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):Read More

Prescribing Information Indication Important Safety Information Patient Site
clear

THE

LEFT SIDE
STORY

paradigm

INTRODUCES
EVIDENCE

from a head-to-head phase 3 study, supporting the efficacy of Vectibix® vs Avastin® in WT RAS* left-sided mCRC.

Find Registrational Pivotal Trial Data
paradigm
First phase 3 study comparison between Vectibix® (panitumumab) and Avastin®

First phase 3 study designed to prospectively compare Vectibix® and Avastin® in combination with mFOLFOX6 for patients with WT RAS* left-sided mCRC1

Head-to-head study

Head-to-head study (N=823) comparing Vectibix® to Avastin® in combination with chemotherapy in Japanese patients with WT RAS* mCRC and left-sided primary tumors1

First prospective study comparing the effects of biologic therapies on patients with left-sided primary tumors

First prospective study comparing the effects of biologic therapies in patients with left-sided primary tumors1

PARADIGM REINFORCES THE VALUE OF:

Conducting early biomarker testing
 to determine a patient’s RAS status

Including tumor sidedness as a criterion
for the selection of biologic therapies

Choosing Vectibix® + FOLFOX
as 1L therapy in newly diagnosed patients
with WT RAS* and left-sided mCRC

*Defined as wild type in both KRAS and NRAS.2

1L = first-line; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; mCRC = metastatic colorectal cancer;
PARADIGM = Panitumumab and RAS, Diagnostically useful Gene Mutation for metastatic colorectal cancer (mCRC); WT = wild type.

THE EFFICACY OF VECTIBIX® AS 1L THERAPY WAS
FIRST ESTABLISHED IN PRIME, A PHASE 3 STUDY

Early targeted therapy with Vectibix® + FOLFOX4 improved survival
in newly diagnosed WT RAS* mCRC patients2,3

RESULTS FROM THE POST-HOC ANALYSIS OF THE WT RAS* SUBGROUP

Median PFS
Months (95% CI)

10.1 months, 7.9 months
10.1 months, 7.9 months

HR = 0.72 (95% CI: 0.58-0.90)

Median OS
Months (95% CI)

25.8 months, 20.2 months
25.8 months, 20.2 months

HR = 0.77 (95% CI: 0.64-0.94)

There are no OS or PFS benefits in patients with RAS-mutant mCRC treated with Vectibix®2

PRIME PHASE 3 STUDY DESIGN

PRIME was an open label, randomized (1:1), multicenter study of Vectibix® Q2W + FOLFOX4 vs FOLFOX4 Q2W alone in treatment of newly diagnosed mCRC patients. Among the study population of 1,183 patients with previously untreated mCRC, 656 were WT KRAS† patients. The extended RAS population in the post-hoc analysis consisted of 512 WT RAS* patients. Of these, 259 received Vectibix® + FOLFOX4 and 253 received FOLFOX4 alone.2,3

*Defined as wild type in both KRAS and NRAS.2

†Exon 2 in codons 12 and 13.1

1L = first-line; CI = confidence interval; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio; mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; PRIME = Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy; Q2W = every 2 weeks; WT = wild type.

paradigm

STUDY DESIGN

Phase 3, randomized, open-label, multicenter study in Japanese patients1

Please see Important Study Considerations below.

PARADIGM study design
PARADIGM study design

Japanese patients with WT RAS† mCRC1

Japanese patients with WT RAS† mCRC1

  • Unresectable disease
  • No previous chemotherapy‡
  • Age: 20–79 years
  • ECOG performance status 0–1
  • At least 1 evaluable lesion
  • Adequate organ function
  • Life expectancy ≥ 3 months

Primary endpoint1

  • OS: left-sided§ and overall population

Secondary endpoints1

  • PFS, RR, DOR, R0 resection: left-sided§ and overall populations
  • Safety: all treated patients

Exploratory endpoints1

  • ETS, depth of response, DCR: left-sided§ and overall populations

*Until disease progression, unacceptable toxicity, withdrawal of consent or investigator’s judgement or curative intent resection.1

†Defined as wild type in both KRAS and NRAS.2

‡Adjuvant fluoropyrimidine monotherapy allowed if completed ≥ 24 weeks before enrollment.

§Primary tumor in descending colon, sigmoid colon, rectosigmoid, and rectum.1

DCR = disease control rate; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; ETS = early tumor shrinkage; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; mCRC = metastatic colorectal cancer; OS = overall survival; PARADIGM = Panitumumab and RAS, Diagnostically useful Gene Mutation for metastatic colorectal cancer (mCRC); PFS = progression-free survival; R0 = curative resection; RR = response rate; WT = wild type.

Vectibix® vs Avastin® in
combination with mFOLFOX6

VECTIBIX® SIGNIFICANTLY INCREASED OVERALL SURVIVAL
IN JAPANESE PATIENTS WITH WT RAS* mCRC1

18% reduction in the risk of death for patients with left-sided tumors treated with Vectibix® vs Avastin®

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in left-sided population graph
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in left-sided population graph

Vectibix® plus mFOLFOX6 provided a survival benefit vs Avastin® plus mFOLFOX6, reinforcing the clinical value of Vectibix® as a first-line treatment in patients with WT RAS*, left-sided metastatic colorectal cancer.

*Defined as wild type in both KRAS and NRAS.2
CI = confidence interval; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio; mCRC = metastatic colorectal cancer; WT = wild type.

Vectibix® vs Avastin® in
combination with mFOLFOX6

No Difference in PFS1

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Progression-free Survival in left sided population graph
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Progression-free Survival in left sided population graph

Analysis was not powered or adjusted for multiplicity to assess efficacy on this endpoint.

Patients who underwent curative resection were censored from the PFS analysis on the final day when
no progressive disease was confirmed. This censoring could have impacted the PFS results.

CI = confidence interval; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio; PFS = progression-free survival.

Vectibix® vs Avastin® in
combination with mFOLFOX6

RESPONSE RATES, DURATION OF RESPONSE,
AND CURATIVE RESECTION RATES1

Response rate, duration of response, and curative resection rates table
Response rate, duration of response, and curative resection rates table

Analyses were not powered or adjusted for multiplicity to assess efficacy on these endpoints.

*DOR was evaluated in patients with complete or partial response.1

CI = confidence interval; DOR = duration of response; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; R0 = curative resection.

Vectibix® vs Avastin® in
combination with mFOLFOX6

RATES OF EARLY TUMOR SHRINKAGE
AT WEEK 8 COMPARED TO BASELINE1

Early tumor shrinkage in 30% or greater and 20% or greater analyses
Early tumor shrinkage in 30% or greater and 20% or greater analyses

Analysis was not powered or adjusted for multiplicity to assess efficacy in this endpoint.

CI = confidence interval; FOLFOX = fluorouracil, leucovorin, and oxaliplatin.

Vectibix® vs Avastin® in
combination with mFOLFOX6

DEPTH OF RESPONSE4

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Depth of response in Left-sided population
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Depth of response in Left-sided population
median-tb

86% of Vectibix® patients showed a reduction of 30% or more target lesion size from baseline.4

Depth of response is defined as the best percentage change from baseline in target lesions. Depth of response evaluated in patients with measurable lesions in baseline.

Horizontal dotted line at ~30% indicates threshold for partial response, a decrease in target lesion size by approximately 30%, as defined by RECIST v1.1.

Predefined exploratory endpoint. Analysis was not powered or adjusted for multiplicity to assess efficacy.

RECIST = Response Evaluation Criteria in Solid Tumors.

Vectibix® vs Avastin® in
combination with mFOLFOX6

NO OVERALL SURVIVAL BENEFIT OBSERVED IN PATIENTS WITH RIGHT-SIDED TUMORS1

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in Right-sided population
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in Right-sided population

Predefined exploratory endpoint. Analysis was not powered or adjusted for multiplicity to assess efficacy.

CI = confidence interval; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio.

Most Frequent Adverse Events In PARADIGM1

Adverse events of any grade ≥ 20% in either treatment arm.1

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Dermatological toxicity reactions
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Dermatological toxicity reactions

Dermatological toxicity reactions occurred predominantly in the Vectibix® arm.1 Prophylactic measures may help reduce the severity of dermatologic toxicities.4 Examples of prophylactic skin treatments can be found here.

IMPORTANT CONSIDERATIONS FOR THE PARADIGM STUDY

Dosing icon

DOSING

  • Bevacizumab was dosed at 5 mg/kg every 2 weeks (Q2W). The recommended doses of bevacizumab are 5 mg/kg or 10 mg/kg Q2W when used in combination with intravenous 5-FU-based chemotherapy. For additional information on the usage of bevacizumab, please refer to the USPI1,5
study population

STUDY POPULATION

  • PARADIGM was conducted in Japanese patients and has not been reviewed for inclusion in US labeling1
    • Analyses of 1200 patients across 14 clinical studies showed comparable pharmacokinetics in response to panitumumab between Japanese and non-Japanese patients6
outcomes

OUTCOMES

  • Investigators modified the primary endpoint after the study began, from overall survival (OS) in all patients to OS in patients with left-sided tumors1
    • This change was based on evidence from at least seven (7) randomized clinical trials suggesting that the benefit of anti-EGFR antibodies combined with chemotherapy is enhanced in patients with left-sided tumors1,7,8,9
    • The statistical analysis plan was modified to require a 2-sided P-value of 0.042 as the threshold for statistical significance in the left-sided population1
  • Panitumumab did not differ from bevacizumab on progression-free survival, and survival curves did not separate before 24 months1
    • Other response outcomes were directionally consistent for panitumumab, including response rates, duration of response, curative resection rates, depth of response, and early tumor shrinkage1
    • Similar proportions of patients in each group received subsequent lines of therapy1
    • Fewer panitumumab vs bevacizumab patients received subsequent anti-EGFR treatments1
      • Two separate studies have shown that anti-EGFR treatments may prolong survival in later lines of therapy2,10
  • Although other response outcomes were directionally consistent for panitumumab, the study was not designed to establish statistical significance on these endpoints1
  • There were no differences between panitumumab and bevacizumab in patients with right-sided tumors1

5-FU = fluorouracil; EGFR = epidermal growth factor receptor; mCRC = metastatic colorectal cancer; PARADIGM = Panitumumab and RAS, Diagnostically useful Gene Mutation for metastatic colorectal cancer (mCRC); US = United States; USPI = United States Prescribing Information.

PARADIGM HYPOTHETICAL PATIENT PROFILE

Hypothetical paradigm patient profile for 65 year old male
ren-mob

NEWLY DIAGNOSED,
METASTATIC,
LEFT-SIDED

Name
Ren*
Gender
Male
Age
65
Occupation
Retired engineer
Lung and liverCase courtesy of Ian Bickle, Radiopaedia.org, rID: 59060

Images are shown for illustrative purposes only

*A hypothetical patient profile of treatment for a newly diagnosed mCRC patient.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; CT = computed tomography; ECOG PS = Eastern Cooperative Oncology Group Performance Status; Hb = hemoglobin; mCRC = metastatic colorectal cancer; PLT = platelet; WBC: white blood count; WT = wild type.

What clinical characteristics affect your treatment decision for newly diagnosed mCRC?

Medical history

  • Mild hyperlipidemia, controlled on statin therapy

Presentation

  • 3-month history of constipation, bloating, and blood in stool
  • 1-month history of mild pain in the upper left quadrant of his abdomen
  • Wife was concerned and insisted he see his doctor
  • Colonoscopy confirmed 4-cm non-obstructing mass in the left colon (distal colon)

Pathology report

  • Moderately differentiated adenocarcinoma

Performance status

  • ECOG PS = 0

Laboratory results

  • ALT: 90 U/L; AST: 160 U/L
  • CBC:
    • WBC: 4.0 x 103 mL/µL
    • Neutrophil: 1.6 x 103 mL/µL
    • Hb: 9.2 g/dL
    • PLT: 120 x 103 mL/µL
  • Bilirubin: 1 mg/dL

Genetic Testing

  • RAS status: WT RAS (WT in both KRAS and NRAS)
  • MSI status: Microsatellite stable (MSS)/non-microsatellite instable (non-MSI)

Imaging results

  • CT scan indicated multiple unresectable metastasis in liver and lung

Surgery consult on metastatic disease

  • Surgeon believes metastatic disease is unresectable—treatment goal is to downgrade the tumor

Images are shown for illustrative purposes only

*A hypothetical patient profile of treatment for a newly diagnosed mCRC patient.

ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; CT = computed tomography; ECOG PS = Eastern Cooperative Oncology Group Performance Status; Hb = hemoglobin; mCRC = metastatic colorectal cancer; PLT = platelet; WBC: white blood count; WT = wild type.

NEXT

EXPLORE PARADIGM POST HOC

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 (NCI0CTC 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 grades 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®.
  • Serious cases of keratitis, ulcerative keratitis, and corneal perforation have occurred with Vectibix® use. Monitor for evidence of keratitis, ulcerative keratitis, or corneal perforation. Interrupt or discontinue Vectibix® therapy for acute or worsening keratitis, ulcerative keratitis, or corneal perforation.
  • 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.

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)].

References

1. Watanabe J, Muro K, Shitara K, et al. JAMA. 2023;329:1271-1282. 2. Vectibix® (panitumumab) prescribing information, Amgen. 3. Douillard J-Y, Oliner KS, Siena S, et al. N Engl J Med. 2013;369:1023-1034. 4. Yoshino, T. Presented at: 2022 ASCO Annual Meeting; June 3-7, 2022; Chicago, IL. 5. Kobayashi Y, Komatsu Y, Yuki S, et al. Future Oncol. 2015;11:617-627. 6. AVASTIN® (bevacizumab) prescribing information, Genentech. 7. Ma P, Yang BB, Wang YM, et al. J Clin Pharmacol. 2009;49:1142-1156. 8. Chen D, Li L, Zhang X, et al. Medicine (Baltimore). 2018;97:e0097. 9. Arnold D, Lueza B, Douillard JY, et al. Ann Oncol. 2017;28:1713-1729. 10. Tejpar S, Stintzing S, Ciardello F, et al. JAMA Oncol. 2017;3;194-201. 11. Loree JM, Dowers A, Tu D, et al. Clin Cancer Res. 2021;27:52-59.

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