"The U.S. Food and Drug Administration today approved Kadcyla (ado-trastuzumab emtansine), a new therapy for patients with HER2-positive, late-stage (metastatic) breast cancer.
HER2 is a protein involved in normal cell growth. It is foun"...
Mechanism 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.
Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2 - 25 mg/kg. Based on a population PK analysis that included 481 patients, the median clearance (CL) of pertuzumab was 0.24 L/day and the median half-life was 18 days. 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.
The population PK analysis suggested no PK differences based on age, gender, ethnicity (Japanese vs. non-Japanese), or disease status (neoadjuvant versus metastatic setting). Baseline serum albumin level and lean body weight as covariates only exerted a minor influence on PK parameters. Therefore, no dose adjustments based on body weight or baseline albumin level are needed.
No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel in a sub-study of 37 patients in Study 1.
No dedicated renal impairment trial for PERJETA has been conducted. Based on the results of the population pharmacokinetic analysis, 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). No relationship between CLcr and pertuzumab exposure was observed over the range of observed CLcr (27 to 244 mL/min).
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 Study 1. No large changes in the mean QT interval (i.e., greater than 20 ms) from placebo based on Fridericia correction method were detected in the trial. 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.
Metastatic Breast Cancer
Study 1 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/m² by intravenous infusion every 3 weeks for at least 6 cycles. The docetaxel dose could be escalated to 100 mg/m² 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 primary endpoint of Study 1 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 women with the exception of 2 patients. Seventeen percent 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 (placebo 47%, PERJETA 46%). 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.
Study 1 demonstrated a statistically significant improvement in IRF-assessed PFS in the PERJETA-treated group compared with the placebo-treated group [hazard ratio (HR)=0.62 (95% CI: 0.51, 0.75), p < 0.0001] and an increase in median PFS of 6.1 months (median PFS of 18.5 months in the PERJETA-treated group vs. 12.4 months in the placebo-treated group) (see Figure 1). The results for investigator-assessed PFS were comparable to those observed for IRFassessed PFS.
Consistent results were observed across several patient subgroups including age ( < 65 or ≥ 65 years), race, geographic region, prior adjuvant/neoadjuvant anti-HER2 therapy or chemotherapy (yes or no), and prior adjuvant/neoadjuvant trastuzumab (yes or no). In the subgroup of patients with hormone receptor-negative disease (n=408), the hazard ratio was 0.55 (95% CI: 0.42, 0.72). In the subgroup of patients with hormone receptor-positive disease (n=388), the hazard ratio was 0.72 (95% CI: 0.55, 0.95). In the subgroup of patients with disease limited to non-visceral metastasis (n=178), the hazard ratio was 0.96 (95% CI: 0.61, 1.52).
At the time of the final PFS analysis, 165 patients had died, and more deaths had occurred in the placebo-treated group (23.6%) compared with the PERJETA-treated group (17.2%); OS was not mature and interim OS analysis results did not meet the pre-specified stopping boundary for statistical significance. A second interim analysis of OS, conducted after an additional year of follow-up, demonstrated a statistically significant improvement in OS [HR=0.66 (95% CI: 0.52, 0.84), p=0.0008]. See Table 4 and Figure 2. 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=1.42 (95% CI: 0.71, 2.84)].
Table 4 : Summary of Efficacy from Study 1
|Parameter||PERJETA + trastuzumab + docetaxel
|Placebo + trastuzumab + docetaxel
|HR (95% CI)||p-value|
|Progression-Free Survival (independent review)|
|No. of patients with an event Median months||191 (47.5%) 18.5||242 (59.6%) 12.4||0.62 (0.51, 0.75)||< 0.0001|
|Overall Survival (second interim analysis)|
|No. of patients who died Median months||113 (28.1%) NR||154 (37.9%) 37.6||0.66 (0.52, 0.84)||0.0008*|
|Objective Response Rate (ORR, independent review)|
|No. of patients analyzed|
|Objective response (CR + PR)||343||336|
|Complete response (CR)||275 (80.2%)||233 (69.3%)|
|Partial Response (PR)||19 (5.5%)||14 (4.2%)|
|Median Duration of Response||256 (74.6%)||219 (65.2%)|
|Difference in ORR 95% CI||10.8% (4.2%, 17.5%)||0.0011|
|* The HR and p-value for the second interim analysis of
Overall Survival crossed the pre-defined efficacy stopping boundary (HR <
0.739, p < 0.0138).
Figure 1 : Kaplan-Meier Curve of IRF-Assessed
Progression-Free Survival for Study 1
Figure 2 : Kaplan-Meier Curve of Overall Survival for
Neoadjuvant Treatment of Breast Cancer
Study 2 was a multicenter, randomized trial conducted in 417 patients with operable, locally advanced, or inflammatory HER2-positive breast cancer (T2-4d) who were scheduled for neoadjuvant therapy. 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 to receive 1 of 4 neoadjuvant regimens prior to surgery as follows: trastuzumab plus docetaxel, PERJETA plus trastuzumab and docetaxel, PERJETA plus trastuzumab, or PERJETA plus docetaxel. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and estrogen receptor (ER) or progesterone receptor (PgR) positivity.
PERJETA was given intravenously at an initial dose of 840 mg, followed by 420 mg every 3 weeks for 4 cycles. Trastuzumab was given intravenously at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks for 4 cycles. Docetaxel was given as an initial dose of 75 mg/m² by intravenous infusion every 3 weeks for 4 cycles. The docetaxel dose could be escalated to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated. Following surgery all patients received 3 cycles of 5-fluorouracil (600 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (600 mg/m²) (FEC) given intravenously every 3 weeks and trastuzumab administered intravenously every 3 weeks to complete 1 year of therapy. After surgery, patients in the PERJETA plus trastuzumab arm received docetaxel every 3 weeks for 4 cycles prior to FEC.
The primary endpoint of the study was pathological complete response (pCR) rate in the breast (ypT0/is). The FDA-preferred definition of pCR is the absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0).
Demographics were well balanced (median age was 49 - 50 years old, the majority were Caucasian (71%) and all were female. Overall, 7% of patients had inflammatory cancer, 32% had locally advanced cancer, and 61% had operable cancer. Approximately half the patients in each treatment group had hormone receptor-positive disease (defined as ER-positive and/or PgRpositive).
The efficacy results are summarized in Table 5. Statistically significant improvements in pCR rates by both the study and FDA-preferred definitions were observed in patients receiving PERJETA plus trastuzumab and docetaxel compared to patients receiving trastuzumab plus docetaxel. The pCR rates and magnitude of improvement with PERJETA were lower in the subgroup of patients with hormone receptor-positive tumors compared to patients with hormone receptor-negative tumors.
Table 5 : Summary of Efficacy from Study 2
|[95% CI]2||[14.1, 30.5]||[30.0, 49.2]||[5.9, 18.8]||[10.7, 26.8]|
|p-value (with Simes correction for CMH test)3||0.0063 (vs. H+T)||0.0223 (vs. H+T)||0.0018 (vs. Ptz+H+T)|
|Hormone receptor-positive subgroup||N=50||N=50||N=514||N=46|
|[95% CI]2||[4.5, 24.3]||[11.5, 36.0]||[0.1, 10.5]||[2.4, 20.8]|
|Hormone receptor-negative subgroup||N=57||N=57||N=554||N=50|
|[95% CI]2||[18.4, 43.4]||[40.7, 67.6]||[10.4, 33.0]||[14.6, 40.3]|
|T=docetaxel, Ptz=PERJETA, H=trastuzumab
1 ypT0/is ypN0 (absence of invasive cancer in the breast and lymph nodes)
2 95% CI for one sample binomial using Pearson-Clopper method.
3 p-value from Cochran-Mantel-Haenszel (CMH) test, with Simes multiplicity adjustment
4 One patient had unknown hormone receptor status. The patient did not achieve a pCR.
An additional phase 2 neoadjuvant study was conducted in 225 patients with HER2-positive locally advanced, operable, or inflammatory (T2-4d) breast cancer designed primarily to assess cardiac safety in which all arms included PERJETA. 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 to receive 1 of 3 neoadjuvant regimens prior to surgery as follows: 3 cycles of FEC followed by 3 cycles of docetaxel all in combination with PERJETA and trastuzumab, 3 cycles of FEC alone followed by 3 cycles of docetaxel and trastuzumab in combination with PERJETA, or 6 cycles of docetaxel, carboplatin, and trastuzumab (TCH) in combination with PERJETA. Randomization was stratified by breast cancer type (operable, locally advanced, or inflammatory) and ER and/or PgR positivity.
PERJETA was given by intravenous infusion at an initial dose of 840 mg, followed by 420 mg every 3 weeks. Trastuzumab was given by intravenous infusion at an initial dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. 5-Fluorouracil (500 mg/m²), epirubicin (100 mg/m²), and cyclophosphamide (600 mg/m²) were given intravenously every 3 weeks for 3 cycles. In the PERJETA plus trastuzumab, docetaxel, and FEC arms, docetaxel was given as an initial dose of 75 mg/m² by intravenous infusion every 3 weeks for 3 cycles with the option to escalate to 100 mg/m² at the investigator's discretion if the initial dose was well tolerated. However, in the PERJETA plus TCH arm, docetaxel was given intravenously at 75 mg/m² (no escalation was permitted) and carboplatin (AUC 6) was given intravenously every 3 weeks for 6 cycles. Following surgery all patients received trastuzumab to complete 1 year of therapy, which was administered intravenously every 3 weeks.
Demographics were well balanced (median age was 49-50 years old, the majority were Caucasian (76%)) and all were female. Overall 6% of patients had inflammatory cancer, 25% had locally advanced cancer and 69% had operable cancer, with approximately half the patients in each treatment group having ER-positive and/or PgR-positive disease.
The pCR (ypT0/is ypN0) rates were 56.2% (95% CI: 44.1%, 67.8%), 54.7% (95% CI: 42.7%, 66.2%), and 63.6% (95% CI: 51.9%, 74.3%) for patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, PERJETA plus trastuzumab and docetaxel following FEC, or PERJETA plus TCH, respectively. The pCR rates were lower in the subgroups of patients with hormone receptor-positive tumors: 41.0% (95% CI: 25.6%, 57.9%), 45.7% (95% CI: 28.8%, 63.4%), and 47.5% (95% CI: 31.5%, 63.9%) than with hormone receptor-negative tumors: 73.5% (95% CI: 55.6%, 87.1%), 62.5% (95% CI: 45.8%, 77.3%), and 81.1% (95% CI: 64.8%, 92.0%), respectively.
Last reviewed on RxList: 10/18/2013
This monograph has been modified to include the generic and brand name in many instances.
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