BCBSNJ Medical Policy for - (Drugs) Policy Number

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Horizon BCBSNJ
Uniform Medical Policy Manual	Section:	Drugs
	Policy Number:	036
	Effective Date:	07/13/2020

	Original Policy Date:	04/22/2005
	Last Review Date:	06/09/2020
	Date Published to Web:	04/02/2012

Subject:
Vascular Endothelial Growth Factor Inhibitor and Human Epidermal Growth Factor Receptor Inhibitor

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Colorectal cancer is the second leading cause of cancer-related deaths behind lung cancer in the United States. Metastatic disease is present at diagnosis in 30% of patients and approximately 50% of early-stage patients will eventually develop metastatic disease. Standard treatment of colorectal cancer has been fluorouracil-based therapy. In recent years newer agents including capecitabine, irinotecan, and oxaliplatin have been added to the management of patients with advanced disease.

Four angiogenesis-inhibiting drugs were approved that target growth factor receptors expressed in this disease state.

Erbitux (cetuximab) is a recombinant human/mouse monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR). Erbitux was approved by the FDA in 2004 for the treatment of patients with metastatic colorectal carcinoma who are refractory to irinotecan. Erbitux binds to EGFR and blocks activation of receptor-associated kinases leading to cell growth inhibition and apoptosis. On March 1, 2006, the FDA additionally approved Erbitux to treat patients with advanced squamous cell cancer of the head and neck. In 2007, Erbitux received FDA approved for the treatment of patients with metastatic colorectal cancer who failed both irinotecan- and oxaliplatin-based regimens or in patients who are intolerant to irinotecan-based regimens. On November 7, 2011, the FDA approved Erbitux for use in combination with chemotherapy for the first-line treatment of metastatic head and neck cancer. The safety and effectiveness of Erbitux for the indication of metastatic head and neck cancer is based on the results of a multi-center clinical study — the Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) trial. Data show that when combined with cisplatin-based chemotherapy, Erbitux improved overall survival, compared with chemotherapy alone. In 2012 the FDA granted approval to Erbitux for use in combination with FOLFIRI (irinotecan, 5-FU, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer. This approval was based on retrospective analyses in the patient subsets according to K-ras mutation status in tumor samples from patients enrolled in the CRYSTAL trial and in two supportive studies, CA225025 and EMR 62 202-047 (OPUS). The addition of Erbitux to chemotherapy or best supportive care (BSC) resulted in improved survival, progression-free survival, and overall responses rates in the subset with K-ras wild-type tumors; whereas, there was no benefit or potential harm in patients with K-ras mutant tumors.

Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody, which inhibits the biological activity of human vascular endothelial growth factor (VEGF). Avastin binds to VEGF and prevents the interaction of VEGF to its receptors on endothelial cells; hence, blocking the endothelial cell proliferation and new blood vessel formation in in-vitro. Avastin was approved by the FDA in 2004 for first line treatment of patients with metastatic carcinoma of the colon or the rectum when used in combination with 5-fluorouracil based chemotherapy. In October 2006, the FDA approved Avastin for first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer in combination with carboplatin and paclitaxel. In February 2008, the FDA granted accelerated approval for Avastin in combination with paclitaxel chemotherapy for the treatment of chemo-naive patients with metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In May 2009, the FDA granted approval of Avastin for use in glioblastoma, as a single agent, for patients with progressive disease following prior therapy. In July 2009, the FDA granted approval of Avastin for in combination with interferon-alfa for the treatment of renal cell carcinoma. In December 2010, the FDA proposed withdrawing Avastin's indication to treat women with metastatic breast cancer following an expert-panel review of clinical data supporting this indication. The panel concluded that there is not enough evidence that the drug is safe and effective for this indication. The announcement will not have any immediate effect on the approval of Avastin to treat metastatic breast cancer and there will be no change to product labeling. Since the marketing approval remains in effect, patients with breast cancer will still have access to the drug until a final decision has been made. As of January 2011, Genentech has notified the FDA of its request for a Notice of Opportunity for a Hearing regarding the proposed indication removal. On November 18, 2011, the FDA officially removed the Avastin indication for metastatic breast cancer because the drug has not proven to be safe and effective for that indication. In August 2014, Genentech got FDA approved indication for Avastin for persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin OR paclitaxel and topotecan. In November 2014, Avastin was FDA approved for treatment in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan. In December of 2017, the FDA changed this approval to the treatment of recurrent glioblastoma in adults. In June of 2018, Avastin was FDA approved for treatment in patients with epithelial ovarian, fallopian tube or primary peritoneal cancer, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, for stage III or IV disease following initial surgical resection.

Vectibix (panitumumab) is a recombinant humanized IgG2 kappa monoclonal antibody that binds to human EGFR. In 2006, Vectibix was approved for monotherapy by the FDA for the treatment of EGFR-expressing, metastatic colorectal carcinoma when disease is progressing on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy agents. Approval is based on progression-free survival only. In May 2014, Vectibix was also approved for combination therapy with FOLFOX (flurouracil, leucovorin, and oxaliplatin) as first-line therapy for the treatment of EGFR expressing, metastatic colorectal carcinoma. Approval was based on overall survival; progression-free survival and objective response rates were also assessed. In June of 2017,the FDA further defined approval for wild-type RAS metastatic colorectal cancer to be both wild-type KRAS and NRAS, as determined by an FDA-approved test.

Zaltrap (ziv-aflibercept) is a recombinant fusion protein that binds to VEGF-A, VEGF-B, and to PIGF. By binding to receptors Zaltrap can inhibit the binding and activation of their cognate receptors which results in decreased neovascularization and decreased vascular permeability. On August 3, 2012 the FDA approved Zaltrap for use in combination with a FOLFIRI (leucovorin, 5-FU, irinotecan) chemotherapy regimen for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing chemotherapy regimen.

In December of 2004, a new warning regarding the use of Avastin in combination with other chemotherapy was issued which stated that it may increase the risk of arterial thromboembolic events such as cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and other arterial thromboembolic events.

The FDA recommended dose for use as monotherapy is Erbitux is 400 mg/m² intravenous infusion as an initial loading dose followed by the weekly maintenance dose of 250 mg/m² intravenous infusion until disease progression or unacceptable toxicity. Initiate Erbitux one week prior to initiation of radiation therapy. Complete Erbitux administration 1 hour prior to platinum-based therapy with 5-FU.

The FDA recommended dose for Erbitux use in combination with radiation therapy or in combination with platinum-based therapy with 5-FU is initial dose of 400 mg/m2 administered ONCE one week prior to initiation of a course of radiation therapy or on the day of initiation of platinum- based therapy with 5-FU. This is followed by weekly dose of 250 mg/m2 IV infusion for the duration of radiation therapy (6-7 weeks) or until disease progression or unacceptable toxicity when administered in combination with platinum-based therapy with 5-FU. Complete Erbitux administration 1 hour prior to platinum-based therapy with 5-FU.

The FDA recommended dose of Avastin is 5 to 15 mg/kg as intravenous infusion until disease is detected. Therapy should not be initiated for at least 28 days following major surgery and should be discontinued if the patient develops gastrointestinal perforation, wound dehiscence, serious bleeding, severe arterial thromboembolic event, nephritic syndrome, or hypertensive crisis.

The FDA recommended dose of Vectibix is 6 mg/kg as intravenous infusion every 14 days until disease progression.

Worldwide, gastric cancer is the fourth most common malignant disease and the second leading cause of cancer mortality. Standard cytotoxic chemotherapy is typically used as first-line treatment for advanced gastric adenocarcinoma, with median survival ranging from 8 months to 10 months. Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signaling and angiogenesis seem to have an important role in the pathogenesis of gastric cancer. In animal models of gastric adenocarcinoma, VEGFR-2 inhibition has reduced tumor growth and vascularity. In patients with gastric cancer, circulating and tumoral concentrations of VEGF are associated with increased tumor aggressiveness and reduced survival

Cyramza™ (ramucirumab) is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model. Vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2)-mediated signaling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer.

Cyramza™ (ramucirumab) as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum containing chemotherapy.

Cyramza™ (ramucirumab) gained FDA approval on April 21, 2014. FDA approve was based on ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomized, multicenter, placebo-controlled, phase 3 trial. The study randomized 355 patients (2:1), with locally advanced or metastatic gastric cancer into groups treated with Cyramza™ plus best supportive care (BSC) versus placebo plus BSC (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. In November 2014, Cyramza received FDA approval for the treatment of patients with advanced gastric cancer or gastro-esophageal junction adenocarcinoma in combination with paclitaxel, after prior fluoropyrimidine- or platinum-containing chemotherapy. In December 2014, Cyramza received an additional indication for treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy, in combination with docetaxel. For patients with EGFR or ALK genomic tumor aberrations, Cyramza is indicated following disease progression on FDA-approved therapy such as crizotinib, erlotinib, afatinib and ceritinib. On April 24,2015, Cyramza received a fourth indication to be used in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. The prescriber’s information was also update with two additional boxed warning of gastrointestinal perforation and impaired wound healing.

Lung cancer is the leading cause of cancer death in the United States, with an estimated 221,200 new cases and an estimated 158,000 deaths in that will occur in the US in 2015. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for roughly 85-90% of lung cancers. There are three main types of NSCLC: Squamous cell carcinoma, Adenocarcinoma, and Large call carcinoma. Squamous cell carcinomas account for 30% of non-small-cell lung cancers worldwide. There are genetic differences between squamous and non-squamous tumors that influence treatment options and treatment effects.

Portrazza (necitumumab) is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody indicated for the first line treatment of metastatic squamous non-small-cell lung cancer. An earlier trial involving patients with non-squamous NSCLC (INSPIRE), had failed to show a meaningful clinical benefit and was associated with significant drug related toxicity. FDA-approval for necitumumab was confirmed through a single, open-label, phase III study (SQUIRE) in patients with stage IV squamous non-small-cell lung cancer. In SQUIRE it was shown that first-line treatment with necitumumab in combination with gemcitabine and cisplatin significantly improved median overall survival (11.5 vs 9.9 months) and median progression-free survival (5.7 vs 5.5 months) compared with gemcitabine and cisplatin alone in patients with stage IV squamous non-small-cell lung cancer (N=1093). Overall survival rate in necitumumab/gemcitabine/cisplatin group compared with the gemcitabine/cisplatin group was 48% versus 43% at 1 year, and 20% versus 17% at 2 years. Necitumumab also improved median time to treatment failure (4.3 vs 3.6 months) but was associated with a higher rate of adverse events that were grade 3 or higher (72% vs 62%) and serious adverse events (48% versus 38%).

In September of 2017, the FDA approved Mvasi (bevacizumab-awwb), a biologic treatment by the FDA for all Avastin-approved indications, except recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan OR platinum-sensitive in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent. It can be used for treating patients with metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, metastatic renal cell carcinoma and cervical cancer. The dose of bevacizumab-awwb varies depending on the indication. Bevacizumab-awwb binds to VEGF and prevents the interaction of VEGF to its receptor on the surface of endothelial cells. Bevacizumab-awwb is administered by intravenous infusion. The dosage form and strength is 100 mg of bevacizumab-awwb in a 4 mL or 400 mg in a 16 mL vial.

In June 2019, the FDA approved Zirabev (bevacizumab-bvzr), a biosimilar to Avastin (bevacizumab). Zirabev (bevacizumab-bvzr) is FDA approved for five different types of cancers: metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, metastatic renal cell carcinoma and cervical cancer. As per the FDA package insert, Zirabev (bevacizumab-bvzr) is not indicated for adjuvant treatment of colon cancer. Zirabev (bevacizumab-bvzr) is approved for all Avastin-approved indications, except recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer that is platinum-resistant in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan OR platinum-sensitive in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent. The dose of Zirabev (bevacizumab-bvzr) varies depending on the indication. Zirabev (bevacizumab-bvzr) binds to VEGF and prevents the interaction of VEGF to its receptor on the surface of endothelial cells. Zirabev (bevacizumab-bvzr) is administered by intravenous infusion. The dosage form and strength is 100 mg of bevacizumab-bvzr in a 4 mL vial or 400 mg in a 16 mL vial.

On May 10, 2019, the FDA approved ramucirumab (Cyramza) as a single agent for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been previously treated with sorafenib. Approval was based on REACH‑2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in 292 patients with advanced HCC with AFP ≥ 400 ng/mL who had disease progression on or after sorafenib or who were intolerant. Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. The trial’s primary endpoint was overall survival (OS). The estimated median OS was 8.5 months (7.0, 10.6) for patients receiving ramucirumab and 7.3 months (5.4, 9.1) for those receiving placebo (HR 0.71; 95% CI: 0.53, 0.95; p=0.020). The most common adverse reactions observed in patients with HCC receiving single-agent ramucirumab (≥ 15% and ≥ 2% higher incidence than placebo) were fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. The most common laboratory abnormalities (≥ 30% and a ≥ 2% higher incidence than placebo) were hypoalbuminemia, hyponatremia, and thrombocytopenia. The recommended ramucirumab dose is 8 mg/kg administered intravenously every 2 weeks.

On May 29, 2020, the FDA approved ramucirumab (Cyramza) in combination with erlotinib for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. Efficacy was evaluated in RELAY (NCT02411448), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with previously untreated metastatic NSCLC whose tumors have EGFR exon 19 deletion or exon 21 (L858R) substitution mutations. A total of 449 patients were randomized (1:1) to receive either ramucirumab 10 mg/kg or placebo every 2 weeks as an intravenous infusion, in combination with erlotinib 150 mg orally once daily, until disease progression or unacceptable toxicity. The major efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator (RECIST 1.1). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DoR). Median PFS was 19.4 months in the ramucirumab plus erlotinib arm compared with 12.4 months in the placebo plus erlotinib arm (HR 0.59; 95% CI: 0.46, 0.76; p<0.0001). ORR was 76% in the ramucirumab plus erlotinib arm and 75% in the placebo plus erlotinib arm, with median DoR of 18.0 months and 11.1 months, respectively. At the time of the final analysis of PFS, OS data were not mature as only 26% of the deaths required for the final analysis had occurred (HR 0.83; 95% CI: 0.53, 1.30). The most common adverse reactions observed in patients treated with ramucirumab with erlotinib at a rate of ≥20% and ≥2% higher than placebo with erlotinib were infections, hypertension, stomatitis, proteinuria, alopecia, epistaxis, and peripheral edema. The most common laboratory abnormalities at a rate of ≥20% and ≥2% higher difference in incidence between arms were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, neutropenia, increased alkaline phosphatase, and hypokalemia. The recommended dose of ramucirumab for metastatic NSCLC in combination with erlotinib is 10 mg/kg every 2 weeks.

On May 29, 2020, the FDA approved atezolizumab in combination with bevacizumab (Tecentriq and Avastin) for patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy. Efficacy was investigated in IMbrave150 (NCT03434379), a multicenter, international, open-label, randomized trial in patients with locally advanced unresectable or metastatic hepatocellular carcinoma who had not received prior systemic therapy. A total of 501 patients were randomized (2:1) to receive either atezolizumab 1200 mg as an intravenous infusion (IV) followed by bevacizumab 15 mg/kg IV on the same day, every 3 weeks, or sorafenib orally twice daily. The main efficacy outcome measures were overall survival (OS) and independent review facility (IRF)-assessed progression-free survival (PFS) per RECIST 1.1. Additional efficacy outcome measures were IRF-assessed overall response rate (ORR) per RECIST 1.1 and mRECIST. Median OS was not reached in the patients who received atezolizumab plus bevacizumab and was 13.2 months (95% CI: 10.4, NE) in the patients who received sorafenib (HR 0.58; 95% CI: 0.42, 0.79; p=0.0006). Estimated median PFS was 6.8 months (95% CI: 5.8, 8.3) vs. 4.3 months (95% CI: 4.0, 5.6), respectively (HR 0.59; 95% CI: 0.47, 0.76; p<0.0001). The ORR per RECIST 1.1 was 28% (95% CI: 23, 33) in the atezolizumab plus bevacizumab group compared with 12% (95% CI: 7,17) in the sorafenib group (p<0.0001). The ORR per mRECIST was 33% (95% CI: 28, 39) vs. 13% (95% CI: 8, 19), respectively (p<0.0001). The most common adverse reactions (reported in ≥20% of patients) with atezolizumab plus bevacizumab in patients with HCC were hypertension, fatigue and proteinuria. The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks. If bevacizumab is discontinued, atezolizumab should be given either as 840 mg every 2 weeks, 1,200 mg every 3 weeks, or 1,680 mg every 4 weeks.

[INFORMATIONAL NOTE: The FDA-approved Avastin (bevacizumab), Mvasi (bevacizumab-awwb) and Zirabev (bevacizumab-bvzr) package inserts have the following warnings and precautions. Black boxed warnings of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage were removed as black boxed warnings in June 2019 and are listed in the warnings and precautions section of the FDA labeled package inserts:

Gastrointestinal Perforations -Discontinue Avastin, Mvasi, or Zirabev for gastrointestinal perforation, tracheoesophageal fistula, grade 4 fistula, or fistula formation involving any organ.
Surgery and Wound Healing Complications -Discontinue Avastin, Mvasi, or Zirabev in patients who develop wound healing complications that require medical intervention or necrotizing fasciitis. Withhold at least 28 days prior to elective surgery. Do not initiate Avastin, Mvasi, or Zirabev for at least 28 days after surgery and until the surgical wound is fully healed.
Hemorrhage -Severe or fatal hemorrhage have occurred. Discontinue Avastin, Mvasi or Zirabev for Grade 3-4 hemorrhage.
Arterial Thromboembolic Events (ATE) - Discontinue Avastin, Mvasi or Zirabev for severe ATE.
Venous Thromboembolic Events (VTE) - Discontinue Avastin, Mvasi or Zirabev for Grade 4 VTE.
Hypertension - Monitor blood pressure and treat hypertension. Withhold Avastin, Mvasi or Zirabev if not medically controlled; resume once controlled. Discontinue Avastin, Mvasi or Zirabev for hypertensive crisis or hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES) - Discontinue Avastin, Mvasi or Zirabev.
Renal Injury and Proteinuria - Monitor urine protein. Discontinue Avastin, Mvasi or Zirabev for nephrotic syndrome. Withhold until less than 2 grams of protein in urine.
Infusion-Related Reactions - Decrease rate for infusion-related reactions. Discontinue Avastin, Mvasi or Zirabev for severe infusion-related reactions and administer medical therapy.
Embryo-Fetal Toxicity - May cause fetal harm. Advise females of potential risk to fetus and need for use of effective contraception.
Ovarian Failure - Advise females of the potential risk.
Congestive Heart Failure (CHF) - Discontinue Avastin, Mvasi or Zirabev in patients who develop CHF.

The FDA-approved Erbitux (cetuximab) package insert has the following black box warnings:

Infusion Reactions - Severe infusion reactions occurred with the administration of Erbitux in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion reactions were associated with the first infusion of Erbitux. Severe infusion reactions are characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension and/or cardiac arrest. Severe infusion reactions require immediate interruption of the Erbitux infusion and permanent discontinuation from further treatment.
Cardiopulmonary Arrest - Cardiopulmonary arrest and/or sudden death occurred in 2% (4/208) of patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone and in 3% of patients with squamous cell carcinoma of the head and neck treated with Erbitux in combination with platinum-based therapy with 5-fluorouracil (5-FU). Fatal events occurred within 1 to 43 days after the last Erbitux treatment. Erbitux in combination with radiation therapy should be used with caution in head and neck cancer patients with known coronary artery disease, congestive heart failure, and arrhythmias. Although the etiology of these events is unknown, close monitoring of serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux therapy is recommended.

The FDA-approved Vectibix (panitumumab) package insert has the following black box warnings:

Dermatologic Toxicity – Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy.

The FDA-approved Zaltrap (ziv-aflibercept) package insert has the following black box warnings:

Hemorrhage – Patients have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In patients with mCRC, bleeding/hemorrhage (all grades) were reported in 38% of patients treated with Zaltrap/FOLFIRI compared to 19% of patients treated with placebo/FOLFIRI. Grade 3-4 hemorrhagic events, including gastrointestinal hemorrhage, hematuria, and post-procedural hemorrhage, were reported in 3% of patients receiving Zaltrap/FOLFIRI compared with 1% of patients receiving placebo/FOLFIRI. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have also occurred in patients receiving Zaltrap. Monitor patients for signs and symptoms of bleeding. Do not initiate Zaltrap in patients with severe hemorrhage and discontinue Zaltrap in patients who develop severe hemorrhage.
Gastrointestinal Perforation- Across three Phase 3 placebo controlled clinical studies (colorectal, pancreatic, and lung cancer populations), the incidence of GI perforation (all grades) was 0.8% for patients treated with Zaltrap and 0.3% for patients treated with placebo. Grade 3-4 GI perforation events occurred in 0.8% of patients treated with Zaltrap and 0.2% of patients treated with placebo. Monitor patients for signs and symptoms of GI perforation. Discontinue Zaltrap therapy in patients who experience GI perforation.
Compromised Wound Healing-Zaltrap impairs wound healing in animal models. Grade 3 compromised wound healing was reported in 2 patients (0.3%) treated with Zaltrap/FOLFIRI regimen and in none of the patients treated with placebo/FOLFIRI regimen. Suspend Zaltrap for at least 4 weeks prior to elective surgery. Do not resume Zaltrap for at least 4 weeks following major surgery and until the surgical wound is fully healed. For minor surgery such as central venous access port placement, biopsy, and tooth extraction, Zaltrap may be initiated/resumed once the surgical wound is fully healed. Discontinue Zaltrap in patients with compromised wound healing.

The FDA-approved Cyramza™ (ramucirumab) package insert has the following black box warnings:

Hemorrhage: Cyramza™ increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for Cyramza™ and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in Cyramza™ -treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for Cyramza plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other antiplatelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore the risk of pulmonary hemorrhage in these groups of patients is unknown.In Study 4, the incidence of severe bleeding was 2.5% for Cyramza plus FOLFIRI and 1.7% for placebo plus FOLFIRI. Permanently discontinue Cyramza in patients who experience severe bleeding.
Gastrointestinal perforation: Cyramza can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received Cyramza as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforation was also increased in patients that received Cyramza plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for Cyramza plus docetaxel and 0.3% for placebo plus docetaxel. In Study 4, the incidence of gastrointestinal perforation was 1.7% for Cyramza plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently discontinue Cyramza in patients who experience a gastrointestinal perforation.
Impaired wound healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Cyramza has not been studied in patients with serious or non-healing wounds. Cyramza, an antiangiogenic therapy, has the potential to adversely affect wound healing. Discontinue Cyramza therapy in patients with impaired wound healing. Withhold Cyramza prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue Cyramza until the wound is fully healed.

The FDA-approved Portrazza (necitumumab) package insert has the following black box warning:

Cardiopulmonary arrest: Cardiopulmonary arrest and/or sudden death occurred in 3% of patients treated with Portrazza in combination with cisplatin and gemcitabine. Closely monitor serum electrolytes (including magnesium, potassium, and calcium, with aggressive replacement when warranted during and after Portrazza administration.
Hypomagnesemia: Hypomagnesemia occurred in 83% of patients receiving Portrazza in combination with gemcitabine and cisplatin, and was severe in 20%. Patients should be monitored for electrolyte disturbances prior to each dose of Portrazza during treatment and for at least 8 weeks following completion of therapy. Withhold Portrazza in Grade 3 or 4 electrolyte abnormalities.]

Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)

The requirements of the Horizon BCBSNJ Vascular Endothelial Growth Factor Inhibitor and Human Epidermal Growth Factor Receptor Inhibitor Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Erbitux (cetuximab), Avastin (bevacizumab), Mvasi (bevacizumab-awwb), Zirabev (bevacizumab-bvzr), Vectibix (panitumumab), Zaltrap (ziv-aflibercept), Cyramza (ramucirumab), and Portrazza (necitumumab) are medically necessary for any of the following FDA approved indications when the following criteria are met:

The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
- Erbitux - for use in combination with FOLFIRI (irinotecan, 5-FU, leucovorin) for first line treatment of patients with K-ras mutation-negative (wild-type), EGFR expressing metastatic colorectal cancer as determined by any FDA-approved or CLIA-compliant tests
- as a single agent for the treatment of members with EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens or in members who are intolerant to irinotecan-based regimens;
- Avastin: if the request is for Avastin, member have a trial and failure, contraindication or allergy to one of the commercially available biosimilar agents
- treatment of metastatic colorectal carcinoma in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment;
- treatment of metastatic colorectal cancer, with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen;
- treatment of recurrent glioblastoma in adults;
- treatment of stage III or stage IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection in combination with carboplatin and paclitaxel, followed by Avastin as a single agent.
- treatment of unresectable or metastatic hepatocellular (HCC) who have not received prior systemic therapy, in combination with atezolizumab

[INFORMATIONAL NOTE: The P&T Committee at Horizon Blue Cross Blue Shield of New Jersey subjects each prescription drug being considered for formulary placement to a rigorous clinical analysis. Based on the the clinical and effective analysis, the P&T Committee recommends the placement of commercially available biosimilar agents as preferred.]
- Mvasi or Zirabev:
- treatment of metastatic colorectal carcinoma in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment;
- treatment of metastatic colorectal cancer, with fluoropyrimidine-, irinotecan-, or fluoropyrimidine-oxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line bevacizumab-containing regimen;
- treatment of recurrent glioblastoma in adults;
- Vectibix - treatment of wild-type KRAS and wild-type NRAS metastatic colorectal cancer (mCRC) as determined by any FDA-approved or CLIA-compliant tests:
- Zaltrap - in combination with 5-FU, leucovorin, and irinotecan (FOLFIRI) for patients with metastatic colon cancer that is resistant to or has progressed following
- Cyramza - advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single-agent or in combination with paclitaxel, after prior fluoropyrimidine- or platinum-containing chemotherapy.
- Portrazza – in combination with gemcitabine and cisplatin for the first line treatment of metastatic squamous non-small cell lung cancer.
  [INFORMATIONAL NOTE: Portrazza is not indicated for the treatment of non squamous non small cell lung cancer. The results of the INSPIRE study showed no benefit in patients with non squamous non small cell lung cancer.]

2. The initial therapy, when medically necessary, will be covered for up to 6 months at the FDA-recommended dose of:

Erbitux -
- As monotherapy
- As combination therapy
Avastin
Mvasi or Zirabev
Vectibix - 6 mg/kg IV infusion every 14 days until disease progression or unacceptable toxicity
Zaltrap- 4mg per kg as an IV infusion every 2 weeks until disease progression or unacceptable toxicity.
[INFORMATIONAL NOTE: As per the FDA approved package insert, administer Zaltrap prior to any component of the FOLFIRI regimen on the day of treatment. In the case of neutropenia or neutropenic complications delay administration of Zaltrap until neutrophil count is ≥ 1.5 x 10⁹/L.]
Cyramza - 8 mg/kg IV every 2 weeks until disease progression for gastric cancer or unacceptable toxicity

[INFORMATIONAL NOTE: In clinical trials, patients received a median of 4 doses of Cyramza™ (ramucirumab); the median duration of exposure was 8 weeks, and 32 (14% of 236) patients received Cyramza™ (ramucirumab) for at least six months]

Portrazza - 800 mg IV infusion over 60 minutes prior to gemcitabine and cisplatin infusion on days 1 and 8 of each 3-week cycle until disease progression or unacceptable toxicity

3. Continued therapy every 6 months is considered medically necessary when disease has stabilized and there are no detectable adverse events associated with drug therapy at the FDA-recommended dose of:

Erbitux -
- As monotherapy - 250 mg/m2 IV infusion every 7 days if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: cardiopulmonary arrest, pulmonary toxicity, severe infusion reactions, hypomagnesemia/electrolyte abnormalities)
- As combination therapy - 250 mg/m2 IV infusion every 7 days if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: cardiopulmonary arrest, pulmonary toxicity, severe infusion reactions)
- With radiation therapy or in combination with platinum-based therapy with 5-FU - Weekly dose of 250 mg/m2 IV infusion for the duration of radiation therapy (6-7 weeks) if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: cardiopulmonary arrest, pulmonary toxicity, severe infusion reactions)
Avastin
- 5 to 10 mg/kg IV infusion every 14 days for metastatic colorectal carcinoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, posterior reversible encephalopathy syndrome (PRES), renal injury/proteinuria, severe infusion-related reactions); AND
  - Patient’s disease has progressed on a first-line bevacizumab-containing regimen; AND
  - Used in combination with intravenous 5-fluorouracil (5FU)- irinotecan (Camptosar) based regimen, if not used in first line regimen; OR
  - Used in combination with intravenous 5-fluorouracil (5FU)-oxaliplatin (Eloxatin) based chemotherapy regimen, if not used in first line regimen; OR
  - Used in combination with oxaliplatin (Eloxatin) and irinotecan(Camptosar), if not used in the first line regimen
- 15 mg/kg IV infusion every 3 weeks for non-squamous, non-small cell lung cancer if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 10 mg/kg IV infusion every 14 days for glioblastoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 10 mg/kg IV every 2 weeks with interferon alfa for metastatic renal cell carcinoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 15 mg/kg IV every 3 weeks with paclitaxel / cisplatin or paclitaxel / topotecan for persistent, recurrent, or metastatic cervical cancer
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 10mg/kg IV every 2 weeks in combination with one of the following weekly chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or topotecan; OR 15 mg/kg IV every 3 weeks in combination with topotecan every 3 weeks for platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 5 mg/kg IV every 3 weeks in combination with carboplatin/paclitaxel for 6-8 cycles, followed by 15 mg/kg IV every 3 weeks as a single agent until disease progression for platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 15 mg/kg IV every 3 weeks in combination with carboplatin/gemcitabine for 6-10 cycles, followed by 15 mg/kg IV every 3 weeks as a single agent until disease progression for platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 15 mg/kg IV every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by 15mg/kg IV every 3 weeks as single agent, for a total of up to 22 cycles or until disease progression:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 15mg/kg IV after administration of 1,200 mg of atezolizumab intravenously on the same day, every 3 weeks until disease progression or unacceptable toxicity:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
Mvasi or Zirabev
- 5 to 10 mg/kg IV infusion every 14 days for metastatic colorectal carcinoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, posterior reversible encephalopathy syndrome (PRES), renal injury/proteinuria, severe infusion-related reactions); AND
  - Patient’s disease has progressed on a first-line bevacizumab-containing regimen; AND
  - Used in combination with intravenous 5-fluorouracil (5FU)- irinotecan (Camptosar) based regimen, if not used in first line regimen; OR
  - Used in combination with intravenous 5-fluorouracil (5FU)-oxaliplatin (Eloxatin) based chemotherapy regimen, if not used in first line regimen; OR
  - Used in combination with oxaliplatin (Eloxatin) and irinotecan(Camptosar), if not used in the first line regimen
- 15 mg/kg IV infusion every 3 weeks for non-squamous, non-small cell lung cancer if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 10 mg/kg IV infusion every 14 days for glioblastoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 10 mg/kg IV every 2 weeks with interferon alfa for metastatic renal cell carcinoma if:
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
- 15 mg/kg IV every 3 weeks with paclitaxel / cisplatin or paclitaxel / topotecan for persistent, recurrent, or metastatic cervical cancer
  - Patient continues to meet initial review criteria; AND
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: perforation or fistula (GI and non-GI), delayed wound healing, hemorrhages, thromboembolic events, hypertensive crisis, ovarian failure)
Vectibix -6 mg/kg IV infusion every 14 days if:
- Patient continues to meet initial review criteria; AND
- Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
- Absence of unacceptable toxicity from the drug (e.g.: dermatologic toxicity, infusion reactions, electrolyte depletion, acute renal failure, pulmonary fibrosis/interstitial lung disease, photosensitivity, ocular toxicity)
Zaltrap- 4mg per kg as an IV infusion every 2 weeks if:
- Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
- Absence of unacceptable toxicity from the drug (e.g.: hemorrhage; gastrointestinal perforation; fistula formation; hypertension; wound healing complications; arterial thromboembolic events; proteinuria; neutropenic complications; reversible posterior leukoencephalopathy syndrome (RPLS))
Cyramza
- 8 mg/kg IV infusion every 2 weeks for gastric cancer if
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: uncontrolled hypertension, GI perforation, reversible posterior leukoencephalopathy syndrome (RPLS), hemorrhage, arterial thromboembolic events, proteinuria including nephrotic syndrome, thyroid dysfunction)
- 10 mg/kg IV infusion on day 1 of a 21-day cycle prior to docetaxel infusion for non-small cell lung cancer if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: uncontrolled hypertension, GI perforation, reversible posterior leukoencephalopathy syndrome (RPLS), hemorrhage, arterial thromboembolic events, proteinuria including nephrotic syndrome, thyroid dysfunction)
- 10 mg/kg IV infusion every 2 weeks for metastatic non-small cell lung cancer with EGFR exon 19 deletions or exon 21 mutations:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: uncontrolled hypertension, GI perforation, reversible posterior leukoencephalopathy syndrome (RPLS), hemorrhage, arterial thromboembolic events, proteinuria including nephrotic syndrome, thyroid dysfunction)
- 8 mg/kg IV infusion every 2 weeks for metastatic colorectal cancer prior to FOLFIRI administration if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: uncontrolled hypertension, GI perforation, reversible posterior leukoencephalopathy syndrome (RPLS), hemorrhage, arterial thromboembolic events, proteinuria including nephrotic syndrome, thyroid dysfunction)
- 8 mg/kg IV every 2 weeks for hepatocellular carcinoma if:
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
  - Absence of unacceptable toxicity from the drug (e.g.: hemorrhage, arterial thrombotic events, uncontrolled hypertension, infusion-related reactions, severe proteinuria/nephrotic syndrome, gastrointestinal perforation, impaired wound healing, posterior reversible encephalopathy syndrome (PRES), thyroid dysfunction, worsening of pre-existing hepatic impairment, etc.)
Portrazza
- 800 mg IV infusion over 60 minutes prior to gemcitabine and cisplatin infusion on days 1 and 8 of each 3-week cycle for metastatic non-small cell lung cancer IF
  - Tumor response with stabilization of disease or decrease in size of tumor or tumor spread AND
  - Absence of unacceptable toxicity from the drug (e.g. Arterial or high grade venous thromboembolism, cardiorespiratory arrest, pulmonary embolism, grade ¾ infusion reactions, hypomagnesemia) AND
  - Continued monitoring prior to each infusion for hypomagnesemia, hypocalcemia, and hypokalemia.

[INFORMATIONAL NOTE: Grade ≥3 treatment-emergent adverse events (TEAEs) were reported by 72% (n = 338) of patients in the NECI+GEM-CIS group and by 62% (n = 333) of patients in the GEM-CIS group. Rates of hypocalcemia, hypokalemia, and hypoemagnesemia were 45%, 28%, and 83%, respectfully.]

4. Avastin (bevacizumab) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [bevacizumab]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/]. AND member has trial and failure, contraindication or allergy to one of the commercially available biosimilar agents.

[Please refer to a separate policy on Angiogenic Inhibitors for the Treatment of

Ophthlamic Macular Conditions

- Policy #080 under the Treatment Section of this database.]

5. Mvasi (bevacizumab-awwb) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [bevacizumab-awwb]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/]. :

6. Zirabev (bevacizumab-bvzr) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [bevacizumab-bvzr]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].

7. Erbitux (cetuximab) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [cetuximab]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].

8. Vectibix (panitumumab) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [panitumumab]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/]. :

9. Zaltrap (ziv-aflibercept) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [ziv-aflibercept]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].:

10. Cyramza (ramucirumab) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - [ramucirumab]. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].

11. Portrazza is NOT considered medically necessary for any off-label indications.

12. Other uses of Erbitux, Avastin/Mvasi/Zirabev, Vectibix, Zaltrap, Cyramza, and Portrazza are considered investigational .

[INFORMATIONAL NOTE:

On September 23, 2005, Genentech announced that enrollment in a multicenter, single-arm phase II study of its cancer drug AVASTIN (bevacizumab) in platinum-refractory ovarian cancer patients had been discontinued after reports of five gastrointestinal perforations in the first 44 patients enrolled in the proposed 53-patient study. According to the company, this represented a higher rate of GI perforations than the rates that had been reported in all previous Avastin trials.]

[INFORMATIONAL NOTE: All 4 studies conducted by Genentech for Avastin use in patients with Breast Cancer (AVF2119g, Ribbon-1, Ribbon-2, AVADO, and more current Study 10) did not show the same magnitude of effect of progression-free survival rate as was seen with the E2100 study. Neither study, including the pivotal E2100 study, found any overall survival benefit or improved quality of life. Instead, severe hypertension, bleeding and hemorrhaging, heart attack or heart failure and perforations of the nose, stomach, and intestines were seen more with the Avastin treated group in most of the studies. There were deaths reported in some trials which were related to Avastin and also majority of the trials showed more grade 3 and 4 adverse events when treated with Avastin. Grade 3 and higher hypertension was about 10 times more frequent in patients receiving Avastin.]

[INFORMATIONAL NOTE: Necitumumab is being evaluated for many types of cancer or as second-line therapy and in combination with other chemotherapeutic agents in NSCLC. Indications under investigation include nonsquamous NSCLC, advanced or metastatic solid tumors (except for colorectal tumors with the

KRAS

mutation). Necitumumab is also being evaluated in combination with paclitaxel and carboplatin, nab-paclitaxel and carboplatin, LY3023414 (an ATP inhibitor), pemetrexed and cisplatin, abemaciclib (CDK 4 and 6 inhibitor) and pembrolizumab (PD-1 inhibitor).]

Medicare Coverage
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Vascular Endothelial Growth Factor Inhibitor
Human Epidermal Growth Factor Receptor Inhibitor
Angiogenesis-Inhibiting Drugs
Avastin
Bevacizumab
Colorectal Cancer
Erbitux
Cetuximab
Vectibix
Panitumumab
Zaltrap
Ziv-aflibercept
Cyramza
ramucirumab
Portrazza
necitumumab
Mvasi
Bevacizumab-awwb
Zirabev
Bevacizumab-bvzr)

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42. ECRI. Health Technology Forecast: Genentech halts trial of Avastin in ovarian cancer patients. September 30, 2005.

43. Ueda M, Terai Y, Kanda K, et al. Tumor angiogenesis and molecular target therapy in ovarian carcinomas. Hum Cell 2005 Mar;18(1):1-16.

44. Nicodemus CF, Berek JS. Monoclonal antibody therapy of ovarian cancer. Expert Rev Anticancer Ther 2005 Feb;5(1):87-96.

45. Monk BJ, Choi DC, Pugmire G, et al. Activity of bevacizumab (rhuMAB VEGF) in advanced refractory epithelial ovarian cancer. Gynecol Oncol 2005 Mar;96(3):902-5.

46. U.S. Food and Drug Administration (FDA). FDA News: FDA approves First Head & Neck Cancer Treatment in 45 years Data Shows Treatment with Erbitux Extends Survival. March 1, 2006.

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101. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer. N Engl J Med 2009;360:1408-1417.

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

Q5107
Q5118

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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