Vectibix (Page 3 of 7)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are presented from two clinical trials in which patients received Vectibix: Study 20020408, an open-label, multinational, randomized, controlled, monotherapy clinical trial (N = 463) evaluating Vectibix with best supportive care (BSC) versus BSC alone in patients with EGFR-expressing mCRC and Study 20050203, a randomized, controlled trial (N = 1183) in patients with mCRC that evaluated Vectibix in combination with FOLFOX chemotherapy versus FOLFOX chemotherapy alone. Safety data for Study 20050203 are limited to 656 patients with wild-type KRAS mCRC. The safety profile of Vectibix in patients with wild-type RAS mCRC is similar with that seen in patients with wild-type KRAS mCRC.

Vectibix Monotherapy

In Study 20020408, the most common adverse reactions (≥ 20%) with Vectibix were skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

The most common (> 5%) serious adverse reactions in the Vectibix arm were general physical health deterioration and intestinal obstruction. The most frequently reported adverse reactions for Vectibix leading to withdrawal were general physical health deterioration (n = 2) and intestinal obstruction (n = 2).

For Study 20020408, the data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered to patients with mCRC as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks).

Table 1: Adverse Reactions (≥ 5% Difference) Observed in Patients Treated with Vectibix Monotherapy and Best Supportive Care Compared to Best Supportive Care Alone (Study 20020408)
Study 20020408
Vectibix Plus Best Supportive Care (N = 229) Best Supportive Care (N = 234)
System Organ Class Preferred Term Any Grade n (%) Grade 3-4 n (%) Any Grade n (%) Grade 3-4 n (%)
E ye D isorders
Growth of eyelashes 13 (6)
G astrointestinal D isorders
Nausea 52 (23) 2 (< 1) 37 (16) 1 (< 1)
Diarrhea 49 (21) 4 (2) 26 (11)
Vomiting 43 (19) 6 (3) 28 (12) 2 (< 1)
Stomatitis 15 (7) 2 (< 1)
G eneral D isorders and A dministration S ite C onditions
Fatigue 60 (26) 10 (4) 34 (15) 7 (3)
Mucosal inflammation 15 (7) 1 (< 1) 2 (< 1)
I nfections and I nfestations
Paronychia 57 (25) 4 (2)
R espiratory , T horacic , and M ediastinal D isorders
Dyspnea 41 (18) 12 (5) 30 (13) 8 (3)
Cough 34 (15) 1 (< 1) 17 (7)
S kin and S ubcutaneous T issue D isorders
Erythema 150 (66) 13 (6) 2 (< 1)
Pruritus 132 (58) 6 (3) 4 (2)
Acneiform dermatitis 131 (57) 17 (7) 2 (< 1)
Rash 51 (22) 3 (1) 2 (< 1)
Skin fissures 45 (20) 3 (1) 1 (< 1)
Exfoliative rash 41 (18) 4 (2)
Acne 31 (14) 3 (1)
Dry skin 23 (10)
Nail disorder 22 (10)
Skin exfoliation 21 (9) 2 (< 1)
Skin ulcer 13 (6) 1 (< 1)

Adverse reactions in Study 20020408 that did not meet the threshold criteria for inclusion in Table 1 were conjunctivitis (4.8% vs < 1%), dry mouth (4.8% vs 0%), pyrexia (16.6% vs 13.2%), chills (3.1% vs < 1%), pustular rash (4.4% vs 0%), papular rash (1.7% vs 0%), dehydration (2.6% vs 1.7%), epistaxis (3.9% vs 0%), and pulmonary embolism (1.3% vs 0%).

In Study 20020408, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 15% of patients. Ocular toxicities occurred in 16% of patients and included, but were not limited to, conjunctivitis (5%). One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients [see Warnings and Precautions ( 5.1)].

In Study 20020408 (N = 229), median time to the development of dermatologic, nail, or ocular toxicity was 12 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 98 days. Severe toxicity necessitated dose interruption in 11% of Vectibix-treated patients [see Dosage and Administration ( 2.3)].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis, and abscesses requiring incisions and drainage were reported.

Vectibix in Combination w ith FOLFOX Chemotherapy

The most commonly reported adverse reactions (≥ 20%) in patients with wild-type KRAS mCRC receiving Vectibix (6 mg/kg every 2 weeks) and FOLFOX therapy (N = 322) in Study 20050203 were diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin (Table 2). Serious adverse reactions (≥ 2% difference between treatment arms) in Vectibix-treated patients with wild-type KRAS mCRC were diarrhea and dehydration. The commonly reported adverse reactions (≥ 1%) leading to discontinuation in patients with wild-type KRAS mCRC receiving Vectibix were rash, paresthesia, fatigue, diarrhea, acneiform dermatitis, and hypersensitivity. One grade 5 adverse reaction, hypokalemia, occurred in a patient who received Vectibix.

Table 2 : Adverse Reactions (≥ 5% Difference) Observed in Patients with Wildt ype KRAS Tumors Treated with Vectibix and FOLFOX Chemotherapy Compared to FOLFOX Chemotherapy Alone ( Study 20050203 )

Vectibix Plus FOLFOX (n = 322) FOLFOX Alone (n = 327)
S ystem O rgan C lass Preferred Term Any Grade n (%) Grade 3-4 n (%) Any Grade n (%) Grade 3-4 n (%)
E ye D isorders
Conjunctivitis 58 (18) 5 (2) 10 (3)
G astrointestinal D isorders
Diarrhea 201 (62) 59 (18) 169 (52) 29 (9)
Stomatitis 87 (27) 15 (5) 42 (13) 1 (< 1)
G eneral D isorders and A dministration S ite C onditions
Mucosal inflammation 82 (25) 14 (4) 53 (16) 1 (< 1)
Asthenia 79 (25) 16 (5) 62 (19) 11 (3)
I nfections and I nfestations
Paronychia 68 (21) 11 (3)
I nvestigations
Weight decreased 58 (18) 3 (< 1) 22 (7)
M etabolism and N utrition D isorders
Anorexia 116 (36) 14 (4) 85 (26) 6 (2)
Hypomagnesemia 96 (30) 21 (7) 26 (8) 1 (< 1)
Hypokalemia 68 (21) 32 (10) 42 (13) 15 (5)
Dehydration 26 (8) 8 (2) 10 (3) 5 (2)
R espiratory , T horacic , and M ediastinal D isorders
Epistaxis 46 (14) 30 (9)
S kin and S ubcutaneous T issue D isorders
Rash 179 (56) 55 (17) 24 (7) 1 (< 1)
Acneiform dermatitis 104 (32) 33 (10)
Pruritus 75 (23) 3 (< 1) 14 (4)
Dry skin 68 (21) 5 (2) 13 (4)
Erythema 50 (16) 7 (2) 14 (4)
Skin fissures 50 (16) 1 (< 1) 1 (< 1)
Alopecia 47 (15) 30 (9)
Acne 44 (14) 10 (3) 1 (< 1)
Nail disorder 32 (10) 4 (1) 4 (1)
Palmar-plantar erythrodysesthesia syndrome 30 (9) 4 (1) 9 (3) 2 (< 1)

Adverse reactions that did not meet the threshold criteria for inclusion in Table 2 were flushing (3% vs < 1%), abdominal pain (28% vs 23%), localized infection (3.7% vs < 1%), cellulitis (2.5% vs 0%), hypocalcemia (5.6% vs 2.1%), and deep vein thrombosis (5.3% vs 3.1%).

Infusion Reactions

Infusional toxicity manifesting as fever, chills, dyspnea, bronchospasm or hypotension was assessed within 24 hours of an infusion during the clinical study. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across clinical trials of Vectibix monotherapy, 3% (24/725) experienced infusion reactions of which < 1% (3/725) were severe (NCI-CTC grade 3-4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [ see Dosage and Administration ( 2.2, 2.3) ].

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