Clinical UM Guideline


Subject: Ziv-aflibercept (Zaltrap®)
Guideline #: CG-DRUG-71 Publish Date:    12/12/2018
Status: Reviewed Last Review Date:    11/08/2018


This document addresses the use of ziv-aflibercept (Zaltrap) for oncological indications. This document does not address the use of aflibercept (Eylea®), an intravitreal injection for age-related macular degeneration. Ziv-aflibercept (Zaltrap, Sanofi U.S., Inc., Bridgewater, NJ) (previously known as aflibercept) is a recombinant fusion protein consisting of vascular endothelial growth factor (VEGF)-binding portions used for treatment of metastatic colorectal cancer (mCRC) under specific circumstances.

Clinical Indications

Medically Necessary:

Ziv-aflibercept (Zaltrap) is considered medically necessary when ALL of the following criteria have been met:

  1. The individual has one of the following:
    1. Metastatic anal adenocarcinoma; or
    2. Metastatic appendiceal adenocarcinoma; or
    3. Metastatic small bowel adenocarcinoma; or
    4. Metastatic colorectal cancer; and
  2. The individual is resistant to or has disease progression following treatment with an oxaliplatin-containing regimen; and
  3. Ziv-aflibercept will be used in combination with an irinotecan based regimen; and
  4. Ziv-aflibercept will be given in a single line of therapy.

Not Medically Necessary:

Ziv-aflibercept (Zaltrap) is considered not medically necessary when given concomitantly with cetuximab, panitumumab, or bevacizumab.

Ziv-aflibercept is considered not medically necessary when used in combination with the same irinotecan based regimen that was previously used in combination with bevacizumab.

Ziv-aflibercept is considered not medically necessary when the above criteria are not met.


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




Injection, ziv-aflibercept, 1 mg [Zaltrap]



ICD-10 Diagnosis




Malignant neoplasm of small intestine



Malignant neoplasm of colon



Malignant neoplasm of rectosigmoid junction



Malignant neoplasm of rectum



Malignant neoplasm of anus and anal canal



Secondary malignant neoplasm of small intestine



Secondary malignant neoplasm of large intestine and rectum



Personal history of other malignant neoplasm of large intestine



Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus



Personal history of other malignant neoplasm of small intestine


Discussion/General Information

Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. Anal cancer refers to malignancies developing from anal tissue (for example, anus, anal canal or anorectum) which include the opening of the rectum to the outer body. Anal adenocarcinoma occurs in the anal glandular tissue. Appendiceal adenocarcinoma, also known as appendix adenocarcinoma occurs in appendiceal glandular tissue. Small bowel adenocarcinoma, also known as small intestine adenocarcinoma occurs in small bowel glandular tissue. Anal adenocarcinoma, appendiceal adenocarcinoma and small bowel adenocarcinoma are all rare cancers.

According to the American Cancer Society, there will be an estimated 50,630 new cases of colon cancer and 43,030 new cases of rectal cancer diagnosed in 2017. It is expected that 50,630 persons will die from colon and rectal cancer combined in 2018.

On August 3, 2012, the United States Food and Drug Administration (FDA) approved ziv-aflibercept injection for use in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of individuals with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. The active ingredient in Zaltrap, aflibercept, is also marketed as Eylea (Regeneron) to treat wet age-related macular degeneration.

Metastatic Colorectal Cancer

The FDA approval was based on results of a randomized double-blind placebo-controlled global multicenter phase III (Aflibercept Versus Placebo in Metastatic Colorectal Cancer After Failure of an Oxaliplatin-Based Regimen) (VELOUR) trial. Van Cutsem and colleagues (2012) enrolled 1226 adults with mCRC whose disease progressed during or within 6 months of receiving oxaliplatin-based combination chemotherapy, with or without prior use of bevacizumab. Study subjects were randomly assigned to receive aflibercept (4 mg/kg intravenously [IV]; 612 subjects) or placebo (614 subjects) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary endpoint was overall survival. The authors concluded that the addition of aflibercept to the FOLFIRI regimen significantly improved both overall and progression-free survival. The addition of aflibercept almost doubled the response rate, from 11% to 20%. Progression-free survival (PFS) improved by about 2 to 3 months, and overall survival (OS) (the primary endpoint of the study) increased from approximately 12.0 months to 13.5 months. Ziv-aflibercept was not studied in the pediatric population.

In a phase II trial, Tang and colleagues (2012) investigated the safety and efficacy of aflibercept in adults with mCRC who had received at least one prior palliative regimen. A total of 75 subjects were enrolled in 2 cohorts, bevacizumab naïve (n=24) and prior bevacizumab (n=51). Aflibercept was administered at 4 mg/kg IV 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 subjects. In the prior bevacizumab cohort, 1 subject achieved a partial response and 6 had stable disease for 16 weeks or more. The median PFS in the bevacizumab-naïve and prior bevacizumab cohorts was 2 months and 2.4 months, respectively. Median OS was 10.4 months and 8.5 months, respectively. The most common grade 3 or higher treatment-related adverse events were hypertension, proteinuria, fatigue, and headache. Ten subjects 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 those with pretreated mCRC with moderate toxicity.

In a post hoc extended analysis of the VELOUR trial, Joulain and colleagues (2013) estimated the difference in mean survival between the trial’s treatment groups with statistical analysis by extrapolating study survival curves. Mean OS was calculated over a 15-year survival period and the estimated difference between aflibercept+FOLFIRI and placebo+FOLFIRI was 4.7 months. The survival advantage with aflibercept was found to be at least 3 months for the intention to treat population.

Tabernero and colleagues (2014) performed a pre-specified subgroup analysis from the VELOUR trial. Of specific interest were the outcomes of individuals stratified by prior treatment with or without bevacizumab. Median OS, for aflibercept versus placebo was found to be 12.5 (10.8-15.5) versus 11.7 (9.8-13.8) in individuals with prior bevacizumab treatment and 13.9 (12.7-15.6) versus 12.4 (11.2-13.5) in those without prior bevacizumab treatment. The authors concluded that the benefits of aflibercept in combination with FOLFIRI in individuals with mCRC previously treated with oxaliplatin were maintained across the specified subgroups, including in cases with or without prior bevacizumab treatment.

In 2015, Ruff and colleagues reported on the safety and OS benefit of aflibercept over the time course of the VELOUR trial. A total of 1226 subjects had been randomized to treatment consisting either of FOLFIRI and placebo (n=614) or FOLFIRI and aflibercept (n=612). There were 863 deaths (460 in the placebo arm and 403 in the aflibercept arm) on which this analysis was based. The estimated survival probabilities were 38.5% vs 30.9% at 18 months, 28% vs 18.7% at 24 months and 22.3% vs 12.0% at 30 months for the aflibercept and placebo-treated groups, respectively. Common adverse events were diarrhea, stomatitis, infection and hypertension. Most of the grade 3-4 adverse events associated with aflibercept occurred during the early treatment cycles and decreased with later cycles. The majority of adverse events were of single occurrence. Fatal adverse events with aflibercept and FOLFIRI (2.3%) were less in number or comparable to those reported for other regimens used for second line therapy of mCRC. The authors reported:

In conclusion, the present survival analysis of the VELOUR trial over different time points up to 30 months demonstrates an increase in survival probability over time for those treated with FOLFIRI plus aflibercept and a persistence of the survival benefit beyond the median survival time of 13.5 months.

The National Comprehensive Cancer Network (NCCN) colon and rectal Clinical Practice Guidelines in Oncology™ (2018) note that no data exists that suggest activity of FOLFIRI plus ziv-aflibercept in individuals who have progressed on FOLFIRI plus bevacizumab, or vice-versa. A FOLFIRI plus ziv-aflibercept regimen has only shown activity when given to FOLFIRI-naïve individuals. Additionally, no data suggests activity of single agent ziv-aflibercept.

Small bowel, appendiceal and anal adenocarcinomas

Small bowel and appendiceal adenocarcinomas are rare cancers and the limited data for therapy consists mainly of small retrospective reports (Czaykowski, 2007) and case series (Gibson, 2005). NCCN guidelines for colon cancer (V3.2018) indicate that small bowel and appendiceal adenocarcinoma may be treated with systemic chemotherapy according to their colon cancer guidelines. Anal adenocarcinoma is also very rare, and there is a lack of published literature identifying treatment of this tumor with ziv-aflibercept. However, NCCN guidelines for anal carcinoma (V2.2018) indicate that anal adenocarcinoma is managed according to their guidelines for rectal cancer.

Other Conditions

Ziv-aflibercept has also been evaluated as a treatment for other indications including, but not limited to, bladder cancer (Zhu, 2012), breast cancer (Perez, 2012), melanoma (Tarhini, 2011), non-small-cell lung cancer (Ramlau, 2012), ovarian cancer (Gotlieb, 2012;Teoh, 2012; Tew, 2014), pancreatic cancer (Rougier, 2013), prostate cancer (Galsky, 2010; Tannock, 2013), and small-cell lung cancer (Allen, 2014). However, the current published evidence does not support that the use of ziv-aflibercept to treat these conditions provides additional benefit.

Adverse Events and Warnings

Black box warnings from the FDA Product Information Label (2016) include the following:

Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in patients who have received ZALTRAP. Do not administer ZALTRAP to patients with severe hemorrhage.

Gastrointestinal Perforation:
Discontinue ZALTRAP therapy in patients who experience GI perforation.

Compromised Wound Healing:
Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume for at least 4 weeks following major surgery and until the surgical wound is fully healed.


Adenocarcinoma: A type of carcinoma (cancerous tumor) derived from glandular tissue, which can occur at various sites (lung, esophagus, cervix, intestinal tract, etc.).

Colorectal cancer: Cancer originating in the colon (the longest part of the large intestine) or the rectum (the last several inches of the large intestine before the anus).

Line of therapy:

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Single line of therapy: One line of therapy.


Peer Reviewed Publications:

  1. Allen JW, Moon J, Redman M, et al. Southwest Oncology Group S0802: a randomized, phase II trial of weekly topotecan with and without ziv-aflibercept in patients with platinum-treated small-cell lung cancer. J Clin Oncol. 2014; 32(23):2463-2470.
  2. Czaykowski P, Hui D. Chemotherapy in small bowel adenocarcinoma: 10-year experience of the British Columbia Cancer Agency. Clin Oncol (R Coll Radiol). 2007; 19(2):143-149.
  3. Galsky MD, Vogelzang NJ. Docetaxel-based combination therapy for castration-resistant prostate cancer. Ann Oncol. 2010; 21(11):2135-2144.
  4. Gibson MK, Holcroft CA, Kvols LK, Haller D. Phase II study of 5-fluorouracil, doxorubicin, and mitomycin C for metastatic small bowel adenocarcinoma. Oncologist. 2005; 10(2):132-137.
  5. Gotlieb WH, Amant F, Advani S, et al. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2012;13(2):154-162.
  6. Joulain F, Proskorovsky I, Allegra C, et al. Mean overall survival gain with aflibercept plus FOLFIRI vs placebo plus FOLFIRI in patients with previously treated metastatic colorectal cancer. Br J Cancer. 2013; 109(7):1735-1743.
  7. Perez EA, Spano JP. Current and emerging targeted therapies for metastatic breast cancer. Cancer. 2012; 118(12):3014-3025.
  8. Ramlau R, Gorbunova V, Ciuleanu TE, et al. Aflibercept and Docetaxel versus Docetaxel alone after platinum failure in patients with advanced or metastatic non-small-cell lung cancer: a randomized, controlled phase III trial. J Clin Oncol. 2012; 30(29):3640-3647.
  9. Rougier P, Riess H, Manges R, et al. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013; 49(12):2633-2642.
  10. Ruff P, Ferry DR, Lakomỳ R, et al. Time course of safety and efficacy of aflibercept in combination with FOLFIRI in patients with metastatic colorectal cancer who progressed on previous oxaliplatin-based therapy. Eur J Cancer. 2015; 51(1):18-26.
  11. Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014; 50(2):320-331.
  12. Tang PA, Cohen SJ, Kollmannsberger C, et al. Phase II clinical and pharmacokinetic study of aflibercept in patients with previously treated metastatic colorectal cancer. Clin Cancer Res. 2012; 18(21):6023-6031.
  13. Tannock IF, Fizazi K, Ivanov S, et al.; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013; 14(8):760-768.
  14. Tarhini AA, Frankel P, Margolin KA, et al. Aflibercept (VEGF Trap) in inoperable stage III or stage iv melanoma of cutaneous or uveal origin. Clin Cancer Res. 2011; 17(20):6574-6581.
  15. Teoh D, Secord AA. Antiangiogenic agents in combination with chemotherapy for the treatment of epithelial ovarian cancer. Int J Gynecol Cancer. 2012; 22(3):348-359.
  16. Tew WP, Colombo N, Ray-Coquard I, et al. Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study. Cancer. 2014; 120(3):335-343.
  17. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 30(28):3499-3506.
  18. Wang TF, Lockhart AC. Aflibercept in the treatment of metastatic colorectal cancer. Clin Med Insights Oncol. 2012; 6:19-30.
  19. Zhu Z, Shen Z, Xu C. Targeted therapy for advanced urothelial cancer of the bladder: Where do we stand? Anticancer Agents Med Chem. 2012; 12(9):1081-1087.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. National Cancer Institute (NCI). Colon cancer treatment (PDQ® ). Last modified August 16, 2018. Available at: Accessed on September 27, 2018.
  2. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: Accessed on September 24, 2018.
  3. NCCN Clinical Practice Guidelines in Oncology™. © 2018 National Comprehensive Cancer Network, Inc. For additional information: Accessed on September 27, 2018.
    • Anal Carcinoma (V2.2018). Revised June 8, 2018.
    • Colon Cancer (V3.2018). Revised August 7, 2018.
    • Rectal Cancer (V3.2018). Revised August 7, 2018.
  4. Zaltrap [Product Information], Bridgewater, NJ. Sanofi-Aventis U.S. LLC, June 2016: Available at: Accessed on September 27, 2018.
  5. Ziv-Aflibercept. In: DrugPoints® System [electronic version]. Truven Health Analytics. Greenwood Village, CO. Updated May 24, 2017. Available at: Accessed on September 27, 2018.
  6. Ziv-Aflibercept monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised April 6, 2016. Accessed on September 27, 2018.
Websites for Additional Information
  1. American Cancer Society. Key Statistics for Colorectal Cancer. How common is colorectal cancer? Available at: Accessed on September 27, 2018.
  2. .National Cancer Institute (NCI). Ziv-Aflibercept. Updated March 8, 2018. Available at: Accessed on September 27, 2018.


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







Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Initial document development. Updated Discussion/General Information, References, Websites for Additional Information and History sections of the document.



MPTAC review.



Hematology/Oncology Subcommittee review. Initial document development. Moved content of DRUG.00051 Ziv-aflibercept (Zaltrap®) to new clinical utilization management guideline document with the same title.