Medical Policies - Prescription Drugs


Necitumumab (Portrazza)

Number:RX502.041

Effective Date:06-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

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, 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.

Necitumumab (Portrazza) may be considered medically necessary for the treatment of metastatic squamous non-small cell lung cancer (NSCLC) when administered:

• As a first-line treatment for adult patients, age 18 or older; AND

• In combination with gemcitabine and cisplatin.

Necitumumab (Portrazza™) is considered experimental, investigational and/or unproven for all other indications, including but not limited to the treatment of non-squamous non-small cell lung cancer (NSCLC).

Description:

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new diagnoses and 158,040 deaths in 2015. The most common type of lung cancer, non-small cell lung cancer (NSCLC), is further divided into two main types named for the kinds of cells found in the cancer – squamous cell and non-squamous cell (which includes adenocarcinoma). (1)

Necitumumab (Portrazza) is a recombinant human IgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. (2) Necitumumab is a monoclonal antibody that blocks activity of EGFR, a protein commonly found on squamous non-small cell lung tumors. (1)

Regulatory Status

In November 24, 2015, the U.S. Food and Drug Administration (FDA) approved Necitumumab (Portrazza) as a first-line treatment when used in combination with gemcitabine and cisplatin. Necitumumab was not found to be an effective treatment for patients with non-squamous NSCLC. The most common side effects include dermatologic conditions (e.g. rash, dermatitis acneiform, pruritus and erythema), severe hypomagnesemia, and venous and arterial thromboembolic events (VTE and ATE). Necitumumab black box warning includes cardiopulmonary arrest, sudden death and severe hypomagnesemia. The label instructs providers to closely monitor serum electrolytes (i.e. magnesium, calcium, potassium) prior to each dose of Necitumumab and for 8 weeks following completion of treatment. The safety and effectiveness of Necitumumab not been established in pediatric patients. (2)

Rationale:

This medical policy was originally created in March 2016 and is based on the Food and Drug Administration (FDA) labelled indications and the available published literature. Following is a summary of the key literature through February 28, 2018.

Squamous non-small-cell lung cancer (NSCLC)

In 2015, Thatcher et al. compared treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous NSCLC. The study was an open-label, randomized phase 3 study at 184 sites in 26 countries. The following patients were eligible for inclusion: a) patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous NSCLC; b) eastern Cooperative Oncology Group (ECOG) performance status of 0-2; c) adequate organ function; d) patient had not received previous chemotherapy for their disease. Enrolled patients were randomly assigned 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplatin chemotherapy with or without necitumumab according to a block randomization scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously (IV) over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered IV over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered IV over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomization was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne like rash a class effect of epidermal growth factor receptor (EGFR) antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analyzed by intention to treat. Between January 7, 2010, and February 22, 2012, they enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival (OS) was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 115 months [95% CI 104-126]) verses 99 months [89-111]; stratified hazard ratio 084 [95% CI 074-096; p=001]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients verses 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group verses six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] verses one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, they noted that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. The study concluded that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves OS in patients with advanced squamous NSCLC and represents a new first-line treatment option for this disease. (3)

In 2016, Reck et al. (4) completed a phase 3 trial evaluating the effect of necitumumab in combination with gemcitabine plus cisplatin on patient tolerability and quality of life. The SQUIRE Trial followed a total of 1093 patients with stage IV squamous NSCLC that were randomized 1:1 to receive necitumumab (800 mg absolute dose IV) plus gemcitabine-cisplatin (gemcitabine = 1250 mg/m(2) IV on days 1 and 8; cisplatin = 75 mg/m(2) IV on day 1) or gemcitabine-cisplatin alone every 21 days for up to 6 cycles. Patients receiving necitumumab plus gemcitabine-cisplatin without disease progression continued necitumumab until progression. Quality of life (QOL) was measured by Eastern Cooperative Oncology Group (ECOG) performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five-Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Most patients in both study arms similarly maintained a ECOG performance status and comparable LCSS and European Quality of Life Five-Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the necitumumab plus gemcitabine-cisplatin arm continued single-agent necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the necitumumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin arms, respectively. Hospitalizations were slightly higher with necitumumab plus gemcitabine-cisplatin (36.4%) than with gemcitabine-cisplatin (34.0%). The study concluded that the addition of necitumumab to gemcitabine-cisplatin was well tolerated, did not negatively affect health related QOL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower health related QOL.

Other Indications

Based on the FDA label, there is a lack of efficacy for necitumumab (Portrazza) for the treatment of patients with metastatic non-squamous NSCLC. This was determined in a randomized, open-label, multicenter trial. The study was closed prematurely after 633 patients were enrolled, due to increased incidence of death and thromboembolic events in the Portrazza arm. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive Portrazza plus pemetrexed and cisplatin or pemetrexed and cisplatin alone. Stratification factors were smoking status (non-smokers versus light smokers versus smokers), ECOG performance status (0 -1 versus 2), histology (adenocarcinoma/large cell versus others), and geographic region. Portrazza (800 mg, days 1 and 8 of each 3-week cycle) was administered prior to pemetrexed and cisplatin. Patients demonstrating at least stable disease on Portrazza plus pemetrexed and cisplatin were to continue Portrazza as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy. Of the 633 patients, 315 were randomized to Portrazza plus pemetrexed and cisplatin arm and 318 in the pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93% were caucasian and 94% had ECOG performance status (PS) 0 or 1. More than 75% were smokers and 89% had adenocarcinoma histology. The main efficacy outcome was overall survival (OS). Progression-free survival (PFS) and overall response rate were also assessed. The addition of Portrazza to pemetrexed and cisplatin did not improve the OS [HR=1.01; 95% confidence interval (CI) (0.84, 1.21); p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the Portrazza plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm). (5)

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this medical policy are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02496663 (6)

Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent NSCLC Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor.

82

June 30, 2018

(recruiting)

NCT03054038 (7)

Afatinib and Necitumumabin Patients with EGFR Mutation Positive Advanced or Metastatic NSCLC.

60

March 2019

(recruiting)

Table key: EGFR: epidermal growth factor receptor; NCT: national clinical trial: NSCLC: Non-Small Cell Lung Cancer.

Professional Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The NCCN Clinical Practice Guidelines for NSCLC (v3.2018) states, “For pts with squamous NSCLC and NSCLC NOS, panel members deleted cisplatin, gemcitabine and Necitumumab regimen from the NCCN guidelines. This decision reflects the fact that the NCCN panel feels the addition of Necitumumab to the regimen is not beneficial based on toxicity, cost, and limited improvement in efficacy when compared to cisplatin, gemcitabine. A phase 3 randomized trial only showed a slight improvement in overall survival (11.5 months vs 9.9 months) The stratified HR was only 0.84. in addition, there were more grade 3 or higher adverse events on patients receiving the necitumumab regimen (388 of 538 patients than in patients receiving only gemcitabine and cisplatin (33 of 541). Although it has been suggested that adding necitumumab to gemcitabine/cisplatin adds value and cost effectiveness, the NCCN panel does not agree” (8)

Summary of Evidence

Necitumumab (Portrazza) is approved by the U.S. FDA as a first-line treatment when used in adult patients in combination with gemcitabine and cisplatin for metastatic squamous non-small cell lung cancer (NSCLC). There are no studies available for the use of necitumumab in the pediatric population. Necitumumab is actively being studied for head and neck cancer and colon cancer. To date, there are no studies that support the safety and efficacy for the use of necitumumab for any other indication other than metastatic squamous NSCLC. After the review of the FDA label, NCCN guidelines and available published literature, the use of Necitumumab (Portrazza) is supported by the FDA labelled indications.

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

J9999

HCPCS Codes

J9295, [Deleted 1/2017: C9475]

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>.

References:

1. FDA – FDA NEW Release: FDA Approves Portrazza to Treat Advanced Squamous Non-Small Cell Lung Cancer. Food and Drug Administration (November 2015). Available at <http://www.fda.gov> (accessed February 28, 2018).

2. FDA –Portrazza (Necitumumab) – Product Label. Food and Drug Administration (November 2015). Available at <http://www.fda.gov> (accessed February 28, 2018).

3. Thatcher N, Hirsh FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncology. 2015; 16 (7):763-774. PMID 26045340.

4. Reck M, Socinski M, Luft A, et al. The Effect of Necitumumab in Combination with Gemcitabine plus Cisplatin on Tolerability and on Quality of Life: Results from the Phase 3 SQUIRE Trial. Thorac Oncol. 2016 Jun; 11(6):808-18. PMID 26980471

5. Paz-Ares L, Mexger J, Ciuleanu TE, et al. Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): an open-label, randomised, controlled phase 3 study. Lancet Oncology. 2015; 16(3):328-37. PMID 25701171.

6. Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-Small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor (NCT02496663). Available at: <https://clinicaltrials.gov> (accessed March 29, 2018).

7. Afatinib and Necitumumab in Patients with EGFR Mutation Positive Advanced or Metastatic Non-Small Cell Lung Cancer (NCT03054038) Available at: <https://clinicaltrials.gov> (accessed March 29, 2018).

8. National Comprehensive Cancer Network (NCCN). NCCN Guidelines: Non-Small Cell Lung Cancer (version 3.2018). Available at: <https://www.nccn.org> (accessed February 28, 2018).

Policy History:

Date Reason
6/1/2018 Document updated with literature review. Coverage unchanged. Added reference 4.
4/1/2017 Reviewed. No changes.
4/1/2016 New medical document. 1) Necitumumab (Portrazza ™ ) may be considered medically necessary for the treatment of metastatic squamous non-small cell lung cancer (NSCLC) when administered as a first-line treatment for adult patients, age 18 or older; and in combination with gemcitabine and cisplatin. 2) Necitumumab (Portrazza ™ ) is considered experimental, investigational and/or unproven for all other indications, including but not limited to the treatment of non-squamous non-small cell lung cancer (NSCLC).

Archived Document(s):

Title:Effective Date:End Date:
Necitumumab (Portrazza)04-01-201705-31-2018
Necitumumab (Portrazza)04-01-201603-31-2017
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