Panitumumab (Vectibix)

Number: 0748

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses panitumumab (Vectibix) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of panitumumab (Vectibix) is required of all Aetna participating providers and members in applicable plan designs. For precertification of panitumumab (Vectibix), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

  1. Criteria for Initial Approval

    Colorectal Cancer (CRC)

    Aetna considers panitumumab (Vectibix) medically necessary for the treatment of colorectal cancer, including appendiceal adenocarcinoma and anal adenocarcinoma, for unresectable/inoperable, advanced, or metastatic disease and the member has not previously experienced clinical failure on cetuximab when either of the following criteria are met:

    1. The member meets all of the following criteria:

      1. The RAS (KRAS and NRAS) mutation status is negative (wild-type); and
      2. If the tumor is positive for BRAF V600E mutation, the requested medication will be used in combination with encorafenib (Braftovi); and
      3. For colon cancer, the tumor is left-sided only; or

    2. The member meets all of the following criteria:

      1. The disease is KRAS G12C mutation positive; and
      2. The requested medication will be used in combination with sotorasib (Lumakras) or adagrasib (Krazati); and
      3. The member previously received treatment with chemotherapy.

    Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

  2. Continuation of Therapy

    Aetna considers continuation of panitumumab (Vectibix) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

  3. Related Policies

    1. CPB 0352 - Tumor Markers
    2. CPB 0516 - Colorectal Cancer Screening
    3. CPB 0684 - Cetuximab (Erbitux)

Dosage and Administration

Panitumumab (Vectibix) is supplied as 100 mg/5 mL (20 mg/mL) and 400 mg/20 mL (20 mg/mL) in single-dose vials for intravenous infusion. The recommended dosage is as follows:

Metastatic colorectal cancer

Panitumumab (Vectibix) is administered as 6 mg/kg every 14 days as an intravenous infusion over 60 minutes (≤ 1000 mg) or 90 minutes (> 1000 mg).

Source: Amgen, 2021

Experimental and Investigational

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

Aetna considers panitumumab (Vectibix) 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, including gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma
  • Bladder cancer
  • Breast cancer
  • Cutaneous squamous cell carcinoma
  • Esophageal cancer
  • Gastric cancer
  • Gastro-esophageal junction adenocarcinomas
  • Glioma
  • Head and neck cancer
  • Intra-hepatic choledocholithiasis
  • 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 panitumumab-DOTA-111In radioimmunotherapy experimental and investigational for the treatment of triple-negative breast cancer.

Aetna considers panitumumab in combination with carboplatin and nabpaclitaxel experimental and investigational for the treatment of metastatic renal medullary carcinoma.

Table:

CPT Codes / HCPCS Codes / ICD-10 codes
Code Code Description

CPT codes covered if selection criteria are met:
81275 KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13)
81276     additional variant(s) (eg, codon 61, codon 146)
81311 NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (eg, colorectal carcinoma), gene analysis, variants in exon 2 (eg, codons 12 and 13) and exon 3 (eg, codon 61)
81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

Other CPT codes related to the CPB:
81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
88363 Examination and selection of retrieved archival (ie, previously diagnosed) tissue(s) for molecular analysis (eg, KRAS mutational analysis)
96365 - 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96379 Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection of infusion
96413 - 96417 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:

212Pb-panitumumab - no specific code:
J9303 Injection, panitumumab, 10 mg

HCPCS codes not covered for indications listed in the CPB:
Panitumumab DOTA-111 - no specific code

Other HCPCS codes related to the CPB:

Vemurafenib, encorafenib (Braftovi), Nabpaclitaxel - no specific code:
J9045 Injection, carboplatin, 50 mg
J9055 Injection, cetuximab, 10 mg
J9190 Injection, fluorouracil, 500 mg
J9206 Injection, irinotecan, 20 mg
J9263 Injection, oxaliplatin, 0.5 mg

ICD-10 codes covered if selection criteria are met:
C18.0 - C18.9 Malignant neoplasm of colon [covered for left-sided tumors only]
C19 - C21.8 Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C15.3 - C15.9 Malignant neoplasm of esophagus
C16.0 - C16.9 Malignant neoplasm of stomach
C22.1 Intrahepatic bile duct carcinoma
C23 - C24.0 Malignant neoplasm of gallbladder and extrahepatic bile ducts
C25.0 - C25.9 Malignant neoplasm of pancreas
C34.00 - C34.92 Malignant neoplasm of bronchus and lung
C41.0 - C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites
C44.02, C44.121 - C44.129, C44.221 - C44.229, C44.320 - C44.329, C44.42, C44.520 - C44.529, C44.621 - C44.629, C44.721 - C44.729, C44.82, C44.92 Squamous cell carcinoma of skin
C49.0 - C49.A9 Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929 Malignant neoplasm of female and male breast
C56.1 - C56.9 Malignant neoplasm of ovary
C60.0 - C60.9 Malignant neoplasm of penis
C64.0 – C64.9 Malignant neoplasm of kidney, except renal pelvis
C67.0 - C67.5 Malignant neoplasm of bladder
C70.0 - C72.9 Malignant neoplasm of brain and other parts of central nervous system [glioma]
C76.0 Malignant neoplasm of head, face, and neck
C79.00 – C79.02 Secondary malignant neoplasm of unspecified kidney and renal pelvis
K80.50 - K80.51 Calculus of bile duct without cholangitis or cholecystitis

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Vectibix is indicated for the treatment of patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer (mCRC):

  • As first-line therapy in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin);
  • As monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy.

Limitation of Use: Vectibix is not indicated for the treatment of patients with RAS-mutant mCRC or for whom RAS mutation status is unknown.

Compendial Use

  • Colorectal cancer

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).

The FDA's approval of Vectibix was based on the findings of a phase III, randomized, controlled, clinical trial of 463 patients with metastatic colorectal cancer (Van Cutsem et al, 2007).  Subjects with 1 % or more EGFR tumor cell membrane staining, measurable disease, and radiological documentation of disease progression during or within 6 months of most recent chemotherapy were randomly assigned to one of the 2 groups
  1. panitumumab 6 mg/kg of body weight every 2 weeks plus best supportive care (BSC; n = 231); or
  2. BSC alone (n = 232). 
Tumor assessments by blinded central review were scheduled from week 8 until disease progression.  The primary end point was PFS.  Secondary end points included objective response, OS, and safety.  Patients in the second group (BSC alone) who progressed could receive panitumumab in a cross-over study.  Panitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95 % CI: 0.44 to 0.66, [p < 0.0001]).  Median PFS time was 8 weeks (95 % CI: 7.9 to 8.4 weeks) for panitumumab and 7.3 weeks (95 % CI: 7.1 to 7.7 weeks) for BSC.  Mean PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC.  Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10 % for panitumumab and 0 % for BSC (p < 0.0001).  No difference was observed in OS (HR, 1.00; 95 % CI: 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76 % of BSC patients entered the cross-over study.  Panitumumab was well-tolerated.  Skin toxicities, hypomagnesemia, and diarrhea were the most common adverse events observed.  No patients had grade 3/4 infusion reactions.  The authors concluded that panitumumab significantly improved PFS with manageable toxicity in patients with chemo-refractory colorectal cancer.

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 effectiveness 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.

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.

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.

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:

  • 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.

Panitumumab after Failure of Cetuximab for Colorectal Cancer

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.

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.

Anal Carcinoma

Vendrely et al (2023) noted that standard treatment of SCC of the anus (SCCA) is 5-FU and mitomycin C (MMC)-based CRT. In a phase-II clinical trial, these researchers examined the tolerance and CR rate at 8 weeks of panitumumab (Pmab) combined with MMC-5-FU-based CRT. Patients with locally advanced tumors without metastases (T2 greater than 3 cm, T3-T4, or N+ whatever T stage) were treated with IMRT up to 65 Gy and concomitant CRT according to the doses defined by a previous phase-I clinical trial (MMC: 10 mg/m2; 5-FU: 400 mg/m2; Pmab: 3mg/kg). The expected CR rate was 80 %. A total of 45 patients (men: 9, women: 36; median age of 60.1 [41.5 to 81]) were enrolled in 15 French centers. The most common related grade 3 to 4 toxicities observed were digestive (51.1 %), hematologic (lymphopenia: 73.4 %; neutropenia: 11.1 %), radiation dermatitis (13.3 %), and asthenia (11.1 %) with RT interruption in 14 patients. One patient died because of mesenteric ischemia during the CRT, possibly related to treatment. In intention-to-treat (ITT) analysis, the CR rate at 8 weeks after CRT was 66.7 % [90 % CI: 53.4 to 78.2]. Median follow-up was 43.6 months [IC 95 %: 38.61 to 47.01]. OS, recurrence-free survival (RFS) and colostomy-free survival (CFS) at 3 years were 80 % [95 % CI: 65.1 to 89], 62.2 % [IC 95 %: 46.5 to 74.6] and 68.8 % [IC 95 %: 53.1 to 80.2], respectively. The authors concluded that panitumumab in combination with CRT for locally advanced SCCA failed to meet the expected CR rate and exhibited a poor tolerance. Furthermore, late RFS, CFS, and OS did not suggest any outcome improvement to justify further clinical trials.

Biliary Tract Cancer

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.

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 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.

Bladder Cancer

In a prospective study, Fransen van de Putte et al (2019) examined the safety and efficacy of concurrent radiotherapy and panitumumab following neoadjuvant/induction chemotherapy and pelvic lymph node dissection as a bladder preserving therapy for invasive bladder cancer.  Patients with cT1-4N0-2M0 bladder cancer were treated with pelvic lymph node dissection and 4 cycles of platinum based induction chemotherapy followed by a 6½-week schedule of weekly panitumumab (2.5 mg/kg) and concurrent radiotherapy to the bladder (33 × 2 Gy).  As the primary objective, these investigators compared concurrent radiotherapy and panitumumab toxicity to a historical control toxicity rate of concurrent cisplatin/radiotherapy (less than 35 % of patients with Grade 3 to 5 toxicity).  A sample size of 31 patients was estimated; secondary end-points included complete remission at 3-month follow-up, the bladder preservation rate, EGFR expression and RAS mutational status.  Of the 38 cases initially included in this study, 34 were staged cN0.  After pelvic lymph node dissection 7 cases (21 %) were up-staged to pN+.  Of the 38 patients, 31 started concurrent radiotherapy and panitumumab.  During concurrent radiotherapy and panitumumab 5 patients (16 %, 95 % CI: 0 to 31) experienced systemic or local grade 3 to 4 toxicity; 4 patients did not complete treatment due to AEs.  Complete remission was achieved in 29 of 31 patients (94 %, 95 % CI: 83 to 100). At a median follow-up of 34 months, 4 patients had local recurrence, for which 3 (10 %) underwent salvage cystectomy.  Two tumors showed EGFR or RAS mutation while 84 % showed positive EGFR expression.  The authors concluded that concurrent radiotherapy and panitumumab following induction chemotherapy and pelvic lymph node dissection had a safety profile that was non-inferior to the historical profile of concurrent cisplatin/radiotherapy; the high complete remission and bladder preservation rates were promising and warrant further study.

Breast Cancer

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.

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.

Cutaneous Squamous Cell Carcinoma

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.

Hu and colleagues (2021) stated that anti-EGFR antibodies and anti-programmed cell death 1 protein (PD-1) antibodies have been used separately to treat metastatic CSCC.  While 2 anti-EGFR antibodies have similar clinical activity, cetuximab is administered weekly, whereas panitumumab is administered every 2 weeks.  These investigators reported findings using panitumumab in combination with anti-PD-1 antibody in patients with relapsed refractory CSCC.  A total of 3 consecutive patients with poor PS and rapidly progressive recurrent CSCC of the face or scalp signed informed consent to receive an anti-PD-1 antibody with the option to add panitumumab if there were inadequate response.  After 2, 5, and 7 cycles of anti-PD-1 antibody treatment, respectively, panitumumab was added and the combination was continued for 27, 7, and 5 cycles, respectively.  Fatigue, rash, and hypomagnesemia were reported, consistent with expectations for either agent alone.  All 3 patients achieved durable complete response (CR).  The authors concluded that the favorable clinical outcomes supported further evaluation of the combination of anti-PD1 and anti-EGFR antibodies to control refractory CSCC of the face or scalp.

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.

FOLFIRI-Panitumumab for the treatment of Patients with RAS Wild-Type Circulating Tumor DNA Metastatic Colorectal Cancer

Aparicio et al (2022) stated that panitumumab plus FOLFOX (P-FOLFOX) is standard 1st-line treatment for RAS wild-type (WT) mCRC; however, the value of panitumumab re-challenge is currently unknown.  In a randomized phase-II clinical trial, these researchers examined the addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB).  Subjects were assigned (3:2 ratio) to 2nd-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B).  LB for circulating tumor DNA analysis was collected at study entry and at disease progression.  Primary endpoint was 6-month PFS; and 2-stage Simon design required 85 patients to be included.  Between February 2019 and November 2020, a total of 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B).  The study was prematurely closed due to inadequate recruitment.  Serious AEs were more frequent in arm A (44 % versus 23 %); ORR was 33 % (arm A) versus 7.7 % (arm B).  Six-month PFS rate was 66.7 % (arm A) and 38.5 % (arm B).  Median PFS was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio [HR], 0.58).  At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36 %) in arm A and 2/10 (20 %) in arm B.  The authors concluded that the findings of the BEYOND study suggested a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB.  moreover, these researchers state that this strategy deserves further investigation.

In a single-arm, multi-center, phase-II clinical trial, Watanabe et al (2022) examined the safety and effectiveness of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable mCRC.  Furthermore, the clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment.  Eligible patients with RAS WT mCRC who had received the 1st-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI.  PFS at 6 months was the primary endpoint, with threshold and expected values of 35 % and 50 %, respectively.  A total of 54 patients were enrolled between October 2017 and October 2019.  The crude 6-month PFS rate was 37.0 %, with a 4.8-month median PFS.  The response rate and disease control rate were 16.7 % and 50.0 %, respectively.  Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline.  The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with WT tumors.  The authors concluded that this phase-II clinical trial failed to show the expected effectiveness of the continuous panitumumab use in the 2nd-line treatment; and LB discriminated the duration of PFS according to the mutation status.  These researchers stated that the effectiveness of continuous treatment with panitumumab should be examined in patients with RAS/BRAF WT mCRC determined by LB at the start of the 2nd-line treatment.

Gastro-Esophageal Cancer / Gastro-Esophageal Junction Adenocarcinomas

Okines and colleagues (2011) reported that cetuximab and panitumumab, 2 MAbs against EGFR, and the dual EGFR and human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) lapatinib are currently undergoing phase III evaluation in esophagogastric cancer. 

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.

In a phase-I/II clinical trial, Kentepozidis and colleagues (2018) defined the MTD of bi-weekly docetaxel/cisplatin/5-fluorouracil (DCF) plus panitumumab (P), its efficacy, and tolerability as 1st-line treatment in advanced gastro-esophageal cancer.  In phase-I part, patients with unresectable locally advanced or metastatic adenocarcinomas of the stomach or the gastro-esophageal junction received cisplatin (40 mg/m2 on day 1), leucovorin (400 mg/m2 on day 1), 5-fluorouracil (400 mg/m2 bolus on day 1), 5-fluorouracil (1,000 mg/m2/day continuous infusion on days 1 to 2), and escalated doses of docetaxel (on day 1) plus P (6 mg/kg on day 1) every 2 weeks.  In phase II part, patients were treated with DCF/P at the MTD and the primary end-point was response rate.  The expected response rate was set at greater than 40 %.  The MTD for docetaxel in the mDCF/P was defined at 40 mg/m2 and a total of 40 evaluable patients were enrolled in the phase-II study; 1 (2.5 %) CR and 13 (32.5 %) PRs (ORR: 35 %), as well as 16 (40 %) SD were documented.  The median PFS was 6.9 months (95 % CI: 3.5 to 10.3) and the median OS was 11.3 months (95 % CI: 7.7 to 14.8).  Grade 3 to 4 neutropenia occurred in 10 patients (25 %) and febrile neutropenia in 2 (5 %).  Allergic reactions (grade 1 to 4) occurred in 9 patients (22.5 %).  There was 1 treatment-related death.  The authors concluded that mDCF/P combination was feasible, though associated with a poor toxicity profile.  Moreover, the study failed to meet its primary end-point and was terminated prematurely due to futility.  These researchers stated that these findings added to the results of large phase-III clinical trials that had shown no benefit from the addition of anti-EGFR antibodies to different chemotherapeutic backbones as 1st-line treatment in metastatic gastric cancer.  They stated that translational studies are needed to identify specific patient sub-populations that may benefit from anti-EGFR treatment.

Malka and colleagues (2019) noted that EGFR and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumor growth and proliferation, are often deregulated in advanced gastro-esophageal adenocarcinomas.  In a randomized, open-label, 3-arm, phase-II clinical trial, these researchers examined if adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to 1st-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) would benefit patients with advanced gastro-esophageal adenocarcinoma.  This study enrolled patients greater than or equal to 18 years, with advanced gastro-esophageal adenocarcinoma, ECOG performance status (PS) of 0 to 1, and no known HER2 over-expression.  Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression.  The primary end-point was the 4-month PFS rate; secondary end-points included OS and tolerance.  The study enrolled 162 patients in 29 French centers.  The median follow-up was 23.6 months (interquartile range [IQR] = 16.4 to 29.0).  The 4-month PFS rate was 71 % (95 % CI: 57 to 82) with chemotherapy alone, 57 % (95 % CI: 42 to 71) combined with panitumumab and 61 % (95 % CI: 47 to 74) combined with rilotumumab.  Median OS was 13.1 months (95 % CI: 8.7 to 16.9) with chemotherapy alone, 8.3 months (95 % CI: 6.2 to 13.2) combined with panitumumab and 11.5 months (95 % CI: 7.9 to 17.1) combined with rilotumumab; AEs of grade greater than or equal to III occurred less frequently with chemotherapy alone (62 %) than with panitumumab (83 %) and rilotumumab (89 %).  The authors found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 1st-line chemotherapy to treat advanced gastro-esophageal adenocarcinoma patients.

Glioma

In a review on targeting ErbB receptors in high-grade glioma, Berezowska and Schlegel (2011) noted that the ErbB receptor family of tyrosine kinases comprises 4 members

  1. EGFR (ErbB1/HER1),
  2. ErbB2 (HER2/neu),
  3. ErbB3 (HER3) and
  4. ErbB4 (HER4). 

Physiologically, signaling is induced by ligand initiated receptor homo- or hetero-dimerization, activating intra-cellular downstream signaling pathways and leading to increased cell proliferation, anti-apoptosis and migration.  A truncated, constitutively activated mutant EGFR (EGFRvIII) is associated with poor survival in glioblastoma multiforme.  Thus, to-date anti-ErbB approaches are mainly focused on EGFR.  The 2 major classes of anti-ErbB therapeutics are monoclonal antibodies (e.g., cetuximab, panitumumab) and small molecule tyrosine kinase inhibitors (e.g., erlotinib, gefitinib, lapatinib).  Some compounds entered clinical trials already, but clinical efficacy needs to be enhanced.

Head and Neck Cancers

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.

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.

Martinez-Trufero and colleagues (2021) noted that sequential treatment of panitumumab (Pb) plus paclitaxel (Px) as induction treatment (IT) followed by concurrent bio-radiotherapy (Bio-RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy.  In a phase-II, single-arm, multi-center clinical trial, with 2-stage design, patients greater than or equal to 18 years with stage III-IVa-b LA-SCCHN unfit for platinum received Px + Pb (9 weeks) as IT followed by Bio-RT + Pb.  Primary endpoint was ORR after IT, defined as more than 70 % of patients achieving complete response (CR) or PR to IT.  Secondary endpoints included PFS, organ preservation rate, safety profile.  Study ended prematurely (51 patients) due to slow recruitment; ORR was 66.7 % (95 % CI: 53.7 to 79.6), 8 (15.7 %) CR and 26 (51.0 %) PR.  A total of 39 patients (76 %) completed RT; Pb and/or Px-related AEs grade 3 to 4: 56.9 % during IT and 63.4 % during the concomitant phase, of which most common were skin toxicity (33.3 %); 5 deaths occurred during treatment, 2 of them (3.9 %) were Pb and/or Px-related.  The authors concluded that although under-powered, ORR was higher than the pre-specified boundary for considering the treatment active.  These researchers stated that although Px + Pb as IT provided some benefit, the safety profile was worse than expected.  To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further investigation is needed.

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.

Intra-Hepatic Choledocholithiasis

Liu and colleagues (2019) stated that in hepatolithiasis, chronic proliferative cholangitis (CPC), an active and longstanding inflammation of stone‑containing bile ducts with enhanced mucin‑producing activity, not only affects the progression of the disease, it can also induce biliary carcinogenesis.  These researchers examined the effect of the panitumumab (Pani) on CPC.  Following the establishment of CPC rat models, periodic acid Schiff staining was used to observe the positive rate of EGFR expression.  The expression levels of EGFR, mucin 5AC (MUC5AC), Ki‑67, type I collagen and mammalian target of rapamycin (mTOR), and the activity of β‑glucuronidase (β‑G), were measured.  The rats treated with Pani demonstrated a significantly lower degree of hyper-proliferation of the epithelium and submucosal glands of the bile duct and collagen fibers of the bile duct wall, a significantly decreased positive rate of EGFR, reduced phosphorylation of mTOR, decreased expression of EGFR, MUC5AC, Ki‑67 and type I collagen, and reduced β‑G activity.  The therapeutic effects in rats treated with 4 and 6 mg/kg of Pani were more marked than those in rats treated with 2 mg/kg of Pani.  The authors concluded that these findings suggested that Pani could effectively inhibit the excessive proliferation and stone‑forming potential of bile duct mucosa in CPC with a receptor saturation effect.  Pani offers promise as a treatment for the prevention and cure of intra-hepatic choledocholithiasis caused by CPC.  However, a positive therapeutic control was not designed in the present study, as no other drug with the same mechanism as Pani has been found to-date; thus, only a blank control was selected.  These researchers stated that large-scale experiments with a positive therapeutic control are needed to validate the results obtained in the present study and to identify more effective treatments for CPC.

Non-Small Cell Lung Cancer

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.

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 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.

Ovarian Cancer

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.

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.

In a phase-II clinical trial, Halfdanarson et al (2022) examined upfront chemoradiotherapy incorporating the EGFR inhibitor panitumumab, followed by gemcitabine and panitumumab for unresectable, non-metastatic pancreatic cancer. The treatment consisted of fluoropyrimidine and panitumumab given concurrently with RT followed by gemcitabine and panitumumab for 3 cycles followed by maintenance panitumumab. The primary endpoint was the 12-month OS rate and secondary endpoints included ORR, OS, PFS, and AEs. Enrollment of 50 patients was planned and the study fully accrued. A total of 52 patients were enrolled, but only 51 were treated and included in the analysis. The median age of patients was 65 years and 54.9 % were women; 22 patients received at least 1 cycle of systemic therapy following RT, but 29 patients received chemoradiotherapy only without receiving subsequent chemotherapy after completion of chemoradiotherapy. The ORR was 5.9 % (95 % CI: 1.2 % to 16.2 %). The 12-month OS rate was 50 % (95 % CI: 38 % to 67%) that fell short of the per-protocol goal for success (51.1 %). The median PFS was 7.4 months (95 % CI: 4.5 to 8.6) and the median OS was 12.1 months (95 % CI: 7.9 to 15.9); grade-3 or higher AEs were reported by 88 %. The authors concluded that the combination of panitumumab, chemotherapy, and external beam RT was associated with very high rates of grades 3 to 4 toxicities and survival results did not meet the trial's goal for success. These researchers stated that this regimen is not recommended for further study.

Panitumumab-DOTA- 111-In Radioimmunotherapy for the Treatment of Triple-Negative Breast Cancer

Facca et al (2022) stated that EGFRs are over-expressed in triple-negative breast cancer (TNBC) and are an attractive target for the development of theranostic radiopharmaceuticals. These researchers examined anti-EGFR panitumumab labeled with 111-In (panitumumab-DOTA-111In) for SPECT/CT imaging and Meitner-Auger electron (MAE) radioimmunotherapy (RIT) of TNBC. Panitumumab-DOTA-111In was bound, internalized, and routed to the nucleus in MCF7, MDA-MB-231/Luc, and MDA-MB-468 human breast cancer (BC) cells dependent on the EGFR expression level (1.5 × 10(4), 1.7 × 10(5), or 1.3 × 10(6) EGFR/cell, respectively). The absorbed dose in the nuclei of MCF7, MDA-MB-231/Luc, and MDA-MB-468 cells incubated with 4.4 MBq of panitumumab-DOTA-111In (20 nM) was 1.20 ± 0.02, 2.2 ± 0.1, and 25 ± 2 Gy, respectively. The surviving fraction (SF) of MDA-MB-231/Luc cells treated with panitumumab-DOTA-111In (10-300 nM; 1.5 MBq/μg) was reduced as the absorbed dose in the cell increased, with clonogenic survival reduced to an SF = 0.12 ± 0.05 at 300 nM corresponding to 12.7 Gy. The SFs of MDA-MB-468, MDA-MB-231/Luc, and MCF7 cells treated with panitumumab-DOTA-111In (20 nM; 1.7 MBq/μg) were < 0.01, 0.56 ± 0.05, and 0.67 ± 0.04, respectively. Unlabeled panitumumab had no effect on SF, and irrelevant IgG-DOTA-111In only modestly reduced the SF of MDA-MB-231/Luc cells but not MCF7 or MDA-MB-468 cells. The cytotoxicity of panitumumab-DOTA-111In was mediated by increased DNA double-strand breaks (DSB), cell cycle arrest at G2/M-phase and apoptosis measured by immunofluorescence detection by flow cytometry. MDA-MB-231/Luc tumors in the mammary fat pad (MFP) of NRG mice were clearly imaged with panitumumab-DOTA-111In by microSPECT/CT at 4 days post-injection (p.i.), and bio-distribution studies revealed high tumor uptake [18 % ± 2 % injected dose/g (% ID/g] and lower normal tissue uptake (less than 10 % ID/g). Administration of up to 24 MBq (15 μg) of panitumumab-DOTA-111In to healthy NRG mice caused no major hematological, renal, or hepatic toxicity with no decrease in body weight. Treatment of NOD SCID mice with MDA-MB-231 tumors with panitumumab-DOTA-111In (22 MBq; 15 μg) slowed tumor growth. The mean time for tumors to reach a volume of 500 mm3 or greater was 61 ± 5 days for RIT with panitumumab-DOTA-111In compared to 42 ± 6 days for mice treated with irrelevant IgG2-DOTA-111In (p < 0.0001) and 35 ± 3 days for mice receiving 0.9 % NaCl (p < 0.0001). However, tumors re-grew at later time-points. The median survival of mice treated with panitumumab-DOTA-111In was 70 days versus 46 days for IgG2-DOTA-111In (p < 0.0001) or 40 days for 0.9 % NaCl (p < 0.0001). the authors concluded that panitumumab-DOTA-111In is a promising theranostic agent for TNBC. Increasing the administered amount of panitumumab-DOTA-111In and/or combination with radio-sensitizing PARP inhibitors used for treatment of patients with TNBC may provide a more durable response to RIT.

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.

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).

Unresectable Colorectal Cancer Liver Metastases

Bond et al (2023) stated that patients with initially unresectable CRC liver metastases might qualify for local treatment with curative intent after reducing the tumor size by induction systemic treatment.  In a randomized, open-label, multi-center, phase-III clinical study (The CAIRO5 Trial), these researchers compared the currently most active induction regimens.  Patients aged 18 years or older with histologically confirmed CRC, known RAS/BRAFV600E mutation status, World health Organization (WHO) performance status of 0 to 1, and initially unresectable CRC liver metastases were enrolled at 46 Dutch and 1 Belgian secondary and tertiary centers.  Resectability or unresectability of CRC liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by pre-defined criteria.  Randomization was performed centrally with the minimization technique via a masked web-based allocation procedure.  Patients with right-sided primary tumor site or RAS or BRAFV600E mutated tumors were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B).  Patients with left-sided and RAS and BRAFV600E wild-type tumors were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles.  Patients were stratified by resectability of CRC liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B).  Bevacizumab was administered intravenously at 5 mg/kg.  Panitumumab was administered intravenously at 6 mg/kg.  FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2,400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI.  FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3,200 mg/m2.  Patients and investigators were not masked to treatment allocation.  The primary outcome was PFS, analyzed on a modified ITT basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic CRC, or previous liver surgery for CRC liver metastases). 

Between November 13, 2014, and January 31, 2022, a total of 530 patients (327 [62 %] men and 203 [38 %] women; median age of 62 years [IQR 54 to 69]) were randomly assigned: 148 (28 %) patients to group A, 146 (28 %) patients to group B, 118 (22 %) patients to group C, and 118 (22 %) patients to group D.  Groups C and D were prematurely closed for futility.  A total of 521 patients were included in the modified ITT population (147 in group A, 144 in group B, 114 in group C, and 116 in group D).  The median follow-up at the time of this analysis was 51.1 months (95 % CI: 47.7 to 53.1) in groups A and B and 49.9 months (44.5 to 52.5) in in groups C and D.  Median PFS was 9.0 months (95 % CI: 7.7 to 10.5) in group A versus 10.6 months (9.9 to 12.1) in group B (stratified HR 0.76 [95 % CI: 0.60 to 0.98]; p = 0.032), and 10.8 months (95 % CI: 9.9 to 12.6) in group C versus 10.4 months (9.8 to 13.0) in group D (stratified HR 1.11 [95 % CI: 0.84 to 1.48]; p = 0.46).  The most frequent grade 3 to 4 events in groups A and B were neutropenia (19 [13 %] patients in group A versus 57 [40 %] in group B; p < 0.0001), hypertension (21 [14 %] versus 20 [14 %]; p = 1.00), and diarrhea (5 [3 %] versus 28 [19 %]; p < 0.0001), and in groups C and D were neutropenia (29 [25 %] versus 24 [21 %]; p = 0.44), skin toxicity (1 [1 %] versus 29 [25 %]; p < 0.0001), hypertension (20 [18 %] versus 8 [7 %]; p = 0.016), and diarrhea (5 [4 %] versus 18 [16 %]; p = 0.0072).  Serious AEs occurred in 46 (31 %) patients in group A, 75 (52 %) patients in group B, 41 (36 %) patients in group C, and 49 (42 %) patients in group D; and 7  treatment-related deaths were reported in group B (2 due to multi-organ failure, and 1 each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), 1 in group C (multi-organ failure), and 3 in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis).  The authors concluded that in patients with initially unresectable CRC liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumor.  In patients with a left-sided and RAS and BRAFV600E wild-type tumor, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab; but was associated with more toxicity.

Dosage Adjustments

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.

References

The above policy is based on the following references:

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