Number = 53)

Objective Response Rate (95% CI)

24 (32%) (22, 44)

15 (28%) (17, 42)

Complete Remission Rate

2 (2.7%)

1 (1.9%)

Partial Remission Rate

22 (30%)

14 (26%)

Duration of Response (median in months) Range

NR (1.4+, 26.5+)

NR (2.8+, 22.1+)

Table Key:

CI: confidence interval;

NR: not reached;

+: denotes ongoing.

The CHECKMATE-142 study authors concluded that Opdivo® had provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic CRC, and could be a new treatment option for those patients that have been diagnosed. (60)

Ongoing and Unpublished Clinical Trials: Opdivo®

According to the National Cancer Institute (NCI)/ClinicalTrials.gov, there are multiple clinical trials targeting the use of Opdivo®, with or without other pharmaceutical preparations, such as to treat colorectal cancer, pancreatic cancer, gastric cancers, hepatocellular cancer, prostatic cancer, breast cancer, solid organ tumors, small-cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, non-Hodgkin lymphoma, glioblastoma and gliosarcoma, ovarian cancer, HIV associated tumors, etc. Some of the studies listed in ClinicalTrials.gov include Keytruda® in combination with radiation therapy or radiosurgery, including stereotactic radiation therapy.

Professional Guidelines and Position Statements: Opdivo®

National Comprehensive Cancer Network (NCCN) – Melanoma

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 recommendation for first-line or in combination with Yervoy™ for the treatment of unresectable or metastatic melanoma. (4, 25) The 2017 NCCN Drugs & Biologics Compendium recommends Opdivo® as a Category 2A for second-line, subsequent or re-induction therapy to treat unresectable or metastatic disease, for patients with ECOG performance status 0-2.

NCCN – Small-Cell Lung Cancer (SCLC)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for SCLC. (5, 25) The indications included subsequent systemic therapy with Opdivo® for patients with ECOG performance status 0-2 when in combination with Yervoy™.

NCCN – Non-Small-Cell Lung Cancer (NSCLC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 recommendation to treat metastatic NSCLC for patients with ECOG performance scale 0-2 as subsequent therapy following progression on a first-line therapy cytotoxic regiment or as a Category 2A for further progression on other systemic therapy. (6, 25)

NCCN – Malignant Pleural Mesothelioma (MPM)

The 2017 NCCN added treatment with Opdivo® as a Category 2A recommendation for MPM without any qualifications. (7, 25)

NCCN – Renal Cell Carcinoma (RCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 for the treatment of clear cell RCC as the preferred subsequent therapy and a 2A for non-clear cell RCC histology as systemic therapy, when the disease has relapsed or classified as Stage IV. (10, 25)

NCCN – Head and Neck Squamous Cell Cancer(HNSCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation as a single agent for non-nasopharyngeal HNSCC if disease progression on or after platinum containing chemotherapy, which includes newly diagnosed or metastatic disease. (8, 25) For use in newly diagnosed disease or for unresectable locoregional recurrent, the NCCN recommends the patient must meet ECOG performance status 3; however, for initial presentation of metastatic disease or other metastatic indications, the patient must meet ECOG performance status 0-2.

NCCN – Hodgkin Lymphoma (classical HL)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for patients ≥18 years for refractory cHL following prior chemotherapy or as palliative therapy for older adult patients >60 years of age with relapsed or refractory disease. (8, 25)

NCCN – Bladder Cancer (Urothelial Carcinoma)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the treatment, locally advanced, for recurrence post-cystectomy bladder cancer or metastatic disease. (11, 25) Additionally, the NCCN has as a 2A recommendation for the treatment using Opdivo® of urothelial carcinoma found in the urethra, upper genitourinary tract, and prostate.

NCCN – Colorectal Cancer (CRC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the following CRC treatments: (13, 14, 25)

Primary therapy for unresectable metachronous metastases following prior specific adjuvant treatment within last 12 months,

Initial therapy for unresectable advanced or metastatic disease when not appropriate for intensive therapy(s), and

Subsequent therapy for unresectable advance or metastatic disease following prior specific treatment.

Atezolizumab (Tecentriq™)

Late 2016, atezolizumab (Tecentriq™) was approved by the FDA for use in the treatment of patients with locally advanced or metastatic bladder cancer (urothelial carcinoma). (21) The NCCN panel published their Drugs & Biologics Compendium incorporating Tecentriq™, which includes the diagnosis of bladder cancer, and bladder cancer with primary carcinoma of the urethra, upper genitourinary tract tumors, and urothelial carcinoma of the prostate. (26)

Bladder Cancer (Urothelial Carcinoma)

The FDA approval was based upon a multi-center, open-label, 2-cohort trial from Rosenberg et al. that included patients with locally advanced or metastatic urothelial carcinoma. (21, 62) In cohort 2 of Study 1, 310 patients with locally advanced or metastatic urothelial carcinoma, had disease progression during or following a platinum-containing chemotherapy regimen or had disease progression within 12-months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. These patients were then treated with Tecentriq™. The major efficacy outcome measures included confirmed objective response rate, which was 22.0% (95% CI: 12.3%, 34.7%), using the RECIST v1.1 (40) and duration of response. Tumor assessments were done every 9 weeks for the first 54-weeks and every 12-weeks thereafter.

The FDA noted that the median age of the patients in Study 1 was 66 years, 78% were male, 91% were Caucasian, 26% had non-bladder urothelial carcinoma, 76% had visceral metastases, 62% had an ECOG score of 1, and 35% of these patients had a baseline creatinine clearance of <60 mL/min. The platinum-containing chemotherapeutic agents included cisplatin, carboplatin, or other types. Overall results are shown in Table 18. (21, 62)

Table 18. Summary of Efficacy from Cohort 2 of Study 1 (21, 62)

Endpoints

All Patients

PD-L1 Expression Subgroups

N=310

PD-L1 Expression of <5% in ICs1

(N=210)

PD-L1 Expression of ≥5% in ICs1

(N=100)

Number of IRF-assessed Confirmed Responders

46

20

26

Overall Response Rate %

(95% CI)

14.8%

(11.1, 19.3)

9.5%

(5.9, 14.3)

26.0%

(17.7, 35.7)

Complete Response (%)

5.5%

2.4%

12.0%

Partial Response (%)

9.4%

7.1%

14.0%

Median Duration of Response, months (range)

NR

(2.1+, 13.8+)

12.7

(2.1+, 12.7+)

NR

(4.2, 13.8+)

Table Key:

N: Number.

NR: Not reached.

PD-L1: Programmed death receptor-1 ligand.

ICs: Immune cells.

IRF: Independent Review Facility.

CI: confidence interval;

+: Denotes a censored value.

1: PD-L1 expression in tumor-infiltrating immune cells (ICs).

The FDA approved a label change for the treatment of urothelial carcinoma in April 2017. (21) Previously the approved label indications were for the treatment locally advanced or metastatic urothelial carcinoma for patients who have disease progression. The change, based on the same study from Rosenberg et al., now states for treatment of locally advanced or metastatic urothelial carcinoma for patients who are not eligible for cisplatin-containing chemotherapy. (21, 62)

Non-small Cell Lung Cancer (NSCLC)

The FDA approval for Tecentriq™ was based upon on two open-label clinical trials of 1512 patients (Study 2 = 1225 patients, Study 3 = 287 patients) combined with metastatic NSCLC who had experienced disease progression during or after receiving platinum-based therapy. (21)

Study 2 randomized the first 850 patients (primary analysis population), with all eligible patients randomized 1:1. While neither trial was published as of August 15, 2017, both studies stratified eligible patients by PD-L1 expression status in tumor-infiltrating immune cells, by the number of prior chemotherapy regimens, and by histology. Patients were given either Tecentriq™ or docetaxel. Tumor assessment were conducted every 6-weeks for the first 36-weeks, and every 9-weeks thereafter. The major efficacy outcome measure of Study 2 was OS in the primary analysis population (first 850 randomized patients). The major efficacy outcome measure of Study 3 was overall survival. Other efficacy outcome measures for Study 3 included investigator-assessed objective response rates and duration of response per RECIST v1.1. (40)

The results of Study 2 with a median follow up of 21 months are presented in Table 19.

Table 19. Efficacy Results in the Primary Analysis Population from Study 2 (21)

Overall Survival (OS)

Tecentriq™

(n=425)

Docetaxel

(n=425)

Death (%)

271 (64%)

298 (70%)

Median (months)

13.8

9.6

(95% CI)

(11.8, 15.7)

(8.6, 11.2)

Hazard Ratio1

(95% CI)

0.74 (0.63, 0.87)

p-value2

0.0004

Table Key:

CI: confidence interval;

1: Stratified by PD-L1 expression in tumor infiltrating immune cells, the number of prior chemotherapy regimens, and histology;

2: Based on the stratified log-rank test.

Ongoing and Unpublished Clinical Trials:

Currently, there are 146 ongoing recruiting/active and/or unpublished completed trials, listed in ClinicalTrials.gov, focused on Tecentriq™, with or without other pharmaceutical preparations to treat solid tumors, small cell lung cancer, metastatic melanoma, breast cancer, non-small cell lung cancer, renal cell carcinoma, peritoneal cancer, acute myeloid leukemia, Hodgkin lymphoma, Non-Hodgkin’s lymphoma, multiple myeloma, chronic lymphocytic leukemia, sarcoma, and colorectal cancer. Some of the studies listed in Clinical Trials.gov include Tecentriq™ with other pharmaceuticals, including Avastin®.

Professional Guidelines and Position Statements: Tecentriq™

National Comprehensive Cancer Network (NCCN) – Non-Small-Cell Lung Cancer (NSCLC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Tecentriq™ as a Category 1 recommendation for progression of NSCLC metastatic disease following a first-line cytotoxic regimen. (6, 26) Additionally, the NCCN has as a 2A recommendation for the treatment of metastatic disease that has further progressed while on other systemic therapy. Both recommendations include the patient having met the ECOG performance status 0-2 when using Tecentriq™ as subsequent therapy.

NCCN – Bladder Cancer (Urothelial Carcinoma)

The 2017 NCCN panel included Tecentriq™ as a standard regimen for second-line systemic therapy for locally advanced or metastatic bladder cancer with a category 2A recommendation. (10, 26) The indications include bladder cancer and/or bladder cancer with primary carcinoma of the urethra, upper genitourinary tract tumor, or urothelial carcinoma of the prostate.

Overall Summary of Evidence

The evidence is insufficient to support the use of Yervoy™, Keytruda®, Opdivo®, or Tecentriq™ beyond their U.S. Food and Drug Administration-approved indications, by incorporating the National Comprehensive Cancer Network (NCCN) 1 and 2A recommendations, as outlined in the NCCN Guidelines and the Drugs & Biologics Compendium, for specific conditions indicated in this medical policy coverage. Therefore, the use of checkpoint-blocking/inhibitor agents for other indications are considered experimental, investigational and/or unproven including, but are not limited to, breast cancer, chronic myeloid leukemia, non-Hodgkin lymphoma, multiple myeloma, myelodysplastic syndrome, mycosis fungoides, Sézary syndrome, and Stage I or Stage II melanoma.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

C9483, J9022, J9228, J9271, J9299

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

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Policy History:

Date Reason
4/30/2018 Document became inactive.
10/15/2017 Document updated with literature review. Based on the U.S. Food and Drug Administration (FDA)-approved label indications and the National Comprehensive Cancer Network recommendations for all checkpoint inhibitors, numerous coverage changes were added, changed, or removed for Yervoy™, Keytruda®, Opdivo®, and Tecentriq™. The medically necessary coverage indications added include the following conditions: malignant pleural mesothelial (MPM) treated with Yervoy™; MPM, bladder cancer (urothelial carcinoma), Merkel cell carcinoma, solid organ tumors, and colorectal cancer (CRC) treated with Keytruda®; and MPM and CRC treated with Opdivo®. The following medically necessary coverage criteria changed: for Yervoy™ - melanoma and small-cell lung cancer (SCLC); for Keytruda® - melanoma, non-small-cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), and Hodgkin lymphoma (HL): for Opdivo® - melanoma, SCLC, NSCLC, renal cell carcinoma (RCC), HNSCC, and bladder cancer (urothelial carcinoma); and for Tecentriq™ - NSCLC and bladder cancer (urothelial carcinoma). For the experimental, investigational and/or unproven coverage statement, removed the following indications for these checkpoint inhibitors: Keytruda® - bladder cancer (urothelial carcinoma), MCC, solid tumors, and CRC; and, Opdivo® - CRC.
6/15/2017 Document updated with literature review. The following coverage was changed for Opdivo® – moved from the experimental, investigational and/or unproven listing to the medically necessary coverage statement with criteria for urothelial carcinoma, a form of bladder cancer. The following coverage criteria was removed for Tecentriq™: “single agent first-line therapy for clinical Stage T4b or node-positive T2-T4a locally advanced urothelial carcinoma”; and “subsequent systemic therapy for recurrence following surgical intervention or metastatic urothelial carcinoma”. The following coverage criteria was added for Tecentriq™ for the treatment of locally advanced or metastatic urothelial carcinoma: “single agent therapy for locally advanced/metastatic urothelial carcinoma when patient is not eligible for cisplatin-containing chemotherapy”; or “single agent therapy for locally advanced/metastatic urothelial cancer when patients has disease progression during or following any platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy”.
1/15/2017 Document updated with literature review. The following coverage was changed according to the U.S. Food and Drug Administration (FDA), listed by agent: 1) Opdivo® - moved from the experimental, investigational and/or unproven listing to the medically necessary coverage statement with criteria for head and neck squamous cell cancer; 2) Opdivo® - added “and if pembrolizumab (Keytruda®) not previously given” to the non-small cell lung cancer single agent indication; and, 3) Tecentriq™ – moved from the experimental, investigational and/or unproven listing to the medically necessary coverage statement with criteria for non-small cell lung cancer.
10/1/2016 Document updated with literature review. Coverage statements reorganized with the following indications with specific criteria added according to the U.S. Food and Drug Administration (FDA) and/or National Comprehensive Cancer Network Compendium (NCCN), listed by agent: 1) Yervoy™ - small cell lung cancer; 2) Keytruda® - head and neck cancer, Hodgkin lymphoma; 3) Opdivo® - small cell lung cancer, Hodgkin lymphoma; and Tecentriq™ - urothelial carcinoma. The following was added for melanoma and using Yervoy™: brain metastasis from primary melanoma tumor. The following was added for renal cell carcinoma and using Opdivo®: “metastatic” and “clear-cell” added to medically necessary statement. The newly FDA approved antibody blocking Tecentriq™ (atezolizumab) was added as medically necessary as a single-agent for first-line therapy for clinical Stage T4b or node-positive T2-T4a locally advanced urothelial carcinoma and subsequent systemic therapy for recurrence following surgical intervention or metastatic urothelial carcinoma. For each of the agents, added wording regarding single agent use, subsequent therapy, and/or U.S. Food and Drug Administration approved combination of agent(s) utilization. Eastern Cooperative Oncology Group (ECOG) Performance Scale scoring was added to the coverage section to assist in determining medical necessity when patient meets 0-2 on the performance scale. For each of the agents, added indications were added to experimental, investigational and/or unproven listing. The title changed from Checkpoint-Blocking Antibody Treatment for Select Cancers.
1/1/2016 Document updated with literature review. The following coverage statements were added for Opdivo® only: 1) Opdivo® may be considered medically necessary as a single agent for patients with BRAF V600 wild -type unresectable or metastatic melanoma; and 2) Opdivo® may be considered medically necessary for patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. Coverage unchanged for Yervoy™ and Keytruda®.
12/15/2015 Document updated with literature review. The following was changed for Yervoy™: Yervoy™ may be considered medically necessary for adjuvant treatment (See NOTE 1) of patients who are at risk of developing recurrence of Stage III melanoma after surgery. NOTE 1: Adjuvant treatment for recurrence risk may be given when diagnosed with cutaneous melanoma with pathologic involvement of regional lymph nodes > 1 mm who have undergone complete resection, including total lymphadenectomy. The following was changed for Opdivo®: Opdivo® may be considered medically necessary for patients with metastatic (squamous and non-squamous [see NOTE 5]) NSCLC that has progressed further or follows platinum-based chemotherapy. NOTE 5: Second-line therapy for non-squamous NSCLC using Opdivo® may include those patients with EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) genomic tumor aberrations, showing disease progression and following FDA approved therapies, e.g., docetaxel (Taxotere®).
11/4/2015 Document updated with literature review. The following was changed for Keytruda® only: Keytruda® may be considered medically necessary for patients with metastatic squamous NSCLC whose tumors express PD-L1 ( programmed death receptor-1 ligand) as determined by the U.S. Food and Drug Administration (FDA)-approved test (see NOTE 3) and that has progressed further or follows platinum-based chemotherapy. NOTE 3: Prior to administration of this agent, the FDA is requiring PD-L1 testing, such as using the “IHC 22C3 pharmDx Kit”.
7/1/2015 Document updated with literature review. The following was changed to coverage: Keytruda® that may be considered medically necessary only following treatment with Yervoy™ TO may be considered medically necessary as a first-line therapy. The following added to coverage: 1) Opdivo® may be considered medically necessary as a first-line treatment option for patients with unresectable or metastatic melanoma and a BRAF inhibitor (such as vemurafenib or dabrafenib) if the BRAF V600 mutation is positive; 2) Opdivo® may be considered medically necessary for patients with metastatic squamous non-small cell lung cancer that has progressed further or follows platinum-based chemotherapy; and 3) Opdivo® is considered experimental, investigational and/or unproven for all other indications, including, but not limited to, Stage I or Stage II melanoma, squamous cell cancer, Merkel cell cancer, small-cell lung cancer, breast cancer, renal cell cancer, urothelial carcinoma, colorectal cancer, solid organ tumors, head and neck cancer, NHL, Hodgkin’s lymphoma, myelodysplastic syndrome, multiple myeloma, mycosis fungoides, and Sézary syndrome. Coverage unchanged for Yervoy™. Title changed from Monoclonal Antibody Treatment for Melanoma.
1/1/2015 Document updated with literature review. The following was added: 1) Pembrolizumab (Keytruda®) may be considered medically necessary for as step therapy for patients with unresectable or metastatic melanoma, disease progression following treatment with ipilimumab (Yervoy™), and when the BRAF V600 (a BRAF inhibitor) mutation is positive; and 2) Pembrolizumab (Keytruda®) is considered experimental, investigational and/or unproven for all other indications, including, but not limited to, Stage I or Stage II melanoma, squamous cell cancer, Merkel cell cancer, non-small-cell lung cancer, small-cell lung cancer, breast cancer, renal cell cancer, urothelial carcinoma, colorectal cancer, solid organ tumors, head and neck cancer, NHL, Hodgkin’s lymphoma, myelodysplastic syndrome, multiple myeloma, mycosis fungoides, and Sézary syndrome. Title changed from - Ipilimumab (Yervoy™). CPT/HCPCS code(s) updated.
4/1/2014 Document updated with literature review. Coverage unchanged.
5/15/2012 Document updated with FDA approved label dosing information and literature review. The following diagnoses were added as examples of experimental, investigation and unproven indications: chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma (NHL), breast cancer, solid organ tumors, urothelial carcinoma, and metastatic renal cancer.
1/1/2012 New medical document. Ipilimumab (Yervoy™) may be considered medically necessary for the treatment of patients with the histological diagnosis of Stage III or Stage IV unresectable or metastatic melanoma. Ipilimumab (Yervoy™) is considered experimental, investigational and unproven for all other indications, including, but not limited to, Stage I or Stage II melanoma, prostate cancer, and non-small cell lung cancer.

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