Ziv-Aflibercept (Zaltrap)

Number: 0842

Policy

Aetna considers ziv-aflibercept (Zaltrap) medically necessary for the treatment of adults with advanced or metastatic colorectal cancer, appendiceal adenocarcinoma, or anal adenocarcinoma in combination with irinotecan or FOLFIRI (leucovorin, irinotecan, 5‐fluorouracil) chemotherapy.

Aetna considers continued treatment with Zaltrap (ziv‐aflibercept) medically necessary in members requesting reauthorization for a medically necessary indication who have not experienced disease progression or an unacceptable toxicity. 

Aetna considers zaltrap (ziv-aflibercept) in combination with Avastin (bevacizumab) experimental and investigational because there is insufficient evidence of the effectiveness and safety of this combination.

Aetna considers ziv-aflibercept experimental and investigational for the treatment of the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established.

• Anal squamous cell carcinoma
• Bladder cancer
• Breast cancer
• Carcinosarcoma of endometrial, fallopian tube, or ovarian origin
• Central serous chorioretinopathy
• Chorioretinitis
• Choroidal neovascular membranes
• Corneal neovascularization
• Diabetic macular edema
• Exudative (or neovascular) age-related macular degeneration
• Glioblastoma
• Inflamed pterygia
• Leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myelogenous leukemia)
• Lymphoma (Hodgkin lymphoma, lymphoplasmacytic lymphoma, and non-Hodgkin’s lymphomas)
• Melanoma
• Non-small-cell lung cancer (NSCLC)
• Non-squamous NSCLC
• Ovarian cancer
• Pancreatic cancer
• Prostate cancer
• Renal cell cancer
• Retinal vein occlusion
• Sarcomas
• Small-cell lung cancer
• Thyroid cancer
• Uterine leiomyosarcoma
• Vitreous hemorrhage
• Waldenstrom’s macroglobulinemia

See also CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications.

Dosing Recommendations

Ziv‐aflibercept is available as Zaltrap in 100 mg and 200 mg single‐use vials.

Zaltrap (ziv‐aflibercept) is administered at 4 mg/kg intravenously over 1 hour every two weeks. Zaltrap (ziv‐aflibercept) should be administered prior to any component of the FOLFIRI regimen on the day of treatment. Treatment cycles should be repeated every 2 weeks until disease progression or unacceptable toxicity.

Source: sanofi-aventis U.S. LLC., 2016.

Background

Ziv-aflibercept (formerly known as aflibercept, VEGF Trap) is a recombinant fusion protein, which acts as a soluble receptor that binds to vascular endothelial growth factor-A (VEGF-A), VEGF-B and placental growth factor (PIGF). By binding to these endogenous ligands, Zaltrap (zivaflibercept)can inhibit the binding and activation of their cognate receptors. This inhibition can result in decreased neovascularization and decreased vascular permeability. Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis (the growth of new blood vessels from pre‐existing vasculature). Ziv-aflibercept is designed to act as a VEGF trap to prevent activation of VEGF receptors and thus inhibit angiogenesis. Inhibition of these factors can result in decreased neo-vascularization and decreased vascular permeability.

On August 3, 2012, the Food and Drug Administration (FDA) approved ziv-aflibercept (Zaltrap) for use in combination with a FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy regimen for the treatment of adults with metastatic colorectal cancer (MCRC).  Zaltrap’s safety and effectiveness was evaluated in a randomized clinical study (Van Cutsem et al, 2012) of 1,226 patients with MCRC whose cancer grew while receiving oxaliplatin-based combination chemotherapy, or whose cancer was removed by surgery but returned within 6 months after receiving oxaliplatin-based combination chemotherapy for post-surgery (adjuvant) treatment.  Participants received treatment until their cancer progressed or side effects became unacceptable.  The study was designed to measure overall survival (OS).  Patients who were assigned to receive the Zaltrap plus FOLFIRI combination (n = 612) lived an average of 13.5 months compared to an average of 12 months for those receiving FOLFIRI plus placebo (n = 614).  A reduction in tumor size occurred in 20 % of patients receiving the Zaltrap plus FOLFIRI combination versus 11 % for those receiving FOLFIRI plus placebo.  In addition, the clinical trial demonstrated an improvement in progression-free survival (PFS).  The PFS for patients receiving the Zaltrap plus FOLFIRI combination was 6.9 months compared with 4.7 months for those receiving FOLFIRI plus placebo. 

Zaltrap is approved with a “Boxed Warning” alerting patients and health care professionals that the drug can cause severe and sometimes fatal bleeding, including gastro-intestinal (GI) bleeding.  The most common adverse events (AEs) observed in patients receiving Zaltrap plus FOLFIRI were abdominal pain, decreased appetite, diarrhea, fatigue, headache, hypertension, leukopenia, proteinuria, stomatitis, and weight loss. 

Black Box Warnings:

• Hemorrhage:  Treatment with Zaltrap (ziv‐aflibercept) may increase risk of hemorrhage, including severe and possibly fatal hemorrhagic events. Hemorrhagic events included gastrointestinal hemorrhage, hematuria, and post‐procedural hemorrhage. Grade 3‐4 hemorrhagic events were reported in 3% of patients treated with Zaltrap (zivaflibercept). Monitor patients for signs symptoms of bleeding. Do not initiate Zaltrap (ziv‐aflibercept) in patients with severe hemorrhage. Discontinue Zaltrap (zivaflibercept) in patients who develop severe hemorrhage.
• Gastrointestinal Perforation: GI perforation, including fatal GI perforation, can occur in patients receiving zivaflibercept. Grade 3‐4 events occurred in 0.8% of patients treated with Zaltrap (zivaflibercept). Monitor patients for signs and symptoms of GI perforation and discontinue therapy in patients who experience GI perforation.
• Compromised Wound Healing: Grade 3 compromised wound healing was reported in 0.3% of patients treated with Zaltrap (ziv‐aflibercept) regimen. Zaltrap (ziv‐aflibercept) should be suspended for at least 4 weeks prior to elective surgery and should not be resumed for at least 4 weeks following major surgery and until the surgical wound is fully healed. Zaltrap (zivaflibercept) should be discontinued in patients with compromised wound healing.

Warnings and Precautions:

• Fistula Formation: Fistula formation (GI and non‐GI sites) was reported in 1.5% of patients treated with Zaltrap (ziv‐aflibercept). Grade 3 GI fistula formation occurred in 0.3% of patients. Therapy should be discontinued for patients who develop fistulas.
• Hypertension: Zaltrap (ziv‐aflibercept) increases the risk of Grade 3‐4 hypertension. No clinical trials have been conducted on patients with NYHA class III or IV heart failure. Grade 3 hypertension was reported in 19% of patients treated with Zaltrap (ziv‐aflibercept). Grade 4 hypertension (hypertensive crisis) was reported in 0.2% of patients. Among the patients that developed Grade 3‐4 hypertension while on ziv‐aflibercept, 54% had onset during the first two cycles of treatment. Blood pressure should be monitored at least every two weeks or as clinically indicated during treatment. Appropriate antihypertensive therapy should be used and blood pressure should be monitored regularly. Zaltrap (ziv‐aflibercept) should be temporarily suspended in patients with uncontrolled hypertension and should be permanently reduced to a 2mg/kg dose for subsequent cycles. Discontinue Zaltrap (ziv‐aflibercept) in patients with hypertensive crisis or hypertensive encephalopathy.
• Arterial Thromboembolic Events (ATE): Arterial thromboembolic events, including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who received Zaltrap (ziv‐aflibercept). ATE was reported in 2.6% of patients treated with zivaflibercept. Grade 3‐4 events occurred in 1.8% of patients. Patients who experience an ATE should discontinue Zaltrap (ziv‐aflibercept).
• Proteinuria: Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy occurred more frequently in patients treated with Zaltrap (ziv‐aflibercept). Grade 3‐4 proteinuria occurred in 8% of patients treated with Zaltrap (ziv‐aflibercept), nephrotic syndrome occurred in 0.5% of patients, and thrombotic microangiopathy was reported in 3 patients of 2258 with cancer enrolled across completed studies. Proteinuria should be monitored using a urine dipstick analysis and urinary protein creatinine ratio. A 24‐hour urine collection should be obtained in patient with a urinary protein creatinine ratio > 1. Zaltrap (ziv‐aflibercept) should be suspended if proteinuria of 2gm/24 hours or more and resume after proteinuria is less than 2gm/24 hours. If recurrent, permanently reduce Zaltrap (ziv‐aflibercept) dose to 2mg/kg. Discontinue Zaltrap (ziv‐aflibercept) in patients who develop nephrotic syndrome or thrombotic microangiopathy.
• Neutropenia/Neutropenic Complications: A higher incidence of neutropenic complications, including febrile neutropenia and neutropenic infection, occurred in patients receiving Zaltrap (ziv‐aflibercept). Grade 3‐4 neutropenia occurred in 37% of patients treated with Zaltrap (ziv‐aflibercept). Monitor CBC with differential count at baseline and prior to initiation of each cycle. Delay treatment with Zaltrap (ziv‐aflibercept) until neutrophil count is at or above 1.5 x 109/L.
• Diarrhea and Dehydration: Severe diarrhea was increased in patients treated with Zaltrap (ziv‐aflibercept). Grade 3‐4 diarrhea was reported in 19% of patients. The incidence of diarrhea was increased in patients 65 years or older so elderly patients should be monitored closely for diarrhea.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS was reported in 0.5% of 3795 patients treated with Zaltrap (ziv‐aflibercept). Diagnosis of RPLS should be confirmed with an MRI and discontinued in patients who develop the syndrome. Symptoms usually resolve or improve within days, although some patients may experience ongoing neurologic symptoms or even death.

In a phase II clinical and pharmacokinetic study, Tang et al (2012) evaluated the safety and effectiveness of aflibercept in patients with MCRC who had received at least 1 prior palliative regimen.  A total of 75 patients were enrolled onto this 2-stage phase II trial in 2 cohorts, bevacizumab naïve (n = 24) and prior bevacizumab (n = 51).  Aflibercept was administered at 4 mg/kg intravenous in 2-week cycles.  The primary endpoint was a combination of objective response rate and 16-week PFS.  In the bevacizumab-naïve cohort, the best response was stable disease for 16 weeks or more in 5 of 24 patients.  In the prior bevacizumab cohort, 1 patient achieved a partial response and 6 patients had stable disease for 16 weeks or more.  The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was 2 months (95 % confidence interval [CI]: 1.7 to 8.6 months) and 2.4 months (95 % CI: 1.9 to 3.7 months), respectively.  Median OS was 10.4 months (95 % CI: 7.6 to 15.5) and 8.5 months (95 % CI: 6.2 to 10.6), respectively.  The most common grade 3 or higher treatment-related AEs were hypertension, proteinuria, fatigue, and headache; 10 patients discontinued study treatment due to toxicity.  Mean free to VEGF-bound aflibercept ratio was 1.82, suggesting that free aflibercept was present in sufficient amount to bind endogenous VEGF.  The authors concluded that aflibercept showed limited single-agent activity in patients with pre-treated MCRC with moderate toxicity. 

Ziv-aflibercept has also been studied for other indications (e.g., bladder cancer, breast cancer, carcinosarcoma, diabetic macular edema, melanoma, non-small-cell lung cancer [NSCLC], ovarian cancer, pancreatic cancer, prostate cancer, and uterine leiomyosarcoma).  However, there is insufficient evidence to support the use of ziv-aflibercept for these conditions.

In a multi-center, phase II study, Tarhini et al (2011) examined the effects of aflibercept in patients with inoperable stage III or stage IV melanoma of cutaneous or uveal origin and no prior chemotherapy.  A 2-stage design was adopted to evaluate 4-month PFS rate (PFSR) and response rate.  Aflibercept was given at 4 mg/kg intravenously every 2 weeks.  Response was assessed every 8 weeks.  First-stage accrual of 21 patients was specified and with an adequate 4-month PFSR accrual continued to a total of 41.  Forty-one patients of aged 23 to 84 years (median = 57) were enrolled.  Thirty-nine had American Joint Committee on Cancer stage IV (5 M1a, 7 M1b, and 27 M1c) and 2 had inoperable stage IIIC (N3).  Eastern Cooperative Oncology Group (ECOG) performance status was 0 (27 patients) or 1 (14 patients).  Ten patients had primary uveal melanoma, 28 cutaneous, and 3 had unknown primaries.  A median of 7 cycles were initiated (range of 1 to 56).  Grade 3 and 4 toxicities included hypertension in 9 patients (22 %) and proteinuria in 6 (15 %).  Among 40 patients evaluable for efficacy (those who initiated aflibercept), 3 (7.5 %) had a confirmed partial response and 20 had PFS of 4 months or above.  The predicted 1-year survival rate derived from the Korn meta-analysis model is 36 % (n = 39), whereas these investigators observed a corresponding 56.4 % survival rate at 1 year (95 % CI: 43 to 74, p < 0.005).  Median OS in this trial was 16.3 months (95 % CI: 9.2 to “not reached”).  These researchers observed a significant association between severity of hypertension following aflibercept and survival improvement.  The authors concluded that aflibercept showed promising activity in patients with metastatic melanoma of cutaneous or uveal origin.  They stated that further evaluation of aflibercept as a single-agent and in combination is warranted.

Zhu et al (2012) stated that the treatment of advanced urothelial cancer of the bladder has evolved substantially during recent years.  Chemotherapy has been the mainstay of treatment and confers survival advantage.  Despite such advances, the chemotherapy of bladder cancer is far from satisfactory due to severe side effects.  Targeted therapy with novel drugs directed at specific molecular pathways opens promising new avenues to improve patient outcome.  A systematic review examined the clinical data for novel targeted agents in 10 phase II clinical trials, with a focus on aflibercept, bevacizumab, gefitinib, lapatinib, sorafenib, sunitinib, and trastuzumab.  Moreover, these researchers presented studies on other novel, promising targeted agents, including cetuximab, everolimus, and pazopanib.  Although bevacizumab and trastuzumab have shown promising results for patients with advanced bladder cancer, other targeted agents have not achieved the same clinical benefit in this disease as seen in other common epithelial cancers.  The authors stated that ultimately, combination targeted therapy, sequential therapy, adjuvant and neoadjuvant therapy may yield the best outcomes.

Perez and Spano (2012) stated that the success of endocrine therapies for hormone receptor-positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 (HER2)-positive tumors has paved the way for the clinical development of several other metastatic breast cancer (MBC)-targeted therapies.  Although the benefit of bevacizumab in the MBC setting has become a topic of debate, clinical trial results are accumulating, and phase 3 evaluations are ongoing for newer HER2-targeted agents (pertuzumab and trastuzumab-maytansine immuno-conjugate) and VEGF-targeted agents (aflibercept), as well as dual, epidermal growth factor receptor/HER2-targeted agents (afatinib [BIBW 2992] and neratinib), multi-targeted tyrosine kinase inhibitors (TKIs) (pazopanib and sunitinib), and mammalian target of rapamycin (everolimus) and poly (ADP-ribose) polymerase 1 inhibitors (iniparib, olaparib).  These agents as well as other novel classes of anti-cancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population.

In a phase II clinical study, Mackay et al (2012) examined the safety and effectiveness of single-agent aflibercept in women with gynecologic soft tissue sarcoma.  Patients were enrolled in 2 cohorts each with Simon 2-stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, fallopian tube, or ovarian origin.  Eligibility criteria included less than or equal to 2 prior lines of chemotherapy for metastatic disease and ECOG performance status of less than or equal to 2.  Aflibercept 4 mg/kg was administered intravenously on day 1 of a 14-day cycle.  Primary endpoints were objective response and disease stabilization (PFS at 6 months).  A total of 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled in this study.  In the leiomyosarcoma cohort, 11 (27 %) patients had stable disease (SD), 4 with SD lasting at least 24 weeks.  The 6-month PFS was 17 %, with median time to progression (TTP) of 1.8 (95 % CI:1.6 to 2.1) months.  In the carcinosarcoma cohort, 2 (9 %) patients had SD, 1 lasting more than 24weeks, median TTP was 1.6 months (95 % CI: 1.1 to 1.7).  No partial responses were observed in patients from either cohort.  Grade 3 or more aflibercept-related toxicity was uncommon and included abdominal pain, fatigue, headache, and hypertension.  The authors concluded that single-agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.

Stewart (2012) stated that aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neo-vascularization.  Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas.  The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-fluorouracil as second line chemotherapy for MCRC experienced extended PFS and OS.  Intra-vitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab).  Ongoing phase III trials are investigating the use of aflibercept for diabetic macular edema and retinal vein occlusions.

In a double-blind, placebo-controlled, phase III clinical trial, Ramlau et al (2012) compared the effectiveness of ziv-aflibercept, with or without docetaxel in platinum-pretreated patients with advanced or metastatic non-squamous NSCLC.  A total of 913 patients were randomly assigned to ziv-aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2).  The primary end point was OS.  Other efficacy outcomes, safety, and immunogenicity were also assessed.  Patient characteristics were balanced between arms; 12.3 % of patients had received prior bevacizumab.  Ziv-aflibercept did not improve OS (hazard ratio [HR], 1.01; 95 % CI: 0.87 to 1.17; stratified log-rank p = 0.90).  The median OS was 10.1 months (95 % CI: 9.2 to 11.6 months) for ziv-aflibercept and 10.4 months (95 % CI: 9.2 to 11.9 months) for placebo.  In exploratory analyses, median PFS was 5.2 months (95 % CI: 4.4 to 5.6 months) for ziv-aflibercept versus 4.1 months (95 % CI: 3.5 to 4.3 months) for placebo (HR, 0.82; 95 % CI: 0.72 to 0.94; p = 0.0035); overall response rate was 23.3 % of evaluable patients (95 % CI: 19.1 % to 27.4 %) in the ziv-aflibercept arm versus 8.9 % (95 % CI: 6.1 % to 11.6 %; p < 0.001) in the placebo arm.  Grade greater than or equal to 3 adverse events occurring more frequently in the ziv-aflibercept arm versus the placebo arm were neutropenia (28.0 % versus 21.1 %, respectively), fatigue (11.1 % versus 4.2 %, respectively), stomatitis (8.8 % versus 0.7 %, respectively), and hypertension (7.3 % versus 0.9 %, respectively).  The authors concluded that the addition of ziv-aflibercept to standard docetaxel therapy did not improve OS.

Teoh and Secord (2012) provided an overview of angiogenesis, including the rationale for targeting angiogenesis as a treatment strategy for epithelial ovarian cancer (EOC) and discussed available clinical trial data with anti-angiogenic agents in EOC.  These researchers stated that several therapies that target angiogenesis-specific pathways are undergoing clinical development for EOC.  Although some of these agents have demonstrated single-agent activity for EOC, there is considerable interest in combining this treatment strategy with chemotherapy in an effort to potentially improve treatment benefits in this patient population.  Bevacizumab is the most studied anti-angiogenic agent in EOC and has shown efficacy as monotherapy and combined with chemotherapy in both the relapsed/recurrent and first-line settings.  However, results from recent phase 3 trials raise questions regarding patient selection and optimal dose, schedule, and duration of bevacizumab therapy.  Other agents in various phases of testing include aflibercept; multi-ligand targeted anti-angiogenic TKIs (e.g., cediranib, pazopanib, sorafenib); and AMG 386, a selective angiopoietin inhibitor.  The authors concluded that results from recently completed and ongoing clinical trials combining anti-angiogenic agents with chemotherapy are awaited in hopes of expanding therapeutic options for patients with EOC.

Gaya and Tse (2012) noted that aflibercept inhibits VEGF-induced angiogenesis in pre-clinical models.  In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation.  Clinical studies are investigating the use of aflibercept alone and in combination with other anti-neoplastic therapies for the treatment of various cancers.  Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept.  Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced NSCLC demonstrated efficacy in PFS and overall objective response rate, but OS was not significantly improved.  The phase III VANILLA trial in metastatic pancreatic cancer showed no improvement in OS.

Agarwal et al (2012) reviewed the next generation of molecular targets in metastatic castration-resistant prostate cancer (mCRPC).  Medline databases were searched for greater than 100 original articles published as of October 18, 2011, with the search terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy.  Proceedings from the last 5 years of conferences of the American Society of Clinical Oncology, American Urological Association, European Society of Medical Oncology, and the European Association of Urology were also searched.  These investigators included novel and promising drugs that have reached clinical trial evaluation.  The major findings were addressed in an evidence-based fashion.  Prospective trials and important pre-clinical data were analyzed.  The authors concluded that mCRPC is a disease with multiple molecular drivers.  Molecular pathways being targeted in ongoing phase III trials are androgen signaling (MDV3100, TAK700), immuno-regulatory pathways (ipilimumab, Prostvac-VF-TRICOM), Src (dasatinib), Met (cabozantinib), clusterin (custirsen), and angiogenesis (aflibercept, tasquinimod).

Wilson et al (2013) reviewed key clinical issues underlying the assessment of in-vivo efficacy when using anti-angiogenic therapies for cancer treatment.  These investigators noted that multi-ligand targeted anti-angiogenic therapies, such as ziv-aflibercept, are currently undergoing clinical evaluation.  Ziv-aflibercept forms monomeric complexes with VEGF-A, VEGF-B, and PlGF, which have a long half-life, allowing optimization of ziv-aflibercept doses and angiogenic blockage.  The authors concluded that although anti-angiogenic therapies have increased therapeutic options for cancer patients, their use is limited by a lack of established and standardized methodology to evaluate their efficacy in-vivo.

Sharma et al (2013) noted that the FDA has recently approved aflibercept for the treatment of CRC.  These researchers reviewed pre-clinical and clinical data on the use of aflibercept alone and in combination with chemotherapy for the treatment of breast cancer, glioblastoma, NSCLC, ovarian cancer, pancreatic cancer, and renal cell cancer.

In a single-arm, multi-center, phase II study, Chen et al (2014) evaluated the safety and effectiveness of ziv-aflibercept in combination with cisplatin and pemetrexed in NSCLC.  This trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC.  Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to 6 cycles.  Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal.  The co-primary end-points were objective response rate (ORR) and PF); planned sample size was 72 patients.  The study was closed prematurely because of 3 confirmed and 2 suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS).  A total of 42 patients were enrolled.  Median age was 61.5 years; 55 % were male, 86 % Caucasian and 50 % had ECOG performance status = 0.  A median of 4 cycles of ziv-aflibercept was administered.  The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69 %) and fatigue (67 %), with hypertension (36 %) as the most common grade 3/4 TEAE.  Of the 38 evaluable patients, ORR was 26 % and median PFS was 5 months.  The authors concluded that cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development program, but the rate observed in this study was higher than previously observed.  This might be related to declining renal function and/or hypertension.  Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

In a randomized, phase II clinical trial, Allen et al (2014) examined the effects of weekly topotecan with or without ziv-aflibercept (VEGF-trap) in patients with platinum-treated small-cell lung cancer (SCLC).  Patients with previously treated SCLC (one line of platinum-based chemotherapy), performance status of 0 to 1, adequate organ function, treated brain metastases, and no recent vascular events or bleeding diatheses were eligible.  Eligible patients were stratified as platinum-sensitive or platinum-refractory and randomly assigned to receive weekly topotecan 4 mg/m(2) intravenously (IV) with or without ziv-aflibercept 6 mg/kg IV every 21 days.  Progression-free survival at 3 months was the primary end-point.  In 189 randomly assigned patients, treatment arms were well-balanced with regard to clinical characteristics.  The 3-month PFS was significantly improved with the addition of ziv-aflibercept in patients who had platinum-refractory disease (27 % versus 10 %; p = 0.02) but not in patients with platinum-sensitive disease (24 % versus 15 %; p = 0.22).  Although response rate was low, disease control rate was higher with combination therapy than with topotecan alone in patients who had platinum-sensitive disease (37 % versus 18 %; p = 0.05) and in those who had platinum-refractory disease (25 % versus 15 %; p = 0.14).  Overall survival was not significantly improved in either strata.  Grades 3 to 5 toxicities were more common with the addition of ziv-aflibercept.  The authors concluded that ziv-aflibercept improved the 3-month PFS in patients who had platinum-refractory SCLC, but its addition increased toxicity; OS was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata.

National Comprehensive Cancer Network (NCCN) Colon Cancer guidelines state that appendiceal adenocarcinoma may be treated with systemic chemotherapy according to NCCN guidelines for colon cancer; NCCN guidelines for anal carcinoma state that anal adenocarcinoma is managed with NCCN guidelines for rectal cancer. The new NCCN guidelines for Small Bowel Adenocarcinoma (v.1.2020) do not list ziv-aflibercept as a recommended therapy. 

Currently, ziv-aflibercept is being studied for treatment of various types of malignancies (e.g., leukemia, lymphoma, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, small cell lung cancer small cell and thyroid cancer). Moreover, NCCN’s clinical practice guidelines on “Acute lymphoblastic leukemia” (Version 1.2015), “Acute myeloid leukemia” (Version 1.2015), “Chronic myelogenous leukemia” (Version 1.2015), “Hodgkin lymphoma” (Version 2.2015), “Non-Hodgkin’s lymphomas” (Version 2.2015), “Thyroid carcinoma” (Version 2.2015), and “Waldenstrom’s macroglobulinemia/lymphoplasmacytic lymphoma” (Version 3.2015) do not mention ziv-aflibercept as a therapeutic option.

Chorioretinitis

In an uncontrolled, prospective, cohort, pilot study, Korol and associates (2017) evaluated the potential benefits of intravitreal aflibercept injections for the treatment of choroidal neovascularization (CNV) secondary to chorioretinitis.  In this study, a total of 15 eyes of 14 consecutive patients affected by CNV associated with ocular toxoplasmosis were treated with intravitreal aflibercept (2 mg) pro re nata and observed over a 12-month follow-up period.  The primary outcome was the change in best-corrected visual acuity (BCVA) from baseline to month 12; secondary outcomes included change in central retinal thickness (CRT) in the foveal area on optical coherence tomography (OCT) from baseline to month 12, the number of intravitreal aflibercept injections administered, and safety.  Mean (standard deviation [SD]) BCVA improved significantly from 0.36 (0.23) at baseline to 0.64 (0.3) at month 12 (p = 0.0002).  Mean (SD) CRT on OCT showed a reduction from 317 (74) µm at baseline to 254 (43) µm (p = 0.0002) at month 12.  A mean (SD) of 1.7 (0.5) injections (range of 1 to 2 injections) were performed during the study period.  No cases of endophthalmitis, uveitis, stroke, or retinal detachment were noted.  No patient demonstrated an intra-ocular pressure (IOP) of greater than 20 mmHg at any study visit.  The authors concluded that intravitreal aflibercept showed a positive clinical effect and was well-tolerated for the treatment of CNV associated with chorioretinitis.  They stated that these  findings could be helpful for selecting a treatment for CNV secondary to chorioretinitis.  These researchers noted that the drawbacks of this this study included its small sample size (n = 14 patients), and no statistical comparison with other studies of CNV secondary to chorioretinitis was provided, due to great differences in protocols and a diverse etiology of chorioretinitis in different studies.

Inflamed Pterygia

In a prospective, pilot study, Mansour (2017) examined the role of high-dose repeated intralesional ziv-aflibercept in causing regression of inflamed or recurring pterygia.  This study from January 2015 to April 2017 consisted of using high-dose of ziv-aflibercept between 0.1 ml (2.5 mg) and 0.3 ml (7.5 mg), depending on the pterygium size and the degree of inflammation.  The injection was deep after tunneling the 30-gauge needle away from the injection site to avoid reflux.  Re-injection was done at the first sign of recurrence of inflammation.  The main outcome measure was regression of pterygial vessels by central retraction as documented by slit-lamp photography and anterior OCT.  A total of 4 subjects, 1 with bilateral pterygia, were treated.  Regression of new vessels and retraction of the leading edge of pterygial vessels occurred in all treated eyes (5 eyes) with dramatic visual gain in 1 eye from counting fingers to 6/9 (20/30).  Numbers of injections were 9 (1 eye; 18 months), 3 (2 eyes; 12 and 18 months), and 1 (2 eyes; 2.5 and 7 months).  The authors concluded that frequent high-dose intralesional ziv-aflibercept can lead to regression and/or retraction of inflamed pterygia.  These preliminary findings from a pilot study need to be validated in well-designed studies.

Treatment of Carcinomas and Sarcomas

Meehan and colleagues (2018) noted that the combination of the anti-angiogenic agent ziv-aflibercept and the heat shock protein 90 inhibitor ganetespib was associated with several serious and unexpected AEs and was not tolerable on the dosing schedule tested.  Studies such as these emphasize the importance of considering overlapping toxicities when designing novel treatment combination regimens.  In a single-arm, phase-I clinical trial, these researchers evaluated the combination of ziv-aflibercept with the Hsp90 inhibitor ganetespib.  Adult patients were eligible if they had recurrent or metastatic GI carcinomas, non-squamous NSCLC, urothelial carcinomas, or sarcomas that had progressed after at least 1 line of standard therapy.  Ziv-aflibercept was administered intravenously on days 1 and 15, and ganetespib was administered intravenously on days 1, 8, and 15, of each 28-day cycle.  A total of 5 patients were treated with the combination.  Although 3 patients achieved SD, study treatment was associated with several serious and unexpected AEs.  The authors concluded that the dose escalation phase of this study was not completed, but the limited data obtained suggested that this combination may be too toxic when administered on this dosing schedule.

Central Serous Chorioretinopathy

In a retrospective, single-center study, Doepfner and colleagues (2018) examined the effect of off-label photodynamic therapy (PDT) in combination with intravitreal off-label ziv-aflibercept or off-label aflibercept injection in patients with chronic or repeatedly recurrent acute central serous chorioretinopathy (CSC).  Changes in BCVA and subfoveal subretinal fluid (sSRF) and maximum subretinal fluid (mSRF) were analyzed in a 17 patients (18 eyes) with persistent subretinal fluid for more than 3 months of duration of CSC.  Treatment efficacy was measured between injection and PDT at 30 ± 15 days, 90 ± 15 days and 180 ± 30 days after PDT.  Significant reduction of sSRF and mSRF was shown after therapy with ziv-aflibercept and aflibercept combined with PDT (p < 0.001).  Course of BCVA showed non-significant improvement within 6 months (p = 0.065); 1 case of allergic reaction after fluorescein angiography (FA) and 1 case of ophthalmic migraine after ziv-aflibercept injection were documented; 1 case of reversible vision loss occurred during 6 months after combination therapy.  No other AEs or side effects were reported.  The authors concluded that combination therapy of ziv-aflibercept and aflibercept with PDT appeared to be beneficial, even in cases of chronic or repeatedly recurrent acute CSC; and is therefore a potential therapeutic option for this challenging disease.  Moreover, these researchers stated that further larger and controlled studies are needed to obtain definite answers for this specific patient population.

Corneal Neovascularization

In the rabbit model, Gore and colleagues (2018) evaluated the efficacy of ziv-aflibercept as a treatment for established corneal neovascularization (NV) and compared its efficacy to that of bevacizumab following ocular chemical insult of sulfur mustard (SM).  Chemical SM burn was induced in the right eye of NZW rabbits by vapor exposure.  Ziv-aflibercept (2 mg) was applied once to neovascularized eyes by subconjunctival injection while subconjunctival bevacizumab (5 mg) was administered twice-weekly, for 3 weeks.  Non-treated exposed eyes served as a control.  A clinical follow-up employed by slit-lamp microscope, was performed up to 12 weeks following exposure and digital photographs of the cornea were taken for measurement of blood vessels length using the image analysis software.  Eyes were taken for histological evaluation 2, 4 and 8 weeks following treatment for general morphology and for visualization of NV, using H&E and Masson Trichrome stainings, while conjunctival goblet cell density was determined by PAS staining.  Corneal NV developed, starting as early as 2 weeks after exposure.  A single subconjunctival treatment of ziv-aflibercept at 4 weeks post-exposure, significantly reduced the extent of existing NV already 1 week following injection, an effect that lasted for at least 8 weeks following treatment, while NV in the non-treated exposed eyes continued to advance.  The extensive reduction in corneal NV in the ziv-aflibercept treated group was confirmed by histological evaluation.  Bevacizumab multiple treatment showed a benefit in NV reduction, but to a lesser extent compared to the ziv-aflibercept treatment.  Finally, ziv-aflibercept increased the density of conjunctival goblet cells as compared to the exposed non-treated group.  The authors concluded that subconjunctival ziv-aflibercept single treatment presented a highly efficient long-term therapeutic benefit in reducing existing corneal NV, following ocular SM exposure.  They stated that these findings showed the robust anti-angiogenic efficacy of ziv-aflibercept and demonstrated the advantage of this treatment over the other anti-angiogenic therapies in ameliorating corneal NV and protecting the ocular surface.  These preliminary findings need to be validated in well-designed studies with human subjects.

Choroidal Neovascular Membranes / Exudative (or Neovascular) Age-Related Macular Degeneration

Singh et al (2019) analyzed the pooled safety data of intravitreal ziv-aflibercept (IVZ) therapy for various retinal conditions. The investigators reported on a retrospective, observational study which included patients from 14 participating centers who received IVZ. The medical records of patients who received IVZ from March 2015 through October 2017 were evaluated. Patient demographics and ocular details were compiled. Ocular and systemic adverse events that occurred within 1 month of IVZ injections were recorded and defined as either procedure-related or drug-related.S: A total of 1704 eyes of 1562 patients received 5914 IVZ injections (mean ± SD: 3.73±3.94) during a period of 2.5 years. The age of patients was 60.6 ± 12.8 years (mean ± SD) and included diverse chorioretinal pathologies. Both ocular (one case of endophthalmitis, three cases of intraocular inflammation, and one case each of conjunctival thinning/necrosis and scleral nodule) and systemic adverse events (two cases of myocardial infarction, one case of stroke and two deaths) were infrequent. This constitutes the largest pooled safety report on IVZ use and includes patients from 14 centers distributed across the globe. The investigators reported that this study shows that IVZ has an acceptable ocular and systemic safety profile with incidences of adverse events similar to those of other vascular endothelial growth factor inhibitory drugs. The analysis supports the continued use of IVZ in various retinal disorders.

Mansour et al (2019) assessed the 30-month outcome of treat and extend (TAE) intravitreal ziv-aflibercept therapy in eyes with macular diseases. In this prospective study, consecutive subjects received intravitreal 0.05 mL ziv-aflibercept (1.25 mg) injections for various macular diseases. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution) and central macular thickness (CMT) on spectral domain optical coherence tomography. Paired comparison was done using Wilcoxon signed-rank test calculator. Fifty-three eyes of 48 subjects (33 naïve eyes) received intravitreal ziv-aflibercept and were followed between 12 and 30 months following TAE included neovascular age-related macular degeneration (nAMD) (35 eyes) and diabetic macular edema (DMO) (18 eyes). In eyes with nAMD, CMT decreased by 107.8 µm at the 30-month follow-up (p=0.012) with BCVA gain of 0.52 (p=0.001). In eyes with DMO, CMT decreased by 224.3 µm at the 30-month follow-up (p=0.027) with BCVA gain of 0.46 (p = 0.042). Combining all disease categories, the mean number of injections was 9.2 at month 12, 2.5 between 12 and 18 months, 1.6 between 18 and 24 months and 1.0 between 24 and 30 months. The investigators concluded that using TAE regimen, intravitreal ziv-aflibercept appeared efficacious at managing retinal disease through month 30 using the TAE regimen.

Mansour et al (2019) assessed the two-year outcome of intravitreal ziv-aflibercept (IVZ) in eyes with macular diseases. Consecutive subjects with various macular diseases that received six or more of 0.05 mL IVZ (1.25 mg) injections with at least 1 year follow-up were included. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution) and central macular thickness (CMT) on spectral domain optical coherence tomography. Paired comparison was done using Wilcoxon signed-rank test calculator. The 107 eyes of 91 subjects received IVZ. Subjects were followed with mean ± SD follow-up interval of 1.48±0.44 months following treat and extend or pro-re-nata protocol. The distribution included neovascular macular degeneration (42 eyes), diabetic macular edema (32 eyes) and macular edema secondary toretinal vein occlusion (11 eyes). Fifty eyes were naive, while 57 eyes were previously treated. Combining all disease categories, CMT decreased significantly by 133.0 ± 153.0 µm at the 24-month follow-up (P<0.001) with BCVA gain of 0.35 ± 0.37 at the 24-month follow-up (P<0.001) with mean number of injections of 8.5 at month 12, 2.4 between 12 and 18 month and 1.7 between 18 and 24 month. Ocular and systemic adverse effects included one episode of transient uveitis and one instance of central retinal artery occlusion after 1121 injections. The investigators concluded that IVZ appears safe and efficacious in the therapy of macular diseases through 2 years.

HodjatJalali et al (2018 investigated the short-term outcomes after intravitreal injection of ziv-aflibercept in the treatment of choroidal and retinal vascular diseases. Thirty-four eyes of 29 patients with age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion (RVO) received a single dose intravitreal injection of 0.05 ml ziv-aflibercept (1.25 mg). Visual acuity, spectral domain optical coherence tomography (SD-OCT) activity, and possible side effects were assessed before and at 1 week and 1 month after the intervention. At 1 month after treatment, mean central macular thickness (CMT) significantly decreased from 531.09 μm to 339.5 μm (P < 0.001), and no signs of side effects were observed in any subject. All patients responded to treatment in terms of reduction in CMT. The improvement in visual acuity was statistically non-significant. The investigators concluded that their findings suggest that a single dose intravitreal injection of ziv-aflibercept may have acceptable relative safety and efficacy in the treatment of patients with intraocular vascular disease. 

Ashraf et al (2017) evaluated the safety and efficacy of ziv-aflibercept in the treatment of refractory diabetic macular edema (DME). The investigators reported on a retrospective case series looking at the safety of ziv-aflibercept in patients with DME refractory to previous anti-vascular endothelial growth factor (VEGF) therapy. Detailed ophthalmologic examination, best-corrected visual acuity, and optical coherence tomography measurements were  performed pre-switch, as well as at each monthly follow-up visit. The study included 34 eyes of 26 patients. The mean number of ziv-aflibercept injections post-switch was 2.03 injections. Visual acuity improved from a mean of 0.63 logMAR pre-switch to 0.51 logMAR after the first visit and 0.46 logMAR after the second visit post-switch (P < .084). Macular thickness improved from a mean of 513.79 μm to 411.79 μm (P = .006) on the first visit and 426.76 μm (P = .029) after the second visit post-switch. No adverse ocular or systemic side effects were reported on any of the follow visits. The investigators concluded that ziv-aflibercept appears to be safe and effective in patients with refractory DME previously treated with other anti-VEGF agents in the short term. 

Braimah et al (2018) evaluated 12-month outcome of intravitreal ziv-aflibercept (IVZ) therapy in eyes with neovascular age-related macular degeneration (nAMD) that were non-responsive to bevacizumab and ranibizumab. This retrospective study included 16 eyes (14 patients) with nAMD who were on prior treatment with bevacizumab and ranibizumab and were treated with as-needed IVZ (1.25 mg/0.05 mL) for 12 months. The primary outcome measure was the mean change in best corrected visual acuity (BCVA) and secondary outcome measures included mean change in central macular thickness (CMT), retinal pigment epithelial detachment (RPED) heights, longest treatment free interval, presence of subretinal fluid (SRF) and intraretinal fluid (IRF) and adverse events. There was no change in the mean logarithm of minimum angle of resolution (logMAR) BCVA at baseline and following treatment with IVZ therapy (p=0.978). The mean number of IVZ injections during 12 months was 5.9±3.3, and the mean number of antivascular endothelial growth factors (VEGFs) injections prior to switching to IVZ was 8.4±4.7. The mean treatment free interval was longer during IVZ therapy (114.4±67.1 days) compared with 76.3±54.6 days before IVZ therapy (p=0.03). Five (31.25%) eyes had visual gains of at least 0.1 logMAR, 3 (18.75%) eyes had stable BCVA (within 0.1 logMAR) and 8 (50%) eyes had BCVA decline of at least 0.1 logMAR. There was no significant difference in the mean CMT, RPED heights and presence of IRF and SRF at 12 months compared with baseline. No adverse events were noted. The authors concluded that IVZ increased the treatment free interval in non-responders but no significant change in visual and anatomic outcomes.

Mansour et al (2017) investigated the long-term safety of intravitreal ziv-aflibercept in eyes receiving six or more intravitreal injections of ziv-aflibercept, an off-label substitute to the approved aflibercept. Consecutive patients with retinal disease receiving six or more of intravitreal 0.05 mL ziv-aflibercept (1.25 mg) injections were followed monthly in three centers. Outcome measures were best-corrected visual acuity (BCVA) (logarithm of the minimum angle of resolution (logMar)) and central macular thickness (CMT) on spectral domain optical coherence tomography and monitoring for ocular inflammation, progression of lens opacities and intraocular pressure rise. Paired comparison was done using Wilcoxon signed-rank test calculator. Sixty-five eyes of 60 consecutive patients received a mean of 8.4 (6-17) intravitreal injections with a baseline mean logMAR BCVA of 0.98±0.56 and CMT 432.7±163.0 μm and followed for a mean of 9.2 months (range 6-18 months). After the sixth injection, mean BCVA improved to 0.57±0.36 (p=0.001) and CMT decreased to 274.8±117.8 μm (p=0.0001). At the 9-month follow-up, mean BCVA improved to 0.62 ± 0.37 (p=0.0004) and mean CMT decreased to 292.0 ± 160.9 μm (p<0.01) in 19 eyes. At 1 year, mean BCVA was 0.73 ± 0.52 and CMT 311.6 ± 232.5 μm in seven eyes. Intraocular pressures did not increase after injections. One subject developed transient mild iritis at the fourth injection but not on subsequent injections. No lens opacity progression or endophthalmitis was noted. Systemic adverse effects were not registered. The authors concluded that repeated intravitreal injections of ziv-aflibercept appear tolerable, safe and efficacious in the therapy of retinal disease.

Braimah et al (2017) reported the short-term outcomes of eyes with choroidal neovascularization (CNV) associated with causes other than age-related macular degeneration (AMD) after treatment with intravitreal ziv-aflibercept (IVZ) injections. This retrospective study included eyes with non-AMD-related CNV that were treated with IVZ (1.25 mg/0.05 mL) on a pro re nata basis. The primary outcome measure is the mean change in best-corrected visual acuity (BCVA) and secondary outcome measures include the mean change in central macular thickness (CMT) and adverse events. Twenty-three eyes of 19 patients with CNV due to high myopia (9), macular telangiectasia (4), central serous chorioretinopathy (3), choroidal osteoma (2),  choroiditis (2), Best's disease (2) and idiopathic (1) were treated. The mean follow-up period was 4±1.9 months. The median number of IVZ injections was 1 (range, 1-3) and the median treatment-free interval at the time of the final visit was 3 months (range, 1-8). The mean BCVA improved from 0.67 LogMAR to 0.58 LogMAR (p=0.0507). Nine of 23 (39%) eyes had BCVA gains of at least 0.1 LogMAR, 11 (48%) eyes had stable BCVA (within 0.1 LogMAR of baseline) and 3 (13%) eyes had a BCVA decline of at least 0.1 LogMAR at the final visit. The mean CMT improved significantly from baseline until the final visit (22 vs 174.5 μm; p=0.037). No ocular or systemic adverse events were noted. The investigators concluded that IVZ improves CMT in patients with CNV associated with causes other than AMD, but improvements in BCVA are modest.

Mansour et al (2016)  investigated the 3-month safety and efficacy in wet age-related macular degeneration (AMD) treated with intravitreal ziv-aflibercept. Prospectively, consecutive patients with wet AMD underwent ziv-aflibercept intravitreal injection (1.25 mg/0.05 mL) from March 2015 to November 2015. Monitoring of best-corrected visual acuity, intraocular inflammation, cataract progression and by spectral domain optical coherence tomography were carried out at baseline day 1, 1 week, 1 month, 2 months and 3 months after injections. Thirty eyes were treated (22 Caucasians, 8 Indians; 16 men, 14 women; 14 right eyes and 16 left eyes) with mean age of 74.3 years with 11 treatment-naïve cases and 19 having had treatment-non-naïve. Best-corrected visual acuity improved from baseline logMAR 1.08-0.74 at 1 week, 0.72 at 1 month, 0.67 at 2 months and 0.71 at 3 months (p<0.001 for all time periods). Central macular thickness in microns decreased from 332.8 to 302.0 at 1 week, 244.8 at 1 month, 229.0 at 2 months and 208.2 at 3 months (p<0.001 for all time periods). There were no signs of intraocular inflammation, or change in lens status or increase in intraocular pressure throughout the study.  The authors concluded that off-label use of ziv-aflibercept improved VA, without detectable ocular toxicity and offered a cheaper alternative to the same molecule aflibercept, especially in low/middle-income countries and in countries where aflibercept (Eylea) is not available.  Moreover, they stated that further studies on long-term safety with multiple injections in various retinal diseases are underway to explore ziv-aflibercept as an alternative intravitreal anti-VEGF injection.  The authors stated that the drawbacks of this study included the small number of eyes treated (n = 30); small sample bias overall; irregular short duration of follow-up (3 months); and 1-armed open-label design.  Furthermore ,these investigators did not perform any electroretinographic tests to confirm any toxicity at 3 months.

de Oliveira Dias and co-workers (2017) evaluated the 6-month safety and efficacy of ziv-aflibercept intravitreal injections for treating exudative AMD.  A total of 15 patients with unilateral exudative AMD were enrolled.  The BCVA was measured and SD-OCT was performed at baseline and monthly.  Full-field electroretinography (ffERG) and multi-focal ERG (mfERG) were obtained at baseline and 4, 13, and 26 weeks after the first injection.  All patients received 3 monthly intravitreal injections of ziv-aflibercept (1.25 mg) followed by as-needed treatment.  Between baseline and 26 weeks, the mean logMAR BCVA improved (p = 0.00408) from 0.93 ± 0.4 (20/200) to 0.82 ± 0.5 (20/160) logarithm of the minimum angle of resolution, respectively; the central retinal thickness decreased significantly (p = 0.0007) from 490.3 ± 155.1 microns to 327.9 ± 101.5 microns; the mean total macular volume decreased significantly (p < 0.0001) from 9.51 ± 1.36 mm to 8.08 ± 1.34 mm, and the a-wave implicit time increased, with no differences in the other ffERG parameters.  The average mfERG macular responses within the first central 15° showed significantly (p < 0.05) increased P1 amplitudes at 26 weeks.  No systemic or ocular complications developed.  The authors concluded that intravitreal ziv-aflibercept significantly improved the BCVA, mfERG amplitudes, central retinal thickness, and total macular volume from baseline to 26 weeks.  No retinal toxicity on ffERG or adverse events (AEs) occurred during the follow-up period.  Moreover, these researchers stated that a longer follow-up is needed to confirm if repeated injections or dose escalations increase the risk of ocular AEs or retinal toxicity.  The authors concluded that the drawbacks of this study were the small number of patients (n = 15), with 11 treatment-naive patients; the non-randomized design; and the short follow-up period (6 months).

Chhablani and colleagues (2017) evaluated the safety of single intravitreal 2 mg ziv-aflibercept (0.08 ml) injections for the treatment of choroidal neovascular membranes (CNVM).  Eyes with CNVM because of several conditions each received single intravitreal injections of 2 mg ziv-aflibercept (0.08 ml).  Comprehensive ophthalmic examinations and detailed systemic evaluations were performed at baseline and days 1, 7, and 30 after injections.  Standard electroretinography (ERG) was performed at baseline and day 30.  Primary outcome measures consisted of safety assessments (signs of clinical toxicity and ERG abnormalities).  Secondary outcome measures included changes in BCVA and central subfield thickness (CST) of the macula.  A total of 21 eyes of 20 patients (12 males) received injections.  Etiologies responsible for the CNVM included age-related macular degeneration (n = 14), polypoidal choroidal vasculopathy (PCV) (n = 3), myopia (n = 2), and idiopathic juxta-foveal telangiectasia (n = 2).  None of the patients complained of worsening vision or pain after the intravitreal injections and no intra-ocular inflammation was seen.  No significant changes in the ERG b/a ratio from baseline to 1 month were measured (scotopic: p = 0.89; photopic: p = 0.13) and mean IOPs were unchanged (14.2 ± 3.6 versus 13.7 ± 3.0 mmHg; p = 0.62).  Mean BCVA did not change significantly from baseline to 1 month (0.66 ± 0.37 logMAR [Snellen equivalent: 20/100] versus 0.61 ± 0.35 logMAR [Snellen equivalent: 20/80]; p = 0.72) but significant improvements in CST were seen (343 ± 177 versus 210 ± 133 μm; p = 0.01).  The authors concluded that single intravitreal injections of 2 mg ziv-aflibercept (0.08 ml) appeared to be safe through 1 month.  This was small (20 patients) safety study with short-term (1 month) follow-up; these preliminary findings need to be validated by well-designed studies.

Elshout and associates (2018) reported the quality, validity and usefulness of CEAs for therapies for neovascular AMD (nAMD).  They performed a systematic review in PubMed, Embase and Cochrane to include CEAs.  Quality and validity assessment was based on current general quality criteria and on elements that are specific to the field of ophthalmology.  A total of 48 CEAs were included in the review; 44 CEAs did not meet 4 basic model quality and validity criteria specific to CEAs in the field of ophthalmology (both eyes analyzed instead of 1; a time horizon extending beyond 4 years; extrapolating visual acuity [VA] and treatment intervals beyond trial data realistically; and including the costs of low-vision).  A total of 4 CEAs aligned with the quality and validity criteria.  In 2 of these CEAs bevacizumab as-needed (PRN) was more cost-effective than bevacizumab monthly; aflibercept (VIEW); or ranibizumab monthly or PRN.  In 2 CEAs, ranibizumab (PRN or treat and extent) was dominant over aflibercept.  In 2 other CEAs, aflibercept was either more cost-effective or dominant over ranibizumab monthly or PRN.  The authors concluded that 2 of the CEAs of sufficient quality and validity showed that bevacizumab PRN is the most cost-effective treatment.  Comparing ranibizumab and aflibercept, either treatment can be more cost-effective depending on the assumptions used for drug prices and treatment frequencies.  The majority of the published CEAs were of insufficient quality and validity.  They wrongly inform decision-makers at the cost of opportunities for ophthalmologists to treat patients.  As such, they may negatively influence overall patient outcomes and societal costs.  For future ophthalmic treatments, CEAs need to be improved and only published when they are of sufficient quality and validity.  This review did not mention ziv-aflibercept.

Barmas-Alamdari and colleagues (2019) stated that AMD is the leading cause of blindness in adults over the age of 50 in the USA; nAMD is sight-threatening, but can be treated by 3 currently utilized, intravitreally administered drugs: aflibercept, bevacizumab, and ranibizumab.  Ziv-aflibercept is an analog of aflibercept, containing the same active molecule in a different buffer solution, and its recent availability has prompted numerous pre-clinical and clinical trials addressing its viability for intra-ocular use, summarized herein.  Trial outcomes demonstrated that ziv-aflibercept has a similar safety profile to other indicated drugs with effective maintenance or improvement of BCVA and reduction of retinal fluid or central foveal thickness (CFT).  Clinical trials of ziv-aflibercept in other neovascular disorders such as diabetic macular edema (DME) and retinal vein occlusion (RVO) have shown similar results.  The authors concluded that further prospective, randomized studies of ziv-aflibercept are needed, particularly in eyes with nAMD.

Combined Capecitabine and Ziv-Aflibercept for the Treatment of Colorectal Cancer

Strickler and colleagues (2019) stated that patients with chemotherapy refractory metastatic colorectal cancer (CRC) have a poor prognosis and limited therapeutic options.  In a phase-Ib/II clinical trial, these researchers established the maximum tolerated dose (MTD) and recommended phase-II dose (RPTD) for the combination of capecitabine and ziv-aflibercept, and then they evaluated the efficacy of the combination in patients with chemotherapy refractory metastatic CRC.  All patients were required to have a Karnofsky Performance Status (KPS) of greater than 70 % and adequate organ function.  The phase-Ib dose escalation cohort included patients with advanced solid tumors who had progressed on all standard therapies.  Using a standard 3 + 3 design, these researchers identified the MTD and RPTD for the combination.  A total of 50 patients with metastatic CRC who had progressed on or were intolerant of a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab were then enrolled in a single-arm phase-II expansion cohort, and were treated at the RPTD.  Prior EGFR antibody therapy was needed for subjects with RAS wildtype tumors.  The primary end-point for the expansion cohort was PFS at 2 months; and secondary end-points included ORR and OS.  A total of 63 patients were enrolled and evaluable for toxicity (13 dose escalation; 50 expansion).  The MTD and RPTD were: capecitabine 850 mg/m2, P.O. bid, days 1 to 14, and ziv-aflibercept 6 mg/kg I.V., day 1, of each 21-day cycle.  In the expansion cohort, 72 % of patients were progression-free at 2 months (95 % CI: 60 to 84 %). Median PFS and OS were 3.9 months (95 % CI: 2.3 to 4.5) and 7.1 months (95 % CI: 5.8 to 10.0), respectively.  Among all patients evaluable for toxicity, the most common treatment related AEs (all grade [%]; grade greater than or equal to 3 [ %]) included palmar-plantar erythrodysesthesia (41 %; 6 %), hypertension (33 %; 22 %), and mucositis (19 %; 5 %).  RNA was isolated from archived tumor specimens and gene expression analyses revealed no association between angiogenic biomarkers and clinical outcomes.  The authors concluded that the combination of capecitabine and ziv-aflibercept at the RPTD demonstrated acceptable safety and tolerability; PFS at 2 months in patients with chemotherapy refractory metastatic CRC was significantly greater than that in historical controls, indicating that this combination warrants further study.

Ziv-Aflibercept for the Treatment of Vitreous Hemorrhage

In a prospective multi-center study, Mansour and colleagues (2020) examined the safety and efficacy of intravitreal ziv-aflibercept (IVZ) in the treatment of vitreous hemorrhage (VH) in eyes with previously lasered proliferative diabetic retinopathy (PDR).  Patients who had dense VH from PDR underwent IVZ (1.25 mg aflibercept).  Demographic characteristics of the patients, baseline and final logMar VA, number of injections, VH clearance time, and need for vitrectomy were recorded.  A total of 27 eyes of 21 patients were included in the study.  Mean age of study patients was 61.3 ± 14.1 years with mean duration of diabetes mellitus of 22.6 ± 7.8 years.  Mean logMAR BCVA at baseline was 1.41 ± 1.26 (Snellen equivalent 20/514) and at the last visit 0.55 ± 0.61 (Snellen equivalent 20/70) with a mean gain of 0.86 Early Treatment Diabetic Retinopathy Study (ETDRS) line (paired student t-test = 5.1; p ≤ 0.001).  Mean number of IVZ 2.4 ± 1.6 (range of 1 to 6).  The mean follow-up time was 11.7 ± 11.1 months (range of 1 to 34).  Mean time for visual recovery and/or VH clearance was 5.7 ± 3.3 weeks.  Eyes, which required multiple injections, the interval period between injections for recurrent VH was 6.4 ± 5.2 months.  No subject required vitrectomy; and no ocular or systemic AEs were noted.  The authors concluded that IVZ injections had good short-term safety and efficacy for the treatment of new or recurrent VH in previously lasered eyes with PDR reducing somewhat the need for vitrectomy.  These preliminary findings need to be validated by well-designed studies.

The authors stated that the drawbacks of this study included the small sample size (n = 21 subjects) and the limited follow-up (mean of 11.7 months), not accounting for systemic factors such as uncontrolled diabetes (hemoglobin A1C level), systemic blood pressure, smoking status, obesity, history of chronic obstructive pulmonary disease (COPD), presence of anemia, anticoagulant use, presence of cough, sleep apnea, etc.

Furthermore, an UpToDate review on “Diabetic retinopathy: Prevention and treatment” (Fraser et al, 2020) states that “In patients with severe proliferative diabetic retinopathy with vitreous hemorrhage and/or traction involving the macula, we recommend early rather than delayed vitrectomy (Grade 1B).  Vitrectomy can also be considered in type 1 and type 2 patients with severe proliferative diabetic retinopathy unresponsive to pan-retinal photocoagulation and as an adjunct to remove media opacity and permit adequate retinal laser ablation”.  This review does not mention intra-vitreal ziv-aflibercept as a therapeutic option.

National Comprehensive Cancer Network (NCCN) Recommendations

The NCCN Drugs and Biologics Compendium (NCCN, 2019) recommends ziv-aflibercept (Zaltrap) for the following:

Colon Cancer

• Primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
  
  
  • in combination with irinotecan
  • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
    
    
• Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen in patients not previously treated with irinotecan-based therapy [2A]

Rectal Cancer 

• Primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
  
  
  • in combination with irinotecan
  • in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
    
    
• Subsequent therapy for progression of unresectable advanced or metastatic disease in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen in patients not previously treated with irinotecan-based therapy [2A]

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9400	Injection, ziv-aflibercept, 1 mg
Other HCPCS codes related to the CPB:
J0640	Injection, leucovorin calcium, per 50 mg [folinic acid]
J0641	Injection, levoleucovorin calcium, 0.5 mg
J8521	Capecitabine, oral, 500 mg
J9035	Injection, bevacizumab, 10 mg
J9190	Injection, fluorouracil, 500 mg
J9206	Injection, irinotecan, 20 mg
J9263	Injection, oxaliplatin, 0.5 mg
Q0083 - Q0085	Chemotherapy administration
Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
ICD-10 codes covered if selection criteria are met:
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid junction, and anus
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of lung
C43.0 - C43.9	Malignant melanoma of skin
C44.520	Squamous cell carcinoma of anal skin
C49.1 - C49.9	Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of breast [male and female]
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C55	Malignant neoplast of uterus, part unspecified
C56.1 - C56.9	Malignant neoplasm of ovary
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C61	Malignant neoplasm of prostate
C64.1 - C64.9	Malignant neoplasm of kidney
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C67.0 - C67.9	Malignant neoplasm of bladder
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C73	Malignant neoplasm of thyroid gland
C81.00 - C88.9	Hodgkin lymphoma
C90.10 - C95.92	Plasma cell leukemia
E08.311, E08.3211 - E08.3219, E08.3311 - E08.3319, E08.3411 - E08.3419, E08.3511 - E08.3559, E09.311, E09.3211 - E09.3219, E09.3311 - E09.3319, E09.3411 - E09.3419, E09.3511 - E09.3559, E10.311, E10.3211 - E10.3219, E10.3311 - E10.3319, E10.3411 - E10.3419, E10.3511 - E10.3559, E11.311, E11.3211 - E11.3219, E11.3311 - E11.3319, E11.3411 - E11.3419, E11.3511 - E11.3559, E13.311, E13.3211 - E13.3219, E13.3311 - E13.3319, E13.3411 - E13.3419, E13.3511 - E13.3559	Other specified diabetes mellitus with diabetic retinopathy with macular edema
H11.001 - H11.609	Pterygium
H16.401 - H16.449	Corneal neovascularization
H30.001 - H30.93	Chorioretinal inflammation
H34.00 - H34.9	Retinal vascular occlusion
H35.051 - H35.059	Retinal neovascularization
H35.321 - H35.329	Exudative age-related macular degeneration
H35.711 - H35.719	Central serous chorioretinopathy
H43.10 - H43.13	Vitreous hemorrhage

The above policy is based on the following references: