Panitumumab (Vectibix)

Number: 0748

Policy

Aetna considers panitumumab (Vectibix) medically necessary for the following indications:

• Advanced or metastatic colorectal cancer in tumors expressing the wild-type KRAS and NRAS genes (i.e., negative for the KRAS and NRAS mutations); or
• Advanced or metastatic anal adenocarcinoma expressing the wild-type KRAS and NRAS genes; or
• Advanced or metastatic adenocarcinomas of the appendix or small bowel expressing the wild-type KRAS and NRAS genes; or
• Colorectal adenocarcinoma in combination with irinotecan and vemurafenib (for BRAF V600E mutation positive) as 
   
  • primary treatment of unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
  • subsequent therapy for progression of unresectable advanced or metastatic disease not previously treated with cetuximab or panitumumab, in members previously treated with
     
    • oxaliplatin-based therapy without irinotecan; or
    • irinotecan-based therapy without oxaliplatin; or 
    • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen; or
    • a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab.

Continued use of panitumumab is considered not medically necessary for persons whose disease has progressed with panitumumab or who have developed intolerance to this drug.

Aetna considers panitumumab experimental and investigational for persons who have had clinical failure (disease progression) on cetuximab (Erbitux) because there is insuficient evidence to support the use of panitumumab after clinical failure on cetuximab.

Use of panitumumab with bevacizumab (Avastin), erlotinib (Tarceva), or gefitinib (Iressa).is considered experimental and investigational because the effectiveness of these drugs in combination has not been established.

Aetna considers panitumumab experimental and investigational for the following indications (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Ampullary adenocarcinoma
• Biliary tract cancer
• Breast cancer
• Cutaneous squamous cell carcinoma
• Esophageal cancer
• Gallbladder cancer
• Gastric cancer
• Glioma
• Head and neck cancer
• Non-small cell lung cancer
• Ovarian cancer
• Pancreatic cancer
• Penile cancer
• Sarcoma (e.g., chondrosarcoma)

Aetna considers ²¹²Pb-panitumumab (a targeted radiopharmaceutical) experimental and investigational for HER1-positive disseminated intraperitoneal disease and all other indications.

Aetna considers the use of K-ras and N-ras mutation analysis medically necessary to predict non-response to panitumumab in persons with advanced or metastatic adenocarcinoma of the colon, rectum, anus, small bowel or appendix.  See CPB 0352 - Tumor Markers.

Background

Colorectal cancer is the third most common cancer and the third most common cause of cancer mortality in the United States (ACS, 2007).  The National Cancer Institute (2007) estimated that there will be 112,340 (colon cancer) and 41,420 (rectal cancer) new cases; and over 52,000 deaths (combined colon and rectal cancer) in 2007.  About 70 to 80 % of all colorectal carcinomas exhibited over-expression of the epidermal growth factor receptor (EGFR), which is known to be involved in carcinogenic processes, such as cell proliferation, apoptosis, angiogenesis and metastasis (Zhang et al, 2006). 

Monoclonal antibodies targeting EGFR have been demonstrated to exhibit anti-tumor activity and improved the effectiveness of chemotherapy.  Panitumumab (Vectibix) is a human monoclonal antibody that blocks the extra-cellular domain of the EGFR, and has not been associated with the formation of antibodies directed against it (Saadeh and Lee, 2007). EGFR is a transmembrane glycoprotein that is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Over expression of EGFR is also detected in many human cancers, including those of the colon and rectum. Interaction of EGFR with normal ligands leads to phosphorylation and activation of a series of intracellular tyrosine kinases, which in turn regulate transcription of molecules involved with cellular growth and survival, motility, proliferation, and transformation.

In a phase II clinical trial, Berlin et al (2007) evaluated the safety and effectiveness of panitumumab administered with first-line irinotecan-containing regimens in patients with metastatic colorectal cancer.  This was a 2-part multi-center study of panitumumab 2.5 mg/kg of body weight weekly with irinotecan, 5-fluorouracil (5-FU), and leucovorin.  Part 1 used bolus 5-FU (IFL), and part 2 used infusional 5-FU (FOLFIRI).  Tolerability (measured by grade 3/4 diarrhea) was the primary endpoint.  Objective response, progression-free survival (PFS), overall survival (OS), and safety were also examined.  Nineteen patients in part 1 and 24 patients in part 2 received panitumumab plus chemotherapy.  Grade 3/4 diarrhea occurred in 11 patients (58 %) in part 1 and 6 patients (25 %) in part 2.  All patients had a skin-related toxicity (no grade 4 events).  Objective response rates were 46 % in part 1 and 42 % in part 2.  Disease control rates were 74 % in part 1 and 79 % in part 2.  Median PFS (95 % confidence interval [CI]) was 5.6 months (4.4 to 8.3 months) for part 1 and 10.9 months (7.7 to 22.5 months) for part 2.  Median OS (95 % CI) was 17 months (13.7 months to not estimable) for part 1 and 22.5 months (14.4 months to not estimable) for part 2.  The authors concluded that in patients with metastatic colorectal cancer, panitumumab/IFL was not well-tolerated.  In contrast, panitumumab/FOLFIRI was well-tolerated and showed promising activity.

In another phase II multi-center study, Hecht and colleagues (2007) examined the safety and effectiveness of panitumumab in patients with metastatic colorectal cancer refractory to available therapies.  Subjects had progressed on chemotherapy that included fluoropyrimidine and irinotecan or oxaliplatin, or both.  All subjects had tumors with greater than or equal to 10 % 1+ EGFR staining by immunohistochemistry.  They were stratified into 2 strata (high or low staining intensity) and received intravenous panitumumab 2.5 mg/kg of body weight weekly 8 of every 9 weeks until disease progression or unacceptable toxicity.  In all, 148 patients received panitumumab (105 in the high EGFR stratum, and 43 in the low EGFR stratum).  Overall response by central review was 9 % (95 % CI: 5 to 15 %) and was similar between strata.  An additional 29 % of patients had stable disease.  Median PFS was 14 weeks (95 % CI, 8 to 16 weeks) and median OS was 9 months (95 % CI: 6 to 10 months).  Toxicities were manageable, with skin toxicity reported in 95 % of patients (5 % grade 3 or 4).  Four patients discontinued therapy because of toxicity.  No anti-panitumumab antibodies were detected.  One patient had an infusion reaction but was able to continue therapy.  The authors concluded that panitumumab given weekly was well-tolerated and had single-agent activity in previously treated patients with colorectal cancer.  Dermatological toxicity was common but rarely severe.

On September 27, 2006, panitumumab (Vectibix) received an accelerated approval from the Food and Drug Administration (FDA) for use as a single agent for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens (Giusti et al, 2007).  There are no data to support the combination of panitumumab with chemotherapy in the treatment of colorectal cancer (National Comprehensive Cancer Network [NCCN], 2009).  In addition, according to the FDA-approved labeling of Vectibix, panitumumab should not be used in combination with other monoclonal antibodies.

The National Comprehensive Cancer Network Drugs & Biologics Compendium (NCCN, 2018) recommends panitumumab for the following indications in colon cancer:

• Therapy for left-sided only tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in patients not appropriate for intensive therapy [2A; 2B as single agent therapy in patients who cannot tolerate intensive therapy]:

  • as primary treatment for locally unresectable or medically inoperable disease
  • for unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy
  • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with imminent or existing obstruction
  • for unresectable synchronous metastases of other sites 
  • as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy 
  • for unresectable metachronous metastases that remain unresectable after primary treatment
     

• Primary treatment for left-sided only tumors expressing KRAS/NRAS wild-type gene for unresectable synchronous liver and/or lung metastases in combination with [2A]

  • FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
  • FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
     

• Therapy for left-sided only tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in patients not appropriate for intensive therapy [2B]

  • as adjuvant treatment following synchronized or staged resection for synchronous liver and/or lung metastases that converted from unresectable to resectable disease after primary treatment
  • as adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy
  • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment
     

• Primary treatment for left-sided only tumors expressing KRAS/NRAS wild-type gene 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
    
    
• Primary treatment in combination with irinotecan and vemurafenib for patients with unresectable metachronous metastases (BRAF V600E mutation positive) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]
   

• Subsequent therapy for progression of tumors expressing KRAS/NRAS wild-type gene for unresectable advanced or metastatic disease not previously treated with cetuximab or panitumumab [2A]

  • in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen if previously treated with oxaliplatin-based therapy without irinotecan
  • in combination with irinotecan if previously treated with irinotecan-based therapy without oxaliplatin
  • in combination with irinotecan if previously treated with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
  • in combination with irinotecan if previously treated with a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
    
    
• Subsequent therapy in combination with irinotecan and vemurafenib for progression of unresectable advanced or metastatic disease (BRAF V600E mutation positive) not previously treated with cetuximab or panitumumab, in patients previously treated with [2A]
   
  • oxaliplatin-based therapy without irinotecan
  • irinotecan-based therapy without oxaliplatin
  • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
  • a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

The NCCN Drugs & Biologics Compendium (NCCN, 2018) recommends panitumumab for the following indications in rectal cancer:

• Used for tumors expressing KRAS/NRAS wild-type gene in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in patients not appropriate for intensive therapy as [2A; 2B for single agent therapy in patients who cannot tolerate intensive therapy]:

  • primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease with no metastases if resection is contraindicated following neoadjuvant therapy
  • for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy
  • following short-course radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy
  • as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction
  • as primary treatment for synchronous unresectable metastases of other sites
  • as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy
  • systemic therapy for unresectable metachronous metastases that remain unresectable after primary treatment
     

• Primary treatment for synchronous liver only and/or lung only metastases tumors expressing KRAS/NRAS wild-type gene that are unresectable or medically inoperable in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen [2A]

• Therapy for KRAS/NRAS wild-type gene tumors in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen, or as a single agent in patients not appropriate for intensive therapy [2B]
   
  • as adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy
  • as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment
    
    
• Primary treatment for patients with unresectable metachronous metastases (KRAS/NRAS wild-type gene only) 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
    
    
• Primary treatment in combination with irinotecan and vemurafenib for patients with unresectable metachronous metastases (BRAF V600E mutation positive) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months [2A]

• Subsequent therapy for progression of tumors expressing KRAS/NRAS wild-type gene for unresectable advanced or metastatic disease not previously treated with cetuximab or panitumumab [2A]

  • in combination with irinotecan or with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen if previously treated with oxaliplatin-based therapy without irinotecan
  • in combination with irinotecan if previously treated with irinotecan-based therapy without oxaliplatin
  • in combination with irinotecan for disease previously treated with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
  • in combination with irinotecan if previously treated with a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab
    
    
• Subsequent therapy in combination with irinotecan and vemurafenib for progression of unresectable advanced or metastatic disease (BRAF V600E mutation positive) not previously treated with cetuximab or panitumumab, in patients previously treated with [2A]
   
  • oxaliplatin-based therapy without irinotecan
  • irinotecan-based therapy without oxaliplatin
  • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen
  • a fluoropyrimidine without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab

Colorectal cancer patients with KRAS mutations should not receive Vectibix (panitumumab) due to known lack of response and possible worse outcomes in this population. Vectibix (panitumumab) and Erbitux (cetuximab) are only indicated for patients with tumors that express the wild type (normal) KRAS gene.

Vectibix (panitumumab) may not be used in conjunction with Erbitux (cetuximab), Tarceva (erlotinib), or Iressa (gefitinib).

Vectibix (panitumumab) may not be used in conjunction with Avastin (bevacizumab) (based on the results from the PACCE trial).

Dosage Adjustments

• Infusion reactions: patients experiencing a grade 1 or 2 (mild or moderate) infusion reaction, infusion rate should be reduced by 50% for the duration of the infusion; patients experiencing a grade 3 or 4 (severe) infusion reaction, panitumumab should be immediately and permanently discontinued.
• Dermatologic toxicities: Grade 3 or higher dermatologic toxicities, or those considered intolerable, panitumumab should be withheld; panitumumab should be permanently discontinued if the toxicity does not improve to Grade 2 or less with one month.
• Dermatologic toxicities: if the dermatologic toxicity improves to Grade 2 or less with symptomatic improvement after withholding no more than two doses, treatment may be resumed at 50% of the original dose; if toxicity recurs, panitumumab should be permanently discontinued; if toxicity does not recur, subsequent doses may be increased by increments of 25% of the original dose until 6 milligrams/kilogram (recommended dose) is reached.

Black Box Warnings

• Dermatologic toxicities related to panitumumab blockade of EGF binding and subsequent inhibition of EGFR‐mediated signaling pathways, were reported in 89% of patients and were severe (NCI‐CTC Grade 3 and higher) in 12% of patients receiving panitumumab monotherapy. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, 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 patients with severe dermatologic toxicities
• Severe infusion reactions occurred with the administration of panitumumab in approximately 1% of patients. 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. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue panitumumab.

Notes:

• KRAS: KRAS testing is recommended prior to initiating panitumumab or cetuximab therapy (NCCN 2013) in metastatic colorectal cancer (mCRC) patients. KRAS is highly predictive of response to panitumumab or cetuxmab in metastatic colorectal cancer setting. Due to lack of response seen in mCRC tumors with KRAS mutations, use in this setting is considered unproven.
• Crystal and Everest trials showed that cetuximab was beneficial in wild‐type mCRC tumors, but patients with KRAS mutations did not benefit from the addition of the EGFR targeted therapy. Cairo2 and Opus trials also demonstrated a lack of clinical benefit by adding the EGFR antibody, but also demonstrated a compelling decrease in PFS when EGFR targeted therapy was added. It is possible that this data reflects mCRC actually doing worse because they received EGFR targeted therapy. Amado demonstrated that KRAS wild‐type verification was also necessary prior to panitumumab therapy due to lack of response seen in tumors with KRAS mutations.
• All NCI sponsored clinical trials analyzing these agents have been reevaluated to take KRAS testing into account. The EMEA already requires KRAS testing and wild‐type verification prior to initiation of cetuximab or panitumumab therapy
• No formal studies of panitumumab have been conducted in patients with renal or hepatic impairment
• Amgen Oncology Assistance program:a financial assistance program that includes a Vectibix cap. Under the cap, patients whose out‐of‐pocket expenses exceed 5% of their adjusted gross income will be eligible for Amgen’ Safety Net Foundation, a patient assistance program that provides Amgen oncology medicines at no cost.
• PACCE trial was discontinued early based on negative preliminary data. The decision to discontinue Vectibix treatment in the trial was based on a preliminary review of data from a pre‐planned interim efficacy analysis scheduled after the first 231 events (death or disease progression). This analysis revealed a statistically significant difference in progression‐free survival in favor of the control arm. An unplanned analysis of overall survival also demonstrated a statistically significant difference favoring the control arm.

Vectibix (panitumumab) should not be utilized in the following:

• Hypersensitivity to Vectibix (panitumumab) or any component of the product.
• Safety and effectiveness of Vectibix (panitumumab) in pediatric and adolescent patients has not been established.
• Patients that are pregnant or breast feeding—without apprising patient of risk vs. benefit.

Grothey (2007) stated that in the past 20 years adjuvant chemotherapy has been the standard of care in patients with early-stage colon cancer at high risk of recurrence.  Until now, treatment entails the use of cytotoxic drugs that have well-demonstrated effectiveness in advanced colorectal cancer.  Most recently, targeted biological agents (i.e., antibodies against the EGFR and vascular endothelial growth factor [VEGF]) have become essential components of the palliative medical treatment of colorectal cancer.  Proof of effectivenss of these agents in advanced disease has led to the initiation of several trials testing EGFR and VEGF antibodies in the adjuvant setting.  Although definitive results of ongoing adjuvant studies will not be available for several years, some oncologists might already inappropriately consider the use of these targeted agents as a component of adjuvant therapy in selected patients.  Whether the results obtained in advanced colorectal cancer can be readily translated into a projected effectiveness in early-stage colon cancer, however, is unclear.  Furthermore, the long-term safety of biological agents in potentially surgically cured patients has yet to be established.

According to guidelines from the NCCN (2009), EGFR testing of colorectal tumor cells has no demonstrated predictive value in determining likelihood of response to panitumumab or cetuximab.  Therefore, NCCN colorectal cancer guidelines do not recommend routine EGFR testing, and states that no patient should be either considered or excluded from cetuximab or panitumumab therapy on the basis of EGFR test results.  The guidelines stated: "In contrast to the results for KRAS genetic testing, the testing of colon cancer tissue for EGFR has demonstrated no predictive value in determining the likelihood of response with cetuximab and panitumumab.  Hence, routine EGFR testing is not recommended, and no patients should be excluded from therapy with either of these drugs on the basis of such testing."

There are no data or compelling rationale to show that panitumumab would be effective after disease progression with cetuximab (Erbitux).  NCCN guidelines on colorectal cancer (2009; updated 2012) state: "If cetuximab is used as initial therapy, then neither cetuximab nor panitumumab should be used in second or subsequent lines of therapy.  There are no data, nor is there compelling rationale, to support the use of panitumumab after clinical failure on cetuximab, or cetuximab after clinical failure on panitumumab.  As such, the use of one of these agents after therapeutic failure on the other is not recommended."

Saif and colleagues (2009a) reported successful re-challenge with panitumumab in 3 patients with gastrointestinal cancers who developed hyper-sensitivity reactions (HSR) to cetuximab.  These patients were challenged with standard dose of panitumumab (6 mg/kg) after experiencing grade 3 HSR to standard dose of cetuximab under strict observation and no pre-medication.  First patient, a 58-year old male with metastatic colorectal cancer (mCRC) developed grade 3 HSR during 8th dose of cetuximab.  Second patient was a 58-year old female with mCRC developed grade 3 HSR during 12th dose of cetuximab.  Third patient was a 61-year old male with pancreatic cancer who reported grade 3 HSR during loading dose of cetuximab.  Charts were reviewed to find history of prior allergy, including H1 blocker use, drug allergy, bee sting allergy, eczema, allergic reactive airways disease, or food allergy.  All patients were Caucasians with an average age of 59 years with no history of prior allergy.  No patient received any pre-medication.  First patient received panitumumab for 2 months, 2nd patient was treated for 6 months, and 3rd patient who was re-challenged 1 week after HSR to cetuximab had a partial response following 6 months of therapy.  The authors concluded that HSR are serious complications associated with monoclonal antibodies (MAbs).  Thanks to hybridoma technology that newer generations of MAbs contain less or no mouse-specific protein sequences, hence reducing the risk of HSR.  Identification of individuals likely to develop severe and sometimes life-threatening HSR is challenging.  They stated that this report of 3 patients successfully treated with panitumumab after they had severe HSR to cetuximab warrant further investigation.

Langerak et al (2009) presented 4 cases from a U.S. panitumumab compassionate-use program in which patients with mCRC who were intolerant to cetuximab received panitumumab.  Eligible patients had failed previous fluoropyrimidine therapy with oxaliplatin- and irinotecan-containing chemotherapy, had cetuximab intolerance (i.e., experienced an infusion reaction), and were unable to participate in a panitumumab clinical trial.  For each patient, individual FDA-approved single-patient treatment use.  Investigational New Drug- and Institutional Review Board-approved protocols were used, informed consent was obtained, and data were collected independently by the investigator.  All 4 patients (2 men, 2 women) had received previous bevacizumab and pre-medications before cetuximab administration.  In response to cetuximab, all 4 patients experienced Common Terminology Criteria for Adverse Events grade 3 or grade 4 infusion-reaction symptoms, which required acute therapy.  Time from cetuximab discontinuation to panitumumab administration ranged from 8 days to 5 months.  Panitumumab monotherapy was given at approximately 6 mg/kg every 2 weeks.  Two patients received pre-medications before panitumumab use. No physician reported any infusion reaction to panitumumab; 1 patient had stable disease, and 3 patients had disease progression.  The authors concluded that although this small case series provided evidence that patients with mCRC intolerant to cetuximab can receive subsequent panitumumab monotherapy without experiencing infusion reactions, additional clinical testing is needed to definitively examine this finding.

Saif et al (2009b) reported successful de-sensitization with cetuximab after an infusion reaction to panitumumab in 2 patients with mCRC.  The first case was a 42-year old female who received panitumumab as a third-line agent.  She developed severe chest tightness, pain, and shortness of breath (SOB) 5 mins after first panitumumab infusion.  The second case was a 70-year old male who developed severe facial flushing, back pain, SOB, tachycardia and hypotension 5 mins after second dose of panitumumab plus irinotecan as a second-line therapy.  These 2 patients received de-sensitization protocol for cetuximab after a test dose of 20 mg IV over 10 mins followed by a slow infusion 10 % of original rate in 0 to 2 hrs, 25 % of original rate in 2 to 2.5 hrs, 50 % reduced rate in 2.5 to 3 hrs, and then 100 % infusion rate after 3 hrs.  Patients were observed 4 hrs after completion of infusion.  First patient received a total of 12 cycles of cetuximab with stable disease, no recurrence of IR, and grade 1 to 2 acniform rash that first developed after third cycle.  Second patient received a total of 8 cycles uneventfully without IR.  The authors concluded that to their knowledge, this is the first report of 2 patients with documented IR with panitumumab being de-sensitized successfully with cetuximab.  Although anecdotal reports suggest safety of panitumumab in patients following IR with cetuximab, panitumumab can also cause severe IR. The authors' experience suggested that in case of limited options, such patients can be successfully challenged with cetuximab in a hospital after appropriate de-sensitization and pre-medication.  They stated that further studies focusing on de-sensitization and identifying hyper-sensitivity profile of different anti-EGFR antibodies are warranted.

Panitumumab is also being evaluated in the treatment of other types of solid tumors (Chua and Cunningham, 2006; Cohenuram and Saif, 2007; Moehler et al, 2007; Harari, 2007).  Socinski (2007) noted that a large dose/schedule trial of panitumumab enrolled 96 patients with EGFR-positive solid tumors.  No responses were seen in patients with lung cancer (n = 14).  A randomized phase II trial of carboplatin/paclitaxel with or without panitumumab in patients with previously untreated advanced stage IIIB/IV non-small cell lung cancer (NSCLC; n = 166) did not find any benefit for the panitumumab arm compared with the chemotherapy alone arm with regard to response rates, time to disease progression, or median survival time.  The author stated that the lack of a biomarker to identify a subset of NSCLC patients who may derive benefit from this agent curtails any potential enthusiasm for further trials of panitumumab in the treatment of NSCLC at the present time.

K-ras is the human homolog of the Kirsten rat sarcoma-2 virus oncogene.  It can harbor oncogenic mutations that yield a constitutively active protein.  Such mutations are found in about 30 % to 50 % of CRC.  Several studies have suggested that the presence of mutant K-ras in lung cancer as well as CRC correlates with poor prognosis, and is associated with lack of response to EGFR inhibitors.

NCCN guidelines (2014) state that all patients with metastatic colorectal cancer should have tumor tissue genotyped for RAS mutations (KRAS and NRAS). The guidelines state that, at the very least, exon 2 KRAS mutation status should be determined. Whenever possible, non-exon 2 KRAS mutation status and NRAS mutation status should also be determined. Patients with any known KRAS mutation (exon 2 or non-exon 2) or NRAS mutation should not be treated with either cetuximab or panitumumab. Mutations in codons 12 and 13 in exon 2 of the coding region of the KRAS gene predict lack of response to therapy with antibodies targeted to the EGFR.The guidelines state that testing for KRAS and NRAS mutations in codons 12 and 13 should be performed only in laboratories that are certified under the clinical laboratory improvement amendments of 1988 (CLIA-88) as qualified to perform high complexity clinical laboratory (molecular pathology) testing. No specific methodology is recommended (eg, sequencing, hybridization). The guidelines note that testing can be performed on formalin-fixed paraffin-embedded tissue. The testing can be performed on the primary colorectal cancers and/or the metastasis, as literature has shown that the KRAS and NRAS mutations are similar in both specimen types. 

Freeman et al (2008) assessed the association of K-ras, BRAF, and PIK3CA gene mutations with tumor resistance to panitumumab alone.  From 3 phase II panitumumab mCRC studies, 62 of 533 patient samples were available.  Mutations were identified from genomic DNA by sequencing.  Of the 62 samples, 24 (38.7 %) harbored a K-ras mutation, and 38 (61.3 %) were wild-type.  In the wild-type K-ras group, 11 % of patients had a partial response (PR), 53 % had stable disease (SD), and 37 % had progressive disease (PD).  In the mutant K-ras group, 21 % of patients had SD, and 79 % of patients had PD; there were no responses.  The absence of a K-ras mutation was associated with response to panitumumab (PR versus SD versus PD; p = 0.0028).  The HR for wild-type versus mutant K-ras was 0.4 (95 % CI: 0.2 to 0.7) for PFS and 0.5 (95 % CI: 0.3 to 0.9) for OS.  Four patients had a V600E BRAF mutation, and 2 patients had a PIK3CA mutation.  The authors concluded that these data suggest that patients with mCRC with activating K-ras mutations are less likely to respond to panitumumab alone.  The small sample size limited the authors from defining a predictive role of PIK3CA and BRAF mutations for panitumumab treatment.

The findings of Freeman et al (2008) are in agreement with those of Amado et al (2008) who reported that wild-type K-ras is needed for panitumumab efficacy in patients with mCRC.  In the study by Amado et al (2008), K-ras mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to BSC.  These researchers tested if the effect of panitumumab on PFS differed by K-ras status.  K-ras status was ascertained in 427 (92 %) of 463 patients (208 panitumumab, 219 BSC).  K-ras mutations were found in 43 % of patients.  The treatment effect on PFS in the wild-type K-ras group (HR, 0.45; 95 % CI: 0.34 to 0.59) was significantly greater (p < 0.0001) than in the mutant group (HR, 0.99; 95 % CI: 0.73 to 1.36).  Median PFS in the wild-type K-ras group was 12.3 weeks for panitumumab and 7.3 weeks for BSC.  Response rates to panitumumab were 17 % and 0 %, for the wild-type and mutant groups, respectively.  Wild-type K-ras patients had longer OS (HR, 0.67; 95 % CI: 0.55 to 0.82; treatment arms combined).  Consistent with longer exposure, more grade III treatment-related toxicities occurred in the wild-type K-ras group.  No significant differences in toxicity were observed between the wild-type K-ras group and the overall population.  The authors concluded that panitumumab monotherapy efficacy in mCRC is confined to patients with wild-type K-ras tumors.  K-ras status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

In an editorial that accompanied the study of Amado et al (2008), Baselga and Rosen (2008) stated that "by enriching our therapy population by excluding those patients with tumors bearing KRAS mutations, we are likely to improve the ability to identify the efficacy of cetuximab- or panitumumab-containing combinations in early stages colon cancer with WT RAS".  Furthermore, the Blue Cross and Blue Shield Association's Technology Evaluation Center (TEC) Medical Advisory Panel (BCBSA, 2008) concluded that the use of K-ras mutation analysis meets TEC criteria for predicting non-response to anti-EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) in the treatment of mCRC.

The National Comprehensive Cancer Network's (NCCN) clinical practice guideline on "Colon cancer" (version 4.2018) states that "small bowel and appendiceal adenocarcinoma may be treated with systemic chemotherapy according to the NCCN Colon Cancer Guidelines; and panitumumab is one of the options (for patients with KRAS wild type only gene or BRAF V600E mutation).

In a phase II clinical trial, Jensen et al (2012) reported the effect of chemotherapy with panitumumab as first-line therapy for KRAS wild-type irresectable biliary tract cancer.  Patients were treated with gemcitabine 1,000 mg/m(2), oxaliplatin 60 mg/m(2), and panitumumab 6 mg/kg i.v. every 2 weeks followed by 2 daily administrations of capecitabine 1,000 mg/m(2) in 7 days.  During 22 months, 46 patients were included in a single institution.  The primary end point, fraction of PFS at 6 months, was 31/42 [74 %; 95 % CI: 58 % to 84 %].  A total of 42 patients had measurable disease.  Response rate was 33 % and disease control rate was 86 %.  Median PFS was 8.3 months (95 % CI: 6.7 to 8.7 months) and median OS was 10.0 months (95 % CI: 7.4 to 12.7 months).  Toxicity was manageable including 8 cases of EGFR-related skin adverse events of grade 2 or more.  The authors concluded that Marker-driven patient selection is feasible in the systemic treatment of biliary tract cancer.  They stated that combination chemotherapy with panitumumab in patients with KRAS wild-type tumors met the efficacy criteria for future testing in a randomized trial.

Gui and Shen (2012) stated that a majority of patients with ovarian carcinoma who receive conventional treatment of surgical staging and platinum-based chemotherapy recur and ultimately succumb to their diseases.  Novel therapies that target specific pathways involved in ovarian tumorigenesis are rapidly emerging.  The EGFR is over-expressed in 30 to 98 % of epithelial ovarian carcinoma (EOC), and the signaling cascades activated are related with cell proliferation, migration and invasion, and angiogenesis, as well as resistance to cell apoptosis.  Various trials are ongoing focusing on EGFR as an attractive target in treatment of EOC.  Anti-EGFR MAbs, cetuximab and panitumumab, and TKIs, erlotinib and gefitinib, are the most advanced in clinical development.  The available data suggested that MAbs and TKIs only show marginal activity when they are used alone, but combination with platinum-based chemotherapy can induce elevated overall response rate in recurrent EOC patients.  Consequently, mechanisms for intrinsic and extrinsic resistance have been explored due to the poor clinical response to EGFR-targeted therapy.  Careful consideration of these clinical studies and the possible mechanisms involved in resistance can provide evidence for improvements in subsequent research.  Identification of responder profiles and development of rational regimen of combination therapy of EGFR-targeted therapy with other effective treatment modalities may eventually bring about substantial progress in the treatment of epithelial ovarian cancers.

In a randomized, open-label, phase III clinical trial, Waddell and colleagues (2013) examined the addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced esophago-gastric adenocarcinoma.  In this randomized, open-label phase III trial (REAL3), these investigators enrolled patients with untreated, metastatic, or locally advanced esophago-gastric adenocarcinoma at 63 centers (tertiary referral centers, teaching hospitals, and district general hospitals) in the United Kingdom.  Eligible patients were randomly allocated (1:1) to receive up to 8 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,250 mg/m(2) per day on days 1 to 21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1,000 mg/m(2) per day on days 1 to 21, and panitumumab 9 mg/kg on day 1).  Randomization was blocked and stratified for center region, extent of disease, and performance status.  The primary end-point was OS in the intention-to-treat population.  These researchers assessed safety in all patients who received at least 1 dose of study drug.  After a pre-planned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn.  Data for patients on treatment were censored at this time-point.  Between June 2, 2008, and Oct 17, 2011, these researchers enrolled 553 eligible patients.  Median OS in 275 patients allocated EOC was 11.3 months (95 % CI: 9.6 to 13.0) compared with 8.8 months (7.7 to 9.8) in 278 patients allocated mEOC+P (HR 1.37, 95 % CI: 1.07 to 1.76; p = 0.013).  mEOC+P was associated with increased incidence of grade 3-4 diarrhea (48 [17 %] of 276 patients allocated mEOC+P versus 29 [11 %] of 266 patients allocated EOC), rash (29 [11 %] versus 2 [1 %]), mucositis (14 [5 %] versus none), and hypomagnesaemia (13 [5 %] versus none) but reduced incidence of hematological toxicity (grade greater than or equal to 3 neutropenia 35 [13 %] versus 74 [28 %]).  The authors concluded that addition of panitumumab to EOC chemotherapy does not increase OS and cannot be recommended for use in an unselected population with advanced esophago-gastric adenocarcinoma.

Nabholtz et al (2014) noted that triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the EGFR pathway may play an important role.  In a phase II study, these researchers investigated the efficacy and toxicity of panitumumab combined with a standard neoadjuvant anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC.  Treatment in this multi-centric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for 8 cycles q.3 weeks combined with 4 cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by 4 cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks.  Following therapy, all patients underwent surgical resection.  Pathologic complete response (pCR) in assessable patients was the main end-point while clinical response, toxicity and ancillary studies were secondary end-points.  Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody.  A total of 60 patients were included with 47 assessable for pathologic response.  The pCR rates were 46.8 % [95 % CI: 32.5 % to 61.1 %] and 55.3 % [95 % CI: 41.1 % to 69.5 %] according, respectively, to Chevallier and Sataloff classifications.  The complete clinical response (cCR) rate was 37.5 %.  Conservative surgery was carried out in 87 % of cases.  Toxicity was manageable.  The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR.  The authors concluded that panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC.  Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC.

In a phase II clinical trial, Hezel et al (2014) reported the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.  Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 were treated with panitumumab 6 mg kg(-1), GEM 1,000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle.  The primary objective was to determine the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v.1.1.  Secondary objectives were to evaluate toxicity, PFS, and OS.  A total of 31 patients received at least 1 cycle of treatment across 3 institutions, 28 had measurable disease.  Response rate was 45 % and disease control rate was 90 %.  Median PFS was 10.6 months (95 % CI: 5 to 24 months) and median OS was 20.3 months (95 % CI: 9 to 25 months).  The most common grade 3/4 adverse events were anemia 26 %, leukopenia 23 %, fatigue 23 %, neuropathy 16 % and rash 10 %.  The authors concluded that the combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.

In a phase II clinical trial, Foote and colleagues (2014) evaluated the safety and effectiveness of single agent panitumumab in the treatment of patients with cutaneous squamous cell carcinoma (CSCC) not suitable for local therapy.  A total of 16 patients received single agent panitumumab at a dose of 6 mg/kg repeated every 2 weeks for a minimum of 3 cycles and continued until progression, a maximum of 9 cycles or dose limiting toxicity.  The primary end-point was the best ORR as assessed by RECIST version 1.1 criteria.  Secondary end-points included evaluation of safety, toxicity and PFS.  Between May 2010 and May 2012, 16 patients were recruited; 14 were males and the median age was 68 years.  Fifteen patients had loco-regionally advanced or recurrent disease with 14 patients receiving previous radiotherapy and 7 patients receiving previous cytotoxic chemotherapy.  The best ORR (PR or CR) was 31 % (3/16 PR, 2/16 CR) with a further 6 of 16 patients achieving SD.  The median PFS and OS were 8 and 11 months, respectively.  Grade 3 or 4 events were observed in 5 patients (4 being skin toxicity) with 1 patient ceasing due to skin toxicity.  With a median follow-up of 24 months, 10 patients died due to progressive disease, 6 are alive, 1 patient with no evidence of disease at the time of analysis.  The authors concluded that single agent panitumumab is safe and effective in the management of patients with advanced CSCC even in a previously extensively pre-treated cohort.  These early results need to be validated by phase III studies.

The NCCN Dugs & Biologics Compendium does not list breast cancer, cutaneous squamous cell carcinoma and gallbladder cancer as recommended indications of panitumumab.

NCCN guidelines previously recommended panitumumb as single-agent therapy for second-line treatment of metastatic penile cancer; NCCN no longer recommends this use of panitumumab (NCCN, 2014).

In a phase II, randomized, open-label study with 2 treatment arms, Schuette et al (2015) investigated the tolerability and effectiveness of panitumumab, a fully human anti-EGFR monoclonal antibody, in combination with pemetrexed/cisplatin in patients with stage IIIB to IV primary non-squamous NSCLC and wild type V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Results were compared with those obtained in a control group of patients who received a pemetrexed/cisplatin regimen only. In total, 96 patients received panitumumab at a dose of 9 mg/kg in combination with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (n = 49) or pemetrexed/cisplatin alone (n = 47). The primary outcome measure was PFS at 6 months. Secondary end-points of the study included OS, tumor response, quality of life (QOL), and safety outcomes. Progression-free survival at 6 months did not indicate a benefit of panitumumab as a supplement to the standard therapy of pemetrexed/cisplatin whereas the OS showed a clear difference between the treatment groups in favor of the standard therapy. Results might be affected by the higher rates of serious adverse events and higher death rates within the panitumumab arm. The authors concluded that results from the present study indicated that combination of cisplatin/pemetrexed with panitumumab should not be recommended for patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of QOL, and because of the increase in toxicity rates compared with patients in the control arm, who received standard chemotherapy of pemetrexed/cisplatin.

In a randomized, controlled, open-label phase II clinical trial, Mesia et al (2015) compared chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. These researchers recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in 9 countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (greater than or equal to 10 mm for at least 1 dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharyngeal) and an ECOG performance status of 0 to 1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (3 cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (3 cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomization with a block size of 5. All patients received 70 Gy to gross tumor and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary end-point was local-regional control at 2 years, analyzed in all randomized patients who received at least 1 dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). Between Oct 26, 2007, and March 26, 2009, a total of 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68 % (95 % CI: 54 to 78) in the chemoradiotherapy group and 61 % (50 to 71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3 to 4 adverse events were dysphagia (17 [27 %] of 63 patients in the chemoradiotherapy group versus 35 [40 %] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24 %] versus 48 [55 %]), and radiation skin injury (8t [13 %] versus 27 [31 %]). Serious adverse events were reported in 20 (32 %) of 63 patients in the chemoradiotherapy group and in 37 (43 %) of 87 patients in the panitumumab plus chemoradiotherapy group. The authors concluded that in patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed.

In a randomized, controlled, open-label phase II clinical trial, Garalt et al (2015) compared panitumumab plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. These investigators recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in 8 countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (greater than or equal to 10 mm for at least 1 dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharyngeal) and an ECOG performance status of 0 to 1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (2 cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (3 cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomization with a block size of 5. All patients received 70 to 72 Gy to gross tumor and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary end-point was local-regional control at 2 years, analyzed in all randomly assigned patients who received at least 1 dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). Between Nov 30, 2007, and Nov 16, 2009, a total of 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61 % (95 % CI: 47 to 72) in the chemoradiotherapy group and 51 % (40 to 62) in the radiotherapy plus panitumumab group. The most frequent grade 3 to 4 adverse events were mucosal inflammation (25 [40 %] of 62 patients in the chemoradiotherapy group versus 37 [42 %] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32 %] versus 36 [40 %]), and radiation skin injury (7 [11 %] versus 21 [24 %]). Serious adverse events were reported in 25 (40 %) of 62 patients in the chemoradiotherapy group and in 30 (34 %) of 89 patients in the radiotherapy plus panitumumab group. The authors concluded that panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III to IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed.

Pancreatic Cancer

In a phase I clinical trial, van Zweeden and colleagues (2015) examined the maximum-tolerated dose (MTD), safety and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC and WHO Performance status 0 to 1 were treated with weekly panitumumab at 4 dose levels (1 to 2.5 mg/kg), combined with weekly gemcitabine 300 mg/m2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity (DLT). Tumor evaluation was performed after CRT and during gemcitabine monotherapy. A total of 14 patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg: 3 of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33 %), fatigue (n = 1; 17 %), nausea (n = 1; 17 %) and vomiting (n = 1; 17 %). Partial response was achieved by 3 patients (23 %), 1 in each dose cohort. Median PFS of the 3 cohorts together was 8.9 months. The authors concluded that the addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC, has manageable toxicity and potential clinical efficacy.

Panitumumab after Failure of Cetuximab

An UpToDate review on “Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations” (Clark and Grothey, 2017) states that “A small subset of patients with RAS wild-type tumors who are resistant to cetuximab will respond to panitumumab, but the best way to identify this subset is unclear.  Testing for specific mutations in the EGFR that might confer cetuximab resistance but panitumumab sensitivity is currently only available in research labs.  In addition, the duration of benefit that these patients might achieve is unknown.  Given the evidence that the majority of patients who have been evaluated in a trial setting do not achieve durable benefit, in our view, the use of panitumumab in patients who progress on cetuximab should only be undertaken in the context of a clinical trial aimed at better defining this question.  This approach is consistent with consensus-based guidelines from the NCCN and ESMO”.

Head and Neck Cancers

In a phase III clinical trial, Ringash and associates (2017) compared QOL between standard (SFX) chemoradiotherapy (arm A) and altered fractionation radiotherapy (AFX) with panitumumab (PMab; arm B).  Patients with T any N + M0 or T3-4N0M0 squamous cell head-neck carcinoma (HNSCC)were randomized to SFX (70 Gy/35/7 weeks) plus cisplatin (100 mg/m2 IV × 3) versus AFX (70 Gy/35/6 weeks) plus PMab (9 mg/kg IV × 3).  QOL was collected at baseline, end of RT and 2, 4, 6, 12, 24 and 36 months post-RT using the Functional Assessment of Cancer Therapy Head and Neck (FACT-H&N), MD Anderson Dysphagia Index (MDADI) and SWAL-QOL.  These researchers hypothesized a 6-point more favorable change in FACT-H&N score from baseline to 1 year in arm B over arm A.  Among 320 patients, median follow-up was 46 (range of 0.1 to 64.3) months, median age was 56 years, 84 % were men, ECOG performance status of 0 (71 %), 1 (29 %).  Primary site was oropharynx in 81 % (p16+ 68 %, p16- 16 %, missing 16 %).  Baseline scores did not differ by arm (A/B): FACT-H&N 116.5/115, MDADI Global 83/77, SWAL-QOL General 67/68.  At 1 year, no difference was seen between arms in FACT-H&N change from baseline: A -1.70, B -4.81, p = 0.194.  Subscale change scores by arm were (A/B): last week RT, FACT-Physical (-11.6, -10, p = 0.049), MDADI Physical (-40.4, -33.9, p = 0.045), and SWAL-QOL Eating Duration (-61.2, -51.2, p = 0.02), Eating Desire (-53.3, -43.9, p = 0.031) and Mental Health (-42, -32.6, p = 0.009); 4 months, HN subscale (-7.7, -10, p = 0.014).  No clinically important differences by arm were observed post-treatment.  The authors concluded that PMab with AFX did not durably improve QOL or swallowing as compared with SFX with cisplatin.

In a multi-center, phase II clinical trial, Siano and associates (2017) examined the safety and effectiveness of panitumumab given as a single agent in platinum-pretreated HNSCC.  Patients with advanced HNSCC previously treated with platinum-containing therapy were included.  Panitumumab was administered intravenously every 2 weeks at a dose of 6 mg/kg.  Primary end-point was ORR according to RECIST version 1.1; secondary end-points were PFS and safety.  A Simon's 2-step design was chosen; 4 PRs in the first 32 patients were required for continuing to step 2.  An exploratory biomarker analysis was performed.  A total of 33 patients were enrolled; 2 obtained a PR for an ORR of 6% , and 15 (45 %) showed SD for at least 2 months, resulting in a 51 % disease control rate.  Median PFS was 2.6 months (95 % CI: 1.7 to 3.7), while median OS was 9.7 months (95 % CI: 6.3 to 17.2).  The most frequent adverse drug reactions were cutaneous rash (64 %) and hypo-magnesemia (55 %).  Overall, 30 % of patients experienced grade 3/4 adverse events (AEs).  No infusion-related reactions occurred; EGFR copy number gain (CNG) was more frequent in patients who benefitted from panitumumab; 2 uncommon KRAS mutations (G48E, T50I) and 3 canonical PIK3CA mutations (all E545K) were detected.  High-risk HPV16 was found in 10 patients and EGFR CNG in 13 treated patients; EGFR CNG appeared to be more frequent in individuals with at least SD compared with patients with progressive disease (59 % versus 30 %); PFS for patients with EGFR CNG was 4.6 months (95 % CI: 1.0 to 9.2 months) and 1.9 months (95 % CI: 1.0 to 3.2 months) for patients without CNG (p = 0.02).  The authors concluded that panitumumab monotherapy in pre-treated HNSCC patients was well-tolerated, but moderately active.  These researchers observed a considerable disease control rate.  They stated that future strategies with this agent comprise right patient selection through the identification of reliable biomarkers and gene signatures predicting response and, considering good tolerability and convenience, combination strategies with novel agents and immune therapeutic agents.

Non-Small Cell Lung Cancer

In a phase II clinical trial, Edelman and colleagues (2017) examined the outcomes of adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC (LANSCLC) with a primary end-point of mediastinal nodal sterilization (MNS).  Resectable LANSCLC patients were eligible if deemed suitable for tri-modality therapy prior to treatment.  Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines.  Concurrent CRT consisted of weekly carboplatin (CBDCA, AUC = 2.0), paclitaxel (50 mg/m2), and 60 Gy radiation (RT) delivered in 30 fractions.  There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks.  The mediastinum was pathologically re-assessed prior to or at the time of resection.  Consolidation chemotherapy was CBDCA AUC = 6, paclitaxel 200 mg/m2 q 21 d x 2.  The study was designed to detect an improvement in MNS from 52 % to 72 %.  Using a 0.15 1-sided type 1 error and 80 % power, 97 patients were needed.  The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients were accrued for futility and excessive toxicity in the experimental arm.  A total of 60 patients were eligible; 19 patients (86 %) on CRT and 29 patients (76 %) on CRT + panitumumab underwent surgery.  Post-operative toxicity: 3 (13.6 %) grade-4 and 0 (0 %) grade-5 AEs on CRT versus 6 (15.8 %) grade-4 and 4 (10.5 %) grade-5 AEs on CRT + panitumumab; MNS rates were 68.2 % (95 % CI: 45.1 % to 86.1 %) and 50.0 % (95 % CI: 33.4 % to 66.6 %), for CRT and CRT + panitumumab, respectively (p = 0.95).  The authors concluded that the addition of panitumumab to CRT did not improve MNS.  There was an unexpectedly high mortality rate on the panitumumab-arm, although the relationship to panitumumab was unclear; and the control-arm had outcomes similar to NRG Oncology RTOG 0229, which demonstrated the feasibility and efficacy of combining full dose radiation (61.2Gy) with chemotherapy followed by resection and chemotherapy.

HER1-Positive Disseminated Intraperitoneal Disease

Milenic and colleagues (2017) noted that identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research.  Panitumumab, a fully human and less immunogenic mAb that binds to the EGFR (Erb1; HER1), was evaluated for targeted α-particle radiation therapy using 212Pb, an in-vivo α generator.  A single dose of 212Pb-panitumumab administered to athymic mice bearing LS-174T intraperitoneal (i.p.) tumor xenografts was found to have greater therapeutic efficacy when directly compared with 212Pb-trastuzumab, which binds to HER2.  A dose escalation study determined a maximum effective working dose of 212Pb-panitumumab to be 20μCi with a median survival of 35 days versus 25 days for the untreated controls.  Pre-treatment of tumor-bearing mice with paclitaxel and gemcitabine 24 hours prior to injection of 212Pb-pantiumumab at 10 or 20 μCi resulted in the greatest enhanced therapeutic response at the higher dose with median survivals of 106 versus 192 days, respectively.  The greatest therapeutic impact, however, was observed in the animals that were treated with topotecan 24 hours prior to RIT and then again 24 hours after RIT; the best response from this combination was also obtained with the lower 10-μCi dose of 212Pb-panitumumab (median survival greater than 280 days).  The authors concluded that 212Pb-panitumumab is an excellent candidate for the treatment of HER1-positive disseminated i intraperitoneal disease.  Moreover, they stated that the potentiation of the therapeutic impact of 212Pb-pantiumumab by chemotherapeutics confirmed and validated the importance of developing a multi-modal therapy regimen.  These preliminary pre-clinical findings need to be further investigated in well-designed clinical studies.

Biliary Cancer

In a phase-II study, Vogel and associates (2018) examined the effect of chemotherapy with panitumumab as therapy for KRAS wild-type biliary cancer.  Patients with advanced biliary tract cancer were randomized (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1,000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v. q3w).  The primary end-point was the evaluation of PFS at 6 months.  Secondary end-points included ORR, OS, and toxicity.  In addition, a post-hoc assessment of genetic alterations was performed.  Finally, these investigators performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies.  A total of 62 patients were randomized in arm A and 28 patients in arm B.  Patients received 7 treatment cycles in median (1 to 35) with a median treatment duration of 4.7 months (141 days, 8 to 765); PFS rate at 6 months was 54 % in patients treated with cisplatin/gemcitabine and panitumumab; but was 73 % in patients treated with cisplatin/gemcitabine without antibody, respectively.  Secondary end-points were an ORR of 45 % in treatment arm A compared with 39 % receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively.  In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival.  In accordance with these findings, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone.  The authors concluded that panitumumab in combination with chemotherapy did not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer.  Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers.

Breast Cancer

Matsuda and colleagues (2018) evaluated the safety and efficacy of panitumumab plus neoadjuvant chemotherapy in patients with primary HER2-negative inflammatory breast cancer (IBC).  Women with primary HER2-negative IBC were enrolled from 2010 to 2015 and received panitumumab plus neoadjuvant chemotherapy.  Median follow-up time was 19.3 months.  Tumor tissues collected before and after the 1st dose of panitumumab were subjected to immunohistochemical staining and RNA sequencing analysis to identify biomarkers predictive of pathologic complete response (pCR).  Patients received 1 dose of panitumumab (2.5 mg/kg) followed by 4 cycles of panitumumab (2.5 mg/kg), nab-paclitaxel (100 mg/m2), and carboplatin weekly and then 4 cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks.  The primary end-point was pCR rate; the secondary end-point was safety.  The exploratory objective was to identify biomarkers predictive of pCR.  A total of 47 patients were accrued; 7 were ineligible.  The 40 enrolled women had a median age of 57 (range of 23 to 68) years; 29 (72 %) were post-menopausal; 3 patients did not complete therapy because of toxic effects (n = 2) or distant metastasis (n = 1); 19  patients had triple-negative and 21 had hormone receptor-positive IBC.  The pCR and pCR rates were overall, 11 of 40 (28 %; 95 % CI: 15 % to 44 %); triple-negative IBC, 8 of 19 (42 %; 95 % CI: 20 % to 66 %); and hormone receptor-positive/HER2-negative IBC, 3 of 21 (14 %; 95 % CI: 3 % to 36 %).  During treatment with panitumumab, nab-paclitaxel, and carboplatin, 10 patients were hospitalized for treatment-related toxic effects, including 5 with neutropenia-related events.  There were no treatment-related deaths.  The most frequent non-hematologic AE was skin rash.  Several potential predictors of pCR were identified, including pEGFR expression and COX-2 expression.  The authors concluded that this combination of panitumumab and chemotherapy showed the highest pCR rate ever reported in triple-negative IBC.  Moreover, they stated that a randomized phase-II clinical trial is ongoing to determine the role of panitumumab in patients with triple-negative IBC and to further validate predictive biomarkers.

Esophageal Cancer

In a randomized, open-label, phase-II clinical trial (NEOPECX), Stahl and colleagues (2018) examined  the role of panitumumab with peri-operative chemotherapy, previously untreated patients with locally advanced esophago-gastric cancer (EGC).  Subjects received standard epirubicin, cisplatin, capecitabine (ECX) chemotherapy with or without panitumumab.  The primary end-point was the histological response rate after neoadjuvant therapy.  The expression status and gene copy number of EGFR, HER2, and MET were determined by immunohistochemistry and fluorescence in situ hybridization (FISH).  Plasma samples were collected before the 1st cycle of neoadjuvant chemotherapy.  A total of 160 patients (80 versus 80) were eligible.  The majority (82 % versus 80 %) showed lymph node involvement.  Rate of R0-resection, percentage of patients with down-staging to ypT0-2 at pathohistological evaluation, and rate of major histological response was equal in both arms.  Toxicity was increased by panitumumab with regard to thromboembolic events and skin toxicity.  Patients with tumor EGFR, HER2 or MET expression had shorter PFS and OS; FISH positivity for these markers was associated with shorter survival independent of therapy.  High levels of soluble EGFR in particular predicted poor survival in the panitumumab arm.  The authors concluded that the addition of panitumumab to ECX did not improve down-staging of locally advanced EGC; low plasma levels of pathway-associated proteins such as sEGFR may identify a group of patients that benefit from EGFR-directed therapy.

Yoon and associates (2018) noted that esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence.  Panitumumab (Pa) is a fully humanized IgG2 monoclonal antibody against human EGFR.  Cetuximab (Cx) combined with irinotecan (Ir) is active for 2nd-line treatment of colorectal cancer.  In a phase-II clinical trial, these researchers evaluated Pa plus Ir as 2nd-line therapy for advanced EAC.  The primary end-point was response rate (RR).  Patients with 1 prior treatment were given Pa 9 mg/m2 on day 1 and Ir 125 mg/m2 on days 1 and 8 of each 21-day cycle.  Inclusion criteria were confirmed EAC, measurable disease, no prior Ir or Pa, performance status of less than 2, and normal organ function.  A total of 24 patients were enrolled; 18 were eligible and evaluable.  These patients were all white, with a median age of 62.5 years (range of 33 to 79 years), and included 15 men and 3 women.  The median number of cycles was 3.5.  The most common grade 1 to 2 AEs were fatigue, diarrhea, anemia, leukopenia, and hypoalbuminemia.  Grade 3 to 4 AEs included hematologic, gastro-intestinal (GI), electrolyte, rash, fatigue, and weight loss.  The median follow-up was 7.2 months (range of 2.3 to 14 months).  There were no complete remissions.  The PR rate was 6 % (1/18; 95 % CI: 0.01 to 0.26).  The clinical benefit (PR plus SD) rate was 50 %.  The median OS was 7.2 months (95 % CI: 4.1 to 8.9) with an 11.1 % 1-year survival rate.  The median PFS was 2.9 months (95 % CI, 1.6 to 5.3).  The authors concluded that irinotecan and panitumumab as 2nd-line treatment for advanced EAC were not active.

Ampullary Adenocarcinoma and Small Bowel Adenocarcinoma

In an open-label, single-center, single-arm, phase-II clinical trial, Gulhati and colleagues (2018) evaluated the benefit of panitumumab in small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC).  The primary objective was RR.  Panitumumab was administered at a dose of 6 mg/kg intravenously (IV) every 14 days.  A total of 9 patients (men/women 7:2, median age of 61 years [range of 40 to 74], ECOG performance status 0/1: 2/7) were enrolled from September 2013 to October 2015; 1 patient had AAC (pancreatico-biliary subtype) and 8 patients had SBA (3 duodenal, 5 jejunal/ileal).  Acneiform rash was the most common toxicity.  The study was stopped early due to futility with no responses, SD in 2 patients, and PD in 7 patients.  Median PFS and OS were 2.4 and 5.7 months, respectively.  No patients had extended RAS mutations (exons 2/3/4), but 2 patients had BRAF G469A and 1 patient had PIK3CA H1074R mutations.  The authors concluded that panitumumab had no clinically meaningful activity in patients with metastatic RAS wild-type SBA and AAC; these findings may relate to the primarily mid-gut and fore-gut derivation of the small bowel and ampulla.

Sarcoma

In a phase-I clinical trial, Vlahovic and co-workers (2018) determined the MTD or recommended phase-II dose (RPTD) and safety and tolerability of the ganitumab and everolimus doublet-regimen followed by the ganitumab, everolimus, and panitumumab triplet-regimen.  This was a standard 3 + 3 dose escalation trial.  Doublet-therapy consisted of ganitumab at 12 mg/kg every 2 weeks; doses of everolimus were adjusted according to DLTs.  Panitumumab at 4.8 mg/kg every 2 weeks was added to the RPTD of ganitumab and everolimus; DLTs were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment.  Treatment continued until disease progression or undesirable toxicity.  Pre-treatment and on-treatment skin biopsies were collected to assess insulin-like growth factor 1 receptor and mammalian target of rapamycin (mTOR) target modulation.  A total of 43 subjects were enrolled.  In the doublet-regimen, 2 DLTs were observed in cohort 1, no DLTs in cohort -1, and 1 in cohort -1B.  The triplet-combination was discontinued because of unacceptable toxicity.  Common AEs were thrombocytopenia/neutropenia, skin rash, mucositis, fatigue, and hyperglycemia.  In the doublet-regimen, 2 patients with refractory NSCLC achieved prolonged complete responses ranging from 18 to more than 60 months; 1 treatment-naive patient with chondrosarcoma achieved prolonged SD of greater than 24 months.  In dermal granulation tissue, the insulin-like growth factor receptor and mTOR pathways were potently and specifically inhibited by ganitumab and everolimus, respectively.  The authors concluded that the triplet-regimen of ganitumab, everolimus, and panitumumab was associated with unacceptable toxicity.  However, the doublet of ganitumab at 12 mg/kg every 2 weeks and everolimus 5 times weekly had an acceptable safety profile and demonstrated notable clinical activity in patients with refractory NSCLC and sarcoma.

Appendix

Panitumumab  is to be given as an intravenous infusion and is supplied as Vectibix 20 mg/mL single‐use vials in 5mL (100 mg), 10 mL (200 mg), and 20mL (400 mg). The FDA-approved labeling of Vectibix states that panitumumab for colorectal cancer should be administered 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg). The labeling recommends to reduce infusion rate by 50% for mild reactions, and to terminate the infusion for severe infusion reactions. The labeling recommends to withhold or discontinue panitumumab for severe or intolerable dermatologic toxicity, and to reduce the dose of panitumumab for recurrent, grade 3 toxicity.

The above policy is based on the following references: