PERJETA Pertuzumab 30 mg/mL Injection, Solution, Concentrate — NDC 50242-145-01 (Billing 50242-0145-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively.

In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC). While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of PERJETA have not been fully characterized. Cardiac Electrophysiology The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer in CLEOPATRA. At the recommended dose of PERJETA, a mean increase in the QTc interval >20 ms was not observed.

A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.

12.3Pharmacokinetics Based on a population PK analysis that included 481 patients, pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose. Elimination The median clearance (CL) of pertuzumab was

0.24L/day and the median half-life was 18 days. Specific Populations No clinically significant differences in the pharmacokinetics of pertuzumab were observed based on age, sex, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant or adjuvant vs. metastatic setting). No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant.

Pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). The pharmacokinetics of pertuzumab in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.

12.6Immunogenicity The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of PERJETA or of other pertuzumab products. Patients in CLEOPATRA were tested at multiple time-points for anti-pertuzumab antibodies.

3% (13/389) of patients in the PERJETA-treated group and 7% (25/372) of patients in the placebo-treated group tested positive for anti-pertuzumab antibodies. Of these 38 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to anti-pertuzumab antibodies. The presence of pertuzumab in patient serum at the levels expected at the time of ADA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies.

In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. In the neoadjuvant period of BERENICE, 0.3% (1/383) of patients treated with PERJETA tested positive for anti-pertuzumab antibodies.

This patient did not experience an… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pertuzumab targets the extracellular dimerization domain (Subdomain II) of the human epidermal growth factor receptor 2 protein (HER2) and, thereby, blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. As a result, pertuzumab inhibits ligand-initiated intracellular signaling through two major signal pathways, mitogen-activated protein (MAP) kinase, and phosphoinositide 3-kinase (PI3K). Inhibition of these signaling pathways can result in cell growth arrest and apoptosis, respectively.

In addition, pertuzumab mediates antibody-dependent cell-mediated cytotoxicity (ADCC). While pertuzumab alone inhibited the proliferation of human tumor cells, the combination of pertuzumab and trastuzumab augmented anti-tumor activity in HER2-overexpressing xenograft models.

12.3Pharmacokinetics Based on a population PK analysis that included 481 patients, pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 – 25 mg/kg. With an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks thereafter, the steady-state concentration of pertuzumab was reached after the first maintenance dose. Elimination The median clearance (CL) of pertuzumab was

0.24L/day and the median half-life was 18 days. Specific Populations No clinically significant differences in the pharmacokinetics of pertuzumab were observed based on age, sex, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant or adjuvant vs. metastatic setting). No dose adjustments based on body weight or baseline albumin level are needed, as the exposure changes are not considered clinically relevant.

Pertuzumab exposure in patients with mild (CLcr 60 to 90 mL/min, n=200) and moderate renal impairment (CLcr 30 to 60 mL/min, n=71) were similar to those in patients with normal renal function (CLcr greater than 90 mL/min, n=200). The pharmacokinetics of pertuzumab in patients with moderate to severe hepatic impairment or severe renal impairment is unknown.

12.2Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of PERJETA have not been fully characterized. Cardiac Electrophysiology The effect of pertuzumab with an initial dose of 840 mg followed by a maintenance dose of 420 mg every three weeks on QTc interval was evaluated in a subgroup of 20 patients with HER2-positive breast cancer in CLEOPATRA. At the recommended dose of PERJETA, a mean increase in the QTc interval >20 ms was not observed.

A small increase in the mean QTc interval (i.e., less than 10 ms) cannot be excluded because of the limitations of the trial design.

14 CLINICAL STUDIES

14.1Metastatic Breast Cancer CLEOPATRA (NCT00567190) was a multicenter, double-blind, placebo-controlled trial of 808 patients with HER2-positive metastatic breast cancer. HER2 overexpression was defined as a score of 3+ IHC or FISH amplification ratio of 2.0 or greater as determined by a central laboratory. Patients were randomly allocated 1:1 to receive placebo plus trastuzumab and docetaxel or PERJETA plus trastuzumab and docetaxel.

Randomization was stratified by prior treatment (prior or no prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy) and geographic region (Europe, North America, South America, and Asia). Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment. PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks thereafter.

Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks thereafter. Patients were treated with PERJETA and trastuzumab until progression of disease, withdrawal of consent, or unacceptable toxicity. Docetaxel was given as an initial dose of 75 mg/m 2 by intravenous infusion every 3 weeks for at least 6 cycles.

The docetaxel dose could be escalated to 100 mg/m 2 at the investigator's discretion if the initial dose was well tolerated. At the time of the primary analysis, the mean number of cycles of study treatment administered was 16.2 in the placebo-treated group and 19.9 in the PERJETA-treated group. The major efficacy outcome measure of CLEOPATRA was progression-free survival (PFS) as assessed by an independent review facility (IRF).

PFS was defined as the time from the date of randomization to the date of disease progression or death (from any cause) if the death occurred within 18 weeks of the last tumor assessment. Additional endpoints included overall survival (OS), PFS (investigator-assessed), objective response rate (ORR), and duration of response. Patient demographic and baseline characteristics were balanced between the treatment arms.

The median age was 54 (range 22 to 89 years), 59% were White, 32% were Asian, and 4% were Black. All were female with the exception of 2 patients (0.2%). Seventeen percent (17%) of patients were enrolled in North America, 14% in South America, 38% in Europe, and 31% in Asia.

Tumor prognostic characteristics, including hormone receptor status (positive 48%, negative 50%), presence of visceral disease (78%) and non-visceral disease only (22%) were similar in the study arms. Approximately half of the patients received prior adjuvant or neoadjuvant anti-HER2 therapy or chemotherapy (PERJETA 46%, placebo 47%). Among patients with hormone receptor positive tumors, 45% received prior adjuvant hormonal therapy and 11% received hormonal therapy for metastatic disease.

Eleven percent of patients received prior adjuvant or neoadjuvant trastuzumab. CLEOPATRA demonstrated a statistically significant improvement in IRF-assessed PFS in the PERJETA-treated group compared with the placebo-treated group. The results for investigator-assessed PFS were comparable to those observed for IRF-assessed PFS.

A statistically significant OS improvement was demonstrated for the PERJETA-treated group compared with the placebo-treated group) with the final OS analysis. OS results in patient subgroups were consistent with those observed for IRF-assessed PFS with the exception of the subgroup of patients with disease limited to non-visceral metastasis [HR=1.11 (95% CI: 0.66, 1.85)]. Table 8: Efficacy Results from CLEOPATRA Endpoint PERJETA + trastuzumab + docetaxel n=402 Placebo + trastuzumab + docetaxel n=406 CI=Confidence Interval Progression-Free Survival (independent review) Number of events (%) 191 (47.5%) 242 (59.6%) Median (months) 18.5

12.4Hazard Ratio (95% CI) 0.62 (0.51, 0.75) p-value < 0.0001 Overall Survival Final analysis of overall survival performed when 389 patien… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed to evaluate the carcinogenic potential of pertuzumab. Studies have not been performed to evaluate the mutagenic potential of pertuzumab. No specific fertility studies in animals have been performed to evaluate the effect of pertuzumab.

No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies of up to six months duration in cynomolgus monkeys.