ERBITUX cetuximab 2 mg/mL Solution — NDC 66733-958-23 (Billing 66733-0958-23)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production.

Signal transduction through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation. In vitro , cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR.

No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors.

Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of cetuximab and encorafenib had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.

12.3Pharmacokinetics ERBITUX administered as a single-agent or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from

0.08 L/h/m 2 to

0.02L/h/m 2 as the dose increased from 20 mg/m 2 to 200 mg/m 2 and plateaued at doses >200 mg/m 2 . The systemic exposure of cetuximab after ERBITUX administration was 22% (90% CI: 6%, 38%) higher than that of another cetuximab product used in EXTREME and CRYSTAL. Distribution The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m 2 .

Elimination Following the recommended dosage (400 mg/m 2 initial dose; 250 mg/m 2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 μg/mL to 235 μg/mL and 41 μg/mL to 85 μg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (63 to 230 hours). Specific Population Age, sex, race, hepatic and renal function had no clinically significant effect on the pharmacokinetics of cetuximab.

Clearance of cetuximab increased 1.8-fold as body surface area increased from 1.3 m 2 to 2.3 m 2 , which is consistent with the recommended dosing of cetuximab on mg/m 2 basis. Drug Interaction Studies No pharmacokinetic interaction was observed between cetuximab and irinotecan, cetuximab and cisplatin, and cetuximab and carboplatin. No clinically significant differences in the pharmacokinetics of cetuximab or encorafenib were observed when the recommended ERBITUX initial dose of 400 mg/m 2… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The epidermal growth factor receptor (EGFR, HER1, c-ErbB-1) is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR, HER2, HER3, and HER4. The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Expression of EGFR is also detected in many human cancers including those of the head and neck, colon, and rectum.

Cetuximab binds specifically to the EGFR on both normal and tumor cells, and competitively inhibits the binding of epidermal growth factor (EGF) and other ligands, such as transforming growth factor-alpha. In vitro assays and in vivo animal studies have shown that binding of cetuximab to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production.

Signal transduction through the EGFR results in activation of wild-type Ras proteins, but in cells with activating Ras somatic mutations, the resulting mutant Ras proteins are continuously active regardless of EGFR regulation. In vitro , cetuximab can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that cetuximab inhibits the growth and survival of tumor cells that express the EGFR.

No anti-tumor effects of cetuximab were observed in human tumor xenografts lacking EGFR expression. The addition of cetuximab to radiation therapy or irinotecan in human tumor xenograft models in mice resulted in an increase in anti-tumor effects compared to radiation therapy or chemotherapy alone. In the setting of BRAF-mutant CRC, induction of EGFR-mediated MAPK pathway activation has been identified as a mechanism of resistance to BRAF inhibitors.

Combinations of a BRAF inhibitor and agents targeting EGFR have been shown to overcome this resistance mechanism in nonclinical models. Coadministration of cetuximab and encorafenib had an anti-tumor effect greater than either drug alone, in a mouse model of colorectal cancer with mutated BRAF V600E.

12.3Pharmacokinetics ERBITUX administered as a single-agent or in combination with concomitant chemotherapy or radiation therapy exhibits nonlinear pharmacokinetics. The area under the concentration time curve (AUC) increased in a greater than dose proportional manner while clearance of cetuximab decreased from

0.08 L/h/m 2 to

0.02L/h/m 2 as the dose increased from 20 mg/m 2 to 200 mg/m 2 and plateaued at doses >200 mg/m 2 . The systemic exposure of cetuximab after ERBITUX administration was 22% (90% CI: 6%, 38%) higher than that of another cetuximab product used in EXTREME and CRYSTAL. Distribution The volume of the distribution for cetuximab appeared to be independent of dose and approximated the vascular space of 2–3 L/m 2 .

Elimination Following the recommended dosage (400 mg/m 2 initial dose; 250 mg/m 2 weekly dose), concentrations of cetuximab reached steady-state levels by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 μg/mL to 235 μg/mL and 41 μg/mL to 85 μg/mL, respectively. The mean half-life of cetuximab was approximately 112 hours (63 to 230 hours). Specific Population Age, sex, race, hepatic and renal function had no clinically significant effect on the pharmacokinetics of cetuximab.

Clearance of cetuximab increased 1.8-fold as body surface area increased from 1.3 m 2 to 2.3 m 2 , which is consistent with the recommended dosing of cetuximab on mg/m 2 basis. Drug Interaction Studies No pharmacokinetic interaction was observed between cetuximab and irinotecan, cetuximab and cisplatin, and cetuximab and carboplatin. No clinically significant differences in the pharmacokinetics of cetuximab or encorafenib were observed when the recommended ERBITUX initial dose of 400 mg/m 2 was co-administered with encorafenib.

14 CLINICAL STUDIES

14.1Squamous Cell Carcinoma of the Head and Neck (SCCHN) In Combination with Radiation Therapy BONNER (NCT00004227) was a randomized, multicenter, controlled trial of 424 patients with locally or regionally advanced SCCHN. Patients with Stage III/IV SCCHN of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized (1:1) to receive either ERBITUX in combination with radiation therapy or radiation therapy alone. Stratification factors were Karnofsky performance status (60–80 versus 90–100), nodal stage (N0 versus N+), tumor stage (T1–3 versus T4 using American Joint Committee on Cancer 1998 staging criteria), and radiation therapy fractionation (concomitant boost versus once-daily versus twice-daily).

Radiation therapy was administered for 6–7 weeks as once-daily, twice-daily, or concomitant boost. ERBITUX was administered intravenously as a 400 mg/m 2 initial dose beginning one week prior to initiation of radiation therapy, followed by 250 mg/m 2 weekly administered 1 hour prior to radiation therapy for the duration of radiation therapy (6–7 weeks). The main efficacy outcome measure was duration of locoregional control.

Another outcome measure was overall survival (OS). Of the 424 randomized patients, the median age was 57 years, 80% were male, 83% were White, and 90% had baseline Karnofsky performance status ≥80. There were 258 patients enrolled in U.S. sites (61%).

Sixty percent of patients had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen. Efficacy results are presented in Table 8 .

Table 8: Efficacy Results in Locoregionally Advanced SCCHN in BONNER ERBITUX plus Radiation (n=211) Radiation Alone (n=213) Hazard Ratio (95% CI a ) Stratified Log-rank p-value a CI = confidence interval. Locoregional Control Median duration (months) 24.4 14.9 0.68 (0.52–0.89) 0.005 Overall Survival Median duration (months) 49.0 29.3 0.74 (0.57–0.97)

0.03In Combination with Platinum-based Therapy with Fluorouracil EXTREME (NCT00122460) was an open-label, randomized, multicenter, controlled trial of 442 patients with recurrent locoregional disease or metastatic SCCHN. Patients with no prior therapy for recurrent locoregional disease or metastatic SCCHN were randomized (1:1) to receive a cetuximab product in combination with platinum-based therapy and fluorouracil or platinum-based therapy and fluorouracil alone. Choice of cisplatin or carboplatin was at the discretion of the investigator.

Stratification factors were Karnofsky performance status (<80 versus ≥80) and previous chemotherapy. Cisplatin (100 mg/m 2 intravenously on Day 1) or carboplatin (AUC 5 mg/mL*min intravenously on Day 1) and fluorouracil (1000 mg/m 2 /day intravenously on Days 1–4) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Cetuximab was administered intravenously at a 400 mg/m 2 initial dose, followed by a 250 mg/m 2 weekly dose.

In the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of platinum-based therapy, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity. If chemotherapy was delayed because of adverse reactions, weekly cetuximab was continued. If chemotherapy was discontinued for adverse reactions, weekly cetuximab as a single-agent could be continued until disease progression or unacceptable toxicity.

The main efficacy outcome measure was OS. Other outcome measures were PFS and objective response rate (ORR). Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were White, and 88% had baseline Karnofsky performance status ≥80.

Thirty-four percent of patients had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyn… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the recommended dose of ERBITUX (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals.

These effects were initially noted beginning on week 25 and continued through the 6-week recovery period. No effects of cetuximab were observed on measured male fertility parameters (i.e., serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys.