Indication and Limitation of use

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, and 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.

PLEASE SEE THE IMPORTANT SAFETY INFORMATION IN THE SECTION BELOW.

COLLAPSE

IMPORTANT SAFETY INFORMATION

BOXED WARNING: DERMATOLOGIC TOXICITY

Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

  • In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
  • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.
  • Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."
  • Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents. Additionally, in Study 20050203, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.
  • Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
  • In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
  • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.
  • Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.
  • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.
  • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.
  • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.
  • In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
  • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
  • Vectibix® can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix®.
  • In monotherapy, the most commonly reported adverse reactions (≥ 20%) in patients with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.
  • The most commonly reported adverse reactions (≥ 20%) with Vectibix® + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2% difference between treatment arms) were diarrhea and dehydration.

Please see Vectibix full Prescribing Information, including Boxed WARNING.

Indication

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.
  • 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.

Vectibix® (panitumumab) was evaluated in phase 3 clinical trials in third-line1

In patients with chemorefractory WTRAS* mCRC1

The third-line 20100007 study1

A phase 3, open-label, multicenter, randomized (1:1) study of 377 patients with chemorefractory WT KRAS mCRC treated with Vectibix® Q2W + BSC or BSC alone1,2

  • The primary endpoint conducted in WT KRAS (exon 2 in codons 12 and 13) was OS. In a prespecified secondary endpoint analysis in the WT RAS subgroup, RAS tumor mutation status was available for 86% of patients: 270 (72%) patients had WT RAS tumors, 54 (14%) had mutant RAS tumors, and 54 (14%) had unknown RAS tumor status1
  • Prespecified key secondary endpoints1:
    • – OS, PFS, and ORR§ in patients with WT RAS mCRC
  • Patient characteristics1,2:
    • – ECOG PS = 0-2
    • – Aged ≥ 18 years
    • – Median age was 61 years

*Defined as wild type in both KRAS and NRAS.1
Exon 2 in codons 12 and 13.1
RAS mutation status was determined for 324 patients using Sanger bidirectional sequencing.2
§Response was evaluated by investigators per RECIST version 1.1.2
BSC = best supportive care; ECOG PS = Eastern Cooperative Oncology Group Performance Status; mCRC = metastatic colorectal cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; Q2W = every 2 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; WT = wild type.

Significant improvement in OS in patients with WT RAS* mCRC (P = 0.0135)1

44.9% increase (3.1-month absolute difference) in median OS with Vectibix® + BSC vs BSC alone1


Efficacy results from the third-line 20100007 study1

*Defined as wild type in both KRAS and NRAS.1
Response was evaluated by investigators per RECIST version 1.1.2
BSC = best supportive care; CI = confidence interval; HR = hazard ratio; mCRC = metastatic colorectal cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; WT = wild type.

In patients with chemorefractory WT KRAS* mCRC1

The third-line ASPECCT study1,3


A phase 3, randomized (1:1), open-label, non-inferiority study of 1,010 patients with chemorefractory WT KRAS mCRC treated with Vectibix® (n = 499) or cetuximab (n = 500)1,3†

  • Primary endpoint was OS assessed for non-inferiority1
  • Key secondary endpoints were PFS, ORR, and safety3

Treatment overview1,3

  Vectibix® Cetuximab
Treatment characteristics
Schedule Q2W QW
Dose
(administration time)
6 mg/kg (60 min) (Doses of > 1,000 mg should be administered over 90 min. If the first infusion is tolerated, the subsequent infusions may be administered over 30 to 60 min) 250 mg/m2 (60 min)
Loading dose
(administration time)
None 400 mg/m2 (120 min)
Premedication None§ H1 antagonist before infusion
Dose modifications
For dermatologic toxicity
For infusion reactions

§No standardized premedication was required in clinical trials. The utility of premedication in preventing infusion toxicity is unknown.1

*Exon 2 in codons 12 and 13.1
Modified intent-to-treat population that included all patients who received at least one dose of therapy.1
Objective tumor response was evaluated by the investigator at each site using RECIST v1.1 criteria.3
ASPECCT = A Study of Panitumumab Efficacy and Safety Compared to Cetuximab; mCRC = metastatic colorectal cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; Q2W = every 2 weeks; QW = weekly; RECIST = Response Evaluation Criteria in Solid Tumors; WT = wild type.

In third-line patients with chemorefractory WT KRAS* mCRC1

Vectibix® demonstrated statistically significant non-inferiority for OS to cetuximab1


Overall survival (OS)1

A RAS subset analysis was not performed in this study. Retrospective subset analyses across several other randomized clinical trials reported that patients with RAS-mutant mCRC treated with Vectibix® experienced increased tumor progression, increased mortality, or lack of benefit.1

Key secondary endpoints1,3

  • Median PFS: 4.1 months (95% CI: 3.2–4.8) with Vectibix® and 4.4 months (95% CI: 3.2–4.8) with cetuximab (HR = 1.00, 95% CI: 0.88–1.14)1
  • ORR§: 22% (95% CI: 18%–26%) with Vectibix® and 19% (95% CI: 16%–23%) with cetuximab1
Incidence of select adverse reactions (all grades)3 Vectibix®
(n = 496)
CetuxImab
(n = 503)
All adverse reactions 98% 98%
Infusion reactions 3% 14%
Skin and subcutaneous tissue toxicity 87% 87%
Hypomagnesemia 27% 18%

*Exon 2 in codons 12 and 13.1
The criterion for non-inferiority was for Vectibix® to retain at least 50% of the OS benefit of cetuximab based on an OS hazard ratio of 0.55 from the NCIC-CTG CO.17 study relative to BSC.1
Modified intent-to-treat population that included all patients who received at least one dose of therapy.1
§Objective tumor response was evaluated by the investigator at each site using RECIST v1.1 criteria.3
BSC = best supportive care; CI = confidence interval; HR = hazard ratio; mCRC = metastatic colorectal cancer; NCIC-CTG = National Cancer Institute of Canada-Clinical Trials Group; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; WT = wild type.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: DERMATOLOGIC TOXICITY

Dermatologic Toxicity: Dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients receiving Vectibix monotherapy [see Dosage and Administration (2.3), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

  • In Study 20020408, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 15% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, acneiform dermatitis, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.
  • Monitor patients who develop dermatologic or soft tissue toxicities while receiving Vectibix® for the development of inflammatory or infectious sequelae. Life-threatening and fatal infectious complications including necrotizing fasciitis, abscesses, and sepsis have been observed in patients treated with Vectibix®. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, and skin sloughing has also been observed in patients treated with Vectibix®. It could not be determined whether these mucocutaneous adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related effects (eg, Stevens Johnson syndrome or toxic epidermal necrolysis). Withhold or discontinue Vectibix® for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Dose modifications for Vectibix® concerning dermatologic toxicity are provided in the product labeling.
  • Vectibix® is not indicated for the treatment of patients with colorectal cancer that harbor somatic RAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146) of either KRAS or NRAS and hereafter is referred to as "RAS."
  • Retrospective subset analyses across several randomized clinical trials were conducted to investigate the role of RAS mutations on the clinical effects of anti-EGFR-directed monoclonal antibodies (panitumumab or cetuximab). Anti-EGFR antibodies in patients with tumors containing RAS mutations resulted in exposing those patients to anti-EGFR related adverse reactions without clinical benefit from these agents. Additionally, in Study 20050203, 272 patients with RAS-mutant mCRC tumors received Vectibix® in combination with FOLFOX and 276 patients received FOLFOX alone. In an exploratory subgroup analysis, OS was shorter (HR = 1.21, 95% CI: 1.01-1.45) in patients with RAS-mutant mCRC who received Vectibix® and FOLFOX versus FOLFOX alone.
  • Progressively decreasing serum magnesium levels leading to severe (grade 3-4) hypomagnesemia occurred in up to 7% (in Study 20080763) of patients across clinical trials. Monitor patients for hypomagnesemia and hypocalcemia prior to initiating Vectibix® treatment, periodically during Vectibix® treatment, and for up to 8 weeks after the completion of treatment. Other electrolyte disturbances, including hypokalemia, have also been observed. Replete magnesium and other electrolytes as appropriate.
  • In Study 20020408, 4% of patients experienced infusion reactions and 1% of patients experienced severe infusion reactions (NCI-CTC grade 3-4). Infusion reactions, manifesting as fever, chills, dyspnea, bronchospasm, and hypotension, can occur following Vectibix® administration. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions.
  • Severe diarrhea and dehydration, leading to acute renal failure and other complications, have been observed in patients treated with Vectibix® in combination with chemotherapy.
  • Fatal and nonfatal cases of interstitial lung disease (ILD) (1%) and pulmonary fibrosis have been observed in patients treated with Vectibix®. Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. In the event of acute onset or worsening of pulmonary symptoms interrupt Vectibix® therapy. Discontinue Vectibix® therapy if ILD is confirmed.
  • In patients with a history of interstitial pneumonitis or pulmonary fibrosis, or evidence of interstitial pneumonitis or pulmonary fibrosis, the benefits of therapy with Vectibix® versus the risk of pulmonary complications must be carefully considered.
  • Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.
  • Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix® use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix® for acute or worsening keratitis.
  • In an interim analysis of an open-label, multicenter, randomized clinical trial in the first-line setting in patients with mCRC, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased OS and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 adverse reactions occurring at a higher rate in Vectibix®-treated patients included rash/acneiform dermatitis (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0).
  • NCI-CTC grade 3-5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 3%) and included fatal events in three (< 1%) Vectibix®-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study compared with those randomized to bevacizumab and chemotherapy.
  • Vectibix® can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 months after the last dose of Vectibix®.
  • In monotherapy, the most commonly reported adverse reactions (≥ 20%) in patients with Vectibix® were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.
  • The most commonly reported adverse reactions (≥ 20%) with Vectibix® + FOLFOX were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2% difference between treatment arms) were diarrhea and dehydration.

Please see Vectibix full Prescribing Information, including Boxed WARNING.

Indication

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.
  • 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.

References:

  1. Vectibix® (panitumumab) prescribing information, Amgen.
  2. Kim TW, Elme A, Kusic Z, et al. A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer. 2016;115:1206-1214.
  3. Price TJ, Peeters M, Kim TW, et al. Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol. 2014;15(6):569-579.