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
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THE

LEFT SIDE STORY:

THE NEXT CHAPTER

paradigm

POST HOC BIOMARKER ANALYSIS

A post hoc investigation from the PARADIGM trial into the impact of tumor sidedness and three clinically relevant biomarkers in 1L treatment of mCRC: RAS, BRAF, and microsatellite status.1

Find Registrational Pivotal Trial Data

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)

Median-PFS
Median-PFS

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

Median OS
Months (95% CI)

Median-OS
Median-OS

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.1

†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 Primary Analysis

Vectibix® significantly increased overall survival in Japanese patients with WT RAS* left-sided mCRC1

37.9 months,34.3 months
37.9 months,34.3 months

PARADIGM Study Design1

A head-to-head, prospective, randomized (1:1), multicenter, open-label, phase 3 study comparing 1L Vectibix® (panitumumab) + mFOLFOX6 vs Avastin® (bevacizumab) + mFOLFOX6 in 802 Japanese patients with WT RAS* mCRC and left-sided primary tumors. Four hundred patients were randomized to the Vectibix® + mFOLFOX6 arm, and 312 of those patients had left-sided primary tumors; 402 patients were randomized to Avastin® + mFOLFOX6, and 292 of those patients had left-sided primary tumors. The primary endpoint of the study was OS in the left-sided population and, if the results were significant, OS in the overall population. Secondary endpoints included PFS, response rate (RR), duration of response (DOR), and curative resection (R0) in both left-sided and overall populations.

paradigm

POST HOC ANALYSIS DESIGN4

The PARADIGM Post Hoc Biomarker Analysis investigates tumor sidedness along with 3 clinically relevant biomarkers: RAS, BRAF, and microsatellite status4

Post Hoc analysis design
Post Hoc analysis design

Baseline plasma ctDNA (>10 ng/mL and >10 nM DNA) was sequenced using a custom panel (PlasmaSELECT-R 91, PGDx) to detect 90 mutations, 26 amplifications, and 3 rearrangements in mCRC-related genes, as well as MSI in 250kb targeted regions using stringent quality criteria.

90% of patients enrolled in PARADIGM with left-sided tumors were Double WT Non-MSI-H (n = 497/554)4

*Double WT Non-MSI-H = WT RAS + WT BRAF V600E + MSS or MSI-L.4

†Some patients had multiple primary lesions in both the left and right sides.

ctDNA = circulating tumor DNA; Double WT Non-MSI-H = WT RAS + WT BRAF V600E + MSS or MSI-L; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; MSI-L = microsatellite instability-low; MSS = microsatellite stable; MT = mutant type; WT = wild type.

Vectibix® vs Avastin® in combination with mFOLFOX6

OVERALL SURVIVAL IN JAPANESE PATIENTS WITH DOUBLE WT NON-MSI-H mCRC1

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in Japanese patients with double WT NON-MSI-H mCRC
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in Japanese patients with double WT NON-MSI-H mCRC

Post hoc analysis: study was not powered to evaluate efficacy or statistical significance

Double WT Non-MSI-H = WT RAS + WT BRAF V600E + MSS or MSI-L; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; mCRC = metastatic colorectal cancer; mOS = median overall survival; MSI-H = microsatellite instability-high; MSI-L = microsatellite instability-low; MSS = microsatellite stable; WT = wild type.

Vectibix® vs Avastin® in combination with mFOLFOX6

OVERALL SURVIVAL IN PATIENTS WITH MSI-H AND/OR RAS/BRAF MUTATION mCRC4

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in patients with MSI-H and/or RAS/BRAF mutation mCRC
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Overall survival in patients with MSI-H and/or RAS/BRAF mutation mCRC

Post hoc analysis: study was not powered to evaluate efficacy or statistical significance.

FOLFOX = fluorouracil, leucovorin, and oxaliplatin; mCRC = metastatic colorectal cancer; mOS = median overall survival; MSI-H = microsatellite instability-high.

Vectibix® vs Avastin® in combination with mFOLFOX6

NO DIFFERENCE IN PFS IN PATIENTS WITH DOUBLE WT NON-MSI-H mCRC4

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: No difference in PFS in patients with double WT NONMSI- H mCRC
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: No difference in PFS in patients with double WT NONMSI- H mCRC

Post hoc analysis: study was not powered to evaluate efficacy or statistical significance.

CI = confidence interval; Double WT Non-MSI-H = WT RAS + WT BRAF V600E + MSS or MSI-L; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; MSI-L = microsatellite instability-low; MSS = microsatellite stable; PFS = progression-free survival; WT = wild-type.

Vectibix® vs Avastin® in combination with mFOLFOX6

NO OVERALL SURVIVAL BENEFIT OBSERVED IN PATIENTS WITH DOUBLE WT NON-MSI-H RIGHT-SIDED mCRC4

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: No overall survival benefit observed in patients with double WT NON-MSI-H Right-sided mCRC
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: No overall survival benefit observed in patients with double WT NON-MSI-H Right-sided mCRC

Post hoc analysis: study was not powered to evaluate efficacy or statistical significance.

CI = confidence interval; Double WT Non-MSI-H = WT RAS + WT BRAF V600E + MSS or MSI-L; FOLFOX = fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio; mCRC = metastatic colorectal cancer; mOS = median overall survival; MSI-H = microsatellite instability-high; MSI-L = microsatellite instability-low; MSS = microsatellite stable; PFS = progression-free survival; WT = wild type.

Most Frequent Adverse Events In PARADIGM1

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

Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Most frequent adverse events in paradigm
Vectibix® (panitumumab) vs Avastin® + mFOLFOX6: Most frequent adverse events in paradigm

Dermatological toxicity reactions occurred predominantly in the Vectibix® arm.1 Prophylactic measures may help reduce the severity of dermatologic toxicities.5 Examples of prophylactic skin treatments can be found here.

The rates of adverse events observed in patients included the Post Hoc Biomarker Analysis were consistent with the rates of adverse events seen in the overall PARADIGM study.6

PARADIGM = Panitumumab and RAS, Diagnostically useful Gene Mutation for metastatic colorectal cancer (mCRC).

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 USPI7
study

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 patients8
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 tumors1,9-11
    • 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 therapy2,12
  • 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 = 5-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.

EXPLORE 20100007 STUDY

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. Yamazaki K, Muro K, Watanabe J, et al. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 2-6, 2023; Chicago 5. Kobayashi Y, Komatsu Y, Yuki S, et al. Future Oncol. 2015;11:617-627. 6. Data on file, PARADIGM Post Hoc Biomarker Analysis Safety AEs; July 2021. 7. AVASTIN® (bevacizumab) prescribing information, Genentech. 8. Ma P, Yang BB, Wang YM, et al. J Clin Pharmacol. 2009;49:1142-1156. 9. Chen D, Li L, Zhang X, et al. Medicine (Baltimore). 2018;97:e0097. 10. Arnold D, Lueza B, Douillard JY, et al. Ann Oncol. 2017;28:1713-1729. 11. Tejpar S, Stintzing S, Ciardello F, et al. JAMA Oncol. 2017;3;194-201. 12. Loree JM, Dowers A, Tu D, et al. Clin Cancer Res. 2021;27:52-59.

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