Panitumumab (Vectibix Amgen, Thousand Oaks, CA) is a human, IgG2 kappa recombinant, monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR). This document addresses the indications for panitumumab in the treatment of oncologic conditions.

For additional information, please refer to the following related document:

• GENE.00014 Analysis of KRAS Status

Medically Necessary:

Panitumumab is considered medically necessary as treatment for individuals who meet all of the following criteria:

1. As a single agent or as part of combination therapy for Stage IV colon*, rectal*, colorectal*, or anal*adenocarcinoma; and
2. KRAS gene mutation testing is documented and the tumor is determined to be KRAS wild-type; and
3. Panitumumab is to be used for only one line of therapy; and
4. Panitumumab is NOT used in combination with anti-VEGF agents (e.g., bevacizumab); and
5. The individual has not received prior treatment** with cetuximab (Erbitux^®, ImClone, Branchburg, NJ) (**Note: A course of cetuximab discontinued because of adverse reaction, not progressive disease, is not considered prior treatment)

*Note: See definitions of colorectal and anal cancer

Investigational and Not Medically Necessary:

Panitumumab is considered investigational and not medically necessary when the above criteria are not met including, but not limited to treatment of squamous cell anal carcinoma.

Panitumumab is considered investigational and not medically necessary when used in combination with other monoclonal antibodies or anti-VEGF agents.

On September 27, 2006, the U.S. Food and Drug Administration (FDA) provided an accelerated approval for panitumumab (Vectibix), a monoclonal antibody. The label was updated in June 2008, stating panitumumab is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal cancer that has progressed despite standard chemotherapy. Additional warnings were added to the label in 2009, stating there has been increased toxicity with combination chemotherapy and panitumumab is not indicated for use in combination with chemotherapy. 

By binding specifically to EGFR, panitumumab inhibits the binding of ligands. This prevents the activation of receptor-associated kinases, resulting in the start of apoptosis and inhibition of cell growth. The blockade of the epidermal growth factor results in a decrease in tumor growth, but does have side effects. Skin rash was the most frequently occurring side effect of panitumumab therapy. Various studies have drawn correlations between the frequency and severity of rash to tumor response rate (Product Information Label, 2009; Giusti, 2007; Lacouture, 2007; Zhu, 2007).

Panitumumab received the accelerated approval based on progression-free survival (PFS) data from a randomized controlled clinical trial involving 463 individuals with metastatic colorectal carcinoma. Individuals had been previously treated with fluoropyrimidine, oxaliplatin and irinotecan, but progressed on or following therapy. There was a statistically significant prolongation of PFS of 96 days with panitumumab compared to 60 days with best supportive care (BSC). Nineteen (8%) partial response rates with a median duration of 17 weeks were noted in individuals randomized to receive panitumumab. There were no measurable responses in the control arm. There was no significant difference in overall survival between the cohort treated with panitumumab and those who received BSC. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival (Product Information Label, 2009).

The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study (Hecht, 2009) was a phase IIIb randomized, open label clinical trial evaluating cohorts of a chemotherapy regimen including bevacizumab, with and without panitumumab as first-line treatment of individuals with previously untreated metastatic colorectal carcinoma (mCRC). Investigators chose a 5-FU, leucovorin and oxaliplatin-based regimen (Ox-CT; n= 823) or a 5-FU, leucovorin and irinotecan-based regimen (Iri-CT; n= 230), each with bevacizumab. Individuals were randomized to receive the selected regimen, or chemotherapy with the addition of panitumumab. A statistically significant difference in PFS in favor of the control arm (without panitumumab) was unveiled at the first planned interim analysis (Zhu, 2007) which resulted in a discontinuation of panitumumab. In the final analysis (Hecht, 2009) median PFS was 10.1 months for panitumumab and 11.7 months for the control group (HR, 1.19; 95% CI, 0.79 to 1.79). In a safety analysis of 804 individuals in the Ox-CT cohort and 224 individuals in the Iri-CT cohort, both groups had more adverse events (AEs) of grade 3 or higher in the panitumumab cohorts compared to the control groups (Ox-CT 367 (90%) versus 305 (77%), respectively; Iri-CT 100 (90%) versus 71 (63%) respectively). Serious AEs included diarrhea, infections and pulmonary embolism. Seven (1%) deaths were attributed to be panitumumab-related. The authors concluded the decreased PFS and increased serious AEs do not support panitumumab in combination with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy as a treatment for mCRC. "Administration of chemotherapy and dual EGFR/VEGF inhibition should be conducted only in a research setting (Hecht, 2009)."

The NCCN colon and rectal Clinical Practice Guidelines in Oncology^™ (2011) noted the PAACE trial results and "strongly recommends against the use of therapy involving the combination of an anti-EGFR agent and an anti-VEGF agent."

The medically necessary criteria for excluding previous use of EGFR monoclonal antibody therapy prior to treatment with panitumumab is based on the selection criteria in the pivotal trial as well as the expert view of medical practitioners practicing in the clinical area of oncology, and who have familiarity with the available evidence at this time. In 2011, the NCCN^® Clinical Practice Guidelines in Oncology^™ for colon cancer and rectal cancer include clarification "if cetuximab is used as initial therapy, then neither cetuximab nor panitumumab should be used in second or subsequent lines of therapy." In a small retrospective series, Saif (2010) reported results of 15 individuals treated with panitumumab after having failed prior cetuximab therapy. Eleven individuals were evaluable for responses and tissue samples from three tumors were retrospectively assessed for KRAS status. Three individuals had minor radiographic improvement and three other individuals had stable disease (SD). Median duration of SD was 4 months with a range from 2 to 8 months. The investigators concluded the evidence may suggest panitumumab, after cetuximab failure, may "exert antitumor activity through different mechanisms, although, further work is required to investigate this potentially interesting issue (Saif, 2010)."

Recommendations by the NCCN (2011) regarding the use of panitumumab and the other FDA approved EGFR inhibitor cetuximab in the treatment of colorectal cancer note that there are no data of head-to-head comparisons between the drugs. Additionally, it is noted that there are no data, nor is there a compelling rationale to support the use of one of these agents after the therapeutic failure of the other and that this practice is not recommended. The NCCN practice guideline (2011) notes skin toxicities are side effects for both cetuximab and panitumumab, and is not considered to be an infusion reaction.

Squamous cell anal cancer is the most common histologic form of anal cancer. Adenocarcinoma and melanoma of the anal canal represents infrequently occurring subtypes of anal cancer. The NCCN Anal Carcinoma Clinical Practice Guideline (2010) recommends management of anal adenocarcinoma according to the NCCN Rectal Cancer Clinical Practice Guidelines (2010). Specialty consensus opinion also supports the NCCN recommendations to treat stage IV anal adenocarcinoma similar to stage IV colorectal adenocarcinoma. 

In 2011, the National Comprehensive Cancer Network^® (NCCN^®₎ Clinical Practice Guidelines in Oncology for advanced stage IV colon and rectal adenocarcinoma include offlabel recommendations for panitumumab as a single agent and in combination therapy based on 2A category of evidence and uniform consensus. The offlabel indications are listed in the Position Statement.

In addition, the NCCN guidelines indicate that EGFR testing of colorectal tumor cells has not demonstrated predictive value in determining the likelihood of a response to panitumumab. Thus, this testing is not required to establish medical necessity or used in treatment determinations. The use of panitumumab for treatment of squamous cell anal cancer is not recognized as an off-label indication by NCCN.

The updated NCCN (2011) guidelines include recommendations for KRAS gene testing for all stage IV colon and rectal disease. Use of panitumumab is indicated for individuals with tumors that express the wild-type KRAS gene. The American Society of Clinical Oncology (ASCO, Allegra, 2009) issued a provisional, consensus clinical opinion based on systematic reviews of literature primarily from phase II and III clinical trials involving individuals with metastatic colorectal cancer. "All patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment."

Studies of metastatic colorectal carcinoma treatment have shown there are subsets of individuals who are not as responsive to anti-EGFR monoclonal antibodies. To understand the variation, there is ongoing research into the genetic signaling pathways that promote the growth of specific cells. The Kirsten rat sarcoma virus also known as the KRAS gene is being analyzed for mutations and correlation of response to anti-EGFR monoclonal antibodies. The desired goal for KRAS status mutation analysis is to identify individuals who would not respond to anti-EGFR monoclonal antibody therapy, thereby saving them the time, expense and unnecessary toxicity of ineffective therapies.

Freeman and colleagues (2008) analyzed gene mutations in metastatic colorectal tumor samples from three phase II panitumumab studies. Sixty-two samples were evaluated from a total of 533 individuals. KRAS mutation was identified in 24 (38.7%) and wild-type KRAS was noted in 38 (61.3%) of the tumors. In the wild-type KRAS group, 11% had a partial response (PR) 53% had stable disease (SD) and 37% had progressive disease (PD). Of the individuals in the mutant KRAS group, 21% had SD, 79% had PD and there were no individuals with responsive disease. Progression-free survival (PFS) was favored in individuals with wild-type KRAS compared with individuals with mutant KRAS (HR 0.4; 95% CI 0.2-0.7; p=.002). Median PFS was 16.2 weeks for the wild-type KRAS versus 7.4 weeks for the mutant KRAS cohort.

The data suggest that the metastatic colorectal population with wild-type KRAS mutation status benefited more from panitumumab alone as compared with those with the activating KRAS mutation. Therefore, analysis of KRAS status is recommended to facilitate treatment plans.

There are ongoing trials studying the expanded use of panitumumab for additional indications such as solid tumors including lung cancer, and at different stages of various diseases. The use of panitumumab in combination with a variety of chemotherapy or biologic agents is also under investigation.

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 (e.g., anus, anal canal or anorectum) which include the opening of the rectum to the outer body. Anal cancer occurs infrequently and represents 4% of all cancers of the lower gastrointestinal tract (National Cancer Institute [NCI], 2009; NCCN, 2010).

A monoclonal antibody is a protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells (NCI, 2009). Panitumumab is a monoclonal antibody that binds specifically to the human Epidermal Growth Factor Receptor. As a result, panitumumab may interfere with the signals necessary for the cancer cells' growth and survival.

Possible Risks:
The product information for Vectibix has black box warnings for dermatologic and severe infusion reactions. Dermatologic toxicities related to the blockade of EGF binding and subsequent inhibition of EGFR-mediated signaling pathways were reported in 89% of individuals and were severe (NCI- Common Toxicity Criteria (CTC) grade 3 and higher) in 12% of individuals receiving panitumumab monotherapy. The clinical manifestations included, but were not limited to dermatitis acneiform, pruritis, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe dermatologic toxicities were complicated by infection including sepsis, septic death, and abscesses requiring incisions and drainage. Withhold or discontinue panitumumab and monitor for inflammatory or infectious sequelae in individuals with dermatologic toxicities (Product Information Label, 2009). Additional toxicities reported involved gastrointestinal mucosa, eye and nail.

Severe infusion reactions occurred with the administration of panitumumab in approximately 1% of individuals. The severe infusion reactions were identified by reports of anaphylactic reaction, bronchospasm, fever, chills and hypotension. Although fatal infusion reactions have not been reported with panitumumab, fatalities have occurred with other monoclonal antibody products. The product label recommends stopping the infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue panitumumab (Product Information Label, 2009). In the event of a severe infusion reaction, the use of another monoclonal antibody or antineoplastic agent may be considered.

Pulmonary fibrosis occurred in less than 1% (2 of 1467) of individuals enrolled in clinical studies. Of these two cases, one occurrence in an individual with underlying idiopathic pulmonary fibrosis who received panitumumab in combination with chemotherapy resulted in death from worsening pulmonary fibrosis after four doses of panitumumab. The second case had CT evidence of pulmonary fibrosis following the 11^th dose of panitumumab as monotherapy. An additional individual died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of panitumumab in combination therapy. Following the initial fatality, individuals with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis or pulmonary fibrosis were excluded from clinical studies. Permanently discontinue panitumumab therapy in individuals developing interstitial lung disease, pneumonitis, or lung infiltrates (Product Information, 2009).

Panitumumab can cause diarrhea and appears to increase the incidence and severity of chemotherapy-induced diarrhea. In a study of 19 individuals receiving panitumumab in combination with irinotecan, bolus 5-fluourouracil, and leucovorin (IFL), the incidence of NCI-CTC grade 3-4 diarrhea was 58% and was fatal in one individual. In a study of 24 individuals receiving panitumumab and FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25% (Product Information, 2009). 

The manufacturer does not recommend panitumumab in combination with IFL (irinotecan, bolus 5-fluourouracil and leucovorin).

In a randomized controlled trial, hypomagnesemia of NCI-CTC grade 3-4 requiring electrolyte repletion occurred in 2% of individuals. Electrolytes should be periodically monitored during and for 8 weeks after the completion of panitumumab therapy (Product Information, 2009).

Precautions:
The manufacturer recommends individuals limit sun exposure while receiving panitumumab as sunlight may exacerbate skin reactions.

At the present time, there is insufficient evidence to demonstrate the safety and effectiveness of panitumumab for either use in the pediatric population.

Adenocarcinoma: Cancer originating in cells that line specific internal organs and that have gland-like (secretory) properties.

Anal cancer: Cancer originating in the tissues of the anus; the anus is the opening of the rectum (last part of the large intestine) to the outside of the body.

Apoptosis: A series of molecular steps resulting in a type of cell death. The body's normal way of getting rid of unneeded or abnormal cells; programmed cell death.

Colon cancer: Cancer originating in the tissues of the colon (the longest part of the large intestine). Most colon cancers are adenocarcinomas that begin in cells that make and release mucus and other fluids.

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:

• First-line therapy: The first or primary treatment for the diagnosis. This may include surgery, chemotherapy, radiation therapy or a combination of these therapies.
• Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
• Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

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. 

Monoclonal antibody:  A protein developed in the laboratory that can locate and bind to a specific substance in the body.

Off-label: Utilization of a United States Food and Drug Administration (FDA) approved drug for uses other than those listed in the FDA approved label.

Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment; also called partial remission.

Rectal cancer: Cancer originating in tissues of the rectum (the last several inches of the large intestine closest to the anus).

The following codes for treatments and procedures applicable to this document 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. 

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 2007; 67(6):2643-2648.
2. Burtness B. Clinical use of monoclonal antibodies to the epidermal growth factor receptor in colorectal cancer. Oncology. 2007; 21(8):964-970.
3. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010; 28(31):4697-4705.
4. Freeman DJ, Juan T, Reiner M, et al. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorecta cancer receiving panitumumab alone. Clin Colorectal Cancer. 2008; 7(3): 184-190.
5. Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer. 2006; 6(1): 29-31.
6. Giusti RM, Shastri KA, Cohen MH, et al. FDA drug approval summary: panitumumab (Vectibix). Oncologist. 2007; 12(5):577-583.
7. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009; 27(5): 672-680.
8. Lacouture ME, Melosky BL. Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. Skin Therapy Lett. 2007; 12(6):1-5.
9. Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010; 28(31):4706-4713.
10. Power DG, Shah MA, Asmis TR, et al. Safety and efficacy of panitumumab following cetuximab: retrospective review of the Memorial Sloan-Kettering experience. Invest New Drugs. 2010; 28(3):353-360.
11. Saif MW, Kaley K, Chu E, Copur MS. Safety and efficacy of panitumumab therapy after progression with cetuximab: experience at two institutions. Clin Colorectal Cancer. 2010; 9(5):315-318.
12. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13):1658-1664.
13. Van Cutsem E, Siena S, Humblet Y, et al. An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy. Ann Oncol. 2007; 19(1):92-98.
14. Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: status and perspectives. Acta Pharmacol Sin. 2007; 28(9):1476-1493.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009.
2. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2011^®_. Bethesda, MD: American Society of Health-System Pharmacists^®_, 2011.
3. National Cancer Institute (NCI). Colon cancer treatment (PDQ^®₎. Last modified March 11, 2011. Available at: http://www.nci.nih.gov/cancertopics/pdq/treatment/colon/healthprofessional. Accessed on March 20, 2011.
4. National Comprehensive Cancer Network^®_. NCCN Drugs & Biologic Compendium^™ (electronic version). For additional information: http://www.nccn.org. Accessed on March 10, 2011.
5. NCCN Clinical Practice Guidelines in Oncology™. © 2011 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on March 10, 2011.
   • Anal Carcinoma (V.2.2012). Revised February 2, 2011.
   • Colon Cancer (V.3.2011). Revised February 25 2011.
   • Rectal Cancer (V.4.2011). Revised February 25, 2011.
6. Panitumumab (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated March 4, 2011. Available at: http://www.thomsonhc.com. Accessed on March 21, 2011.
7. Vectibix (Panitumumab) [Product Information], Thousand Oaks, CA. Amgen. July 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s067lbl.pdf. Accessed on March 18, 2011.

1. American Cancer Society. Available at: http://www.cancer.org/index.  Accessed on March 18, 2011.

Epidermal Growth Factor Receptor (EGFR)
Erbitux
Monoclonal Antibody
Panitumumab
Vectibix

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.