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 patients^2,3

Results from the post-hoc analysis of the WT RAS* subgroup

Median PFS
Months (95% CI)

PRIME: Phase 3^2,3

10.1 months

7.9 months

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

Median OS
Months (95% CI)

PRIME: Phase 3^2,3

25.8 months

20.2 months

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

Per the Vectibix^® Prescribing Information, there are no OS or PFS benefits in patients treated with Vectibix^® with RAS-mutant mCRC²

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 13.²

1L = first-line; CI = confidence interval; 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.

Study Design

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

Please see Important Study Considerations Below.

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^§ population; if significant, analyzed in overall population

Secondary endpoints¹

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

Key exploratory endpoints¹

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; 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

Response Rates, Duration of Response, and Curative Resection Rates¹

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

^aDOR was evaluated in patients with complete or partial response.
CI = confidence interval, DOR = duration of response; R0 = curative resection.

Vectibix^® vs Avastin^® in combination with mFOLFOX6

No Overall Survival Benefit Observed in Patients
With Right-Sided Tumors¹

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

CI = confidence interval; HR = hazard ratio.

Most Frequent Adverse Events In PARADIGM¹

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

Vectibix® vs Avastin® + mFOLFOX6: Dermatological toxicity reactions

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

IMPORTANT CONSIDERATIONS FOR THE PARADIGM STUDY

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 USPI^5,6

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 patients⁷

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 tumors^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 months
- Other response outcomes were directionally consistent for panitumumab, including response rates, duration of response, curative resection rates and depth of response
- 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 therapy^1,10
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

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®.
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 WARNINGBoxed 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

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,

INDICATION AND LIMITATION OF USE

THE
LEFT SIDE STORY

INTRODUCES EVIDENCE

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

THE
LEFT SIDE STORY

INTRODUCES EVIDENCE

The Efficacy of Vectibix® as 1L Therapy Was
First Established in PRIME, a Phase 3 Study

Study Design

Vectibix^® Significantly Increased Overall Survival in Japanese Patients With WT *RAS** mCRC¹

No Difference in PFS¹

Response Rates, Duration of Response, and Curative Resection Rates¹

No Overall Survival Benefit Observed in Patients
With Right-Sided Tumors¹

Most Frequent Adverse Events In PARADIGM¹