Precision medicine and personalized breast cancer: combination pertuzumab therapy

Figures & data

Figure 1 Schema outlining the activation of the human epidermal growth-factor receptor 2 pathway and antibody blockade by trastuzumab and pertuzumab.

Abbreviations: HER, human epidermal growth-factor receptor; FGFR, fibroblast growth-factor receptor; IGFR, insulin-like growth-factor receptor; IV, intravenous; PI3K, phosphoinositide 3-kinase; MEK, mitogen-activated protein kinase kinase; ERK, extracellular signal-regulated kinase; mTOR, mammalian target of rapamycin.

Table 1 Key randomized clinical trials evaluating pertuzumab therapy for HER2-positive breast cancer

Study	Setting	Regimen	Sample size	Efficacy
NeoSphere	Neoadjuvant	A. Trastuzumab with docetaxel q3 weeks ^*4 cycles B. Pertuzumab with docetaxel q3 weeks ^*4 cycles C. Trastuzumab and pertuzumab with docetaxel q3 weeks ^*4 cycles Trastuzumab and pertuzumab q3 weeks ^*4 cycles	417	pCR 29% in arm A vs 24% in arm B vs 45.8% in arm C vs 16.8% in arm D P=0.01 C vs A P=0.03 C vs B P=0.01 D vs A
TRYPHAENA	Neoadjuvant	A. Trastuzumab, pertuzumab and 5-fluorouracil, epirubicin, cyclophosphamide (FEC) q3 weeks ^*3 cycles, followed by trastuzumab, pertuzumab, and docetaxel q3 weeks ^*3 cycles B. 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) q3 weeks ^*3 cycles, followed by trastuzumab, pertuzumab, and docetaxel q3 weeks ^*3 cycles C. Trastuzumab, pertuzumab, docetaxel, and carboplatin chemotherapy q3 weeks ^*6 cycles	225	pCR in arm A: 56.2% In arm B: 54.7% In arm C: 63.6% (study not powered to compare the arms)
APHINITY	Adjuvant	Chemotherapy with trastuzumab, with or without pertuzumab	4,800 (planned)	Trial ongoing (NCT01358877)^Citation66
CLEOPATRA	Metastatic (first-line)	Docetaxel and trastuzumab, with or without pertuzumab	808	Median DFS: 18.5 vs 12.4 months (P<0.05) HR 0.62, 95% CI 0.51–0.75; P<0.001 Median OS: 37.6 months in placebo arm, median OS not reached in pertuzumab arm HR 0.66, 95% CI 0.52–0.84; P=0.0008)
MARIANNE	Metastatic (first-line)	A. T-DM1 and placebo B. T-DM1 and pertuzumab C. Trastuzumab and taxane	1,095 (planned)	Trial ongoing (NCT01120184)^Citation67
PHEREXA	Metastatic (second-line)	Capecitabine and trastuzumab, with or without pertuzumab	450 (planned)	Trial ongoing (NCT01026142)^Citation68

Abbreviations: HER, human epidermal growth-factor receptor; pCR, pathological complete response; DFS, disease-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; vs, versus; q3 weeks, every 3 weeks; NeoSphere, Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation; TRYPHAENA, Neoadjuvant Pertuzumab and Trastuzumab Concurrent or Sequential with an Anthracycline-Containing or Concurrent with an Anthracycline-Free Standard Regimen: A Randomized Phase II Study; APHINITY, Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer; CLEOPATRA, Clinical Evaluation of Pertuzumab and Trastuzumab; MARIANNE, A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer; PHEREXA, A Study of a Combination of Trastuzumab and Capecitabine with or Without Pertuzumab in Patients with HER2-Positive Metastatic Breast Cancer.

Figure 2 Schema of the NeoSphere clinical trial comparing various neoadjuvant HER2-directed therapies for localized HER2-positive breast cancer.

Abbreviations: HER, human epidermal growth-factor receptor; pCR, pathological complete response.

Figure 3 Schema of the APHINITY clinical trial evaluating efficacy of adjuvant pertuzumab based therapy in localized HER2-positive breast cancer.

Notes: ^aTrastuzumab 6 mg/kg IV q3 weeks, pertuzumab 420 mg IV q3 weeks; ^beither anthracycline-based regimen with a taxane, or Taxotere with carboplatin; ^cHER2 therapy for 1 year (52 weeks).
Abbreviations: HER, human epidermal growth-factor receptor; IV, intravenous; q3 weeks, every 3 weeks; APHINITY, Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer.

Table 2 Pertuzumab-based chemotherapy regimens as per the US Food and Drug Administration prescribing label (updated September 2013)

Regimen	Dose and frequency
Neoadjuvant regimen
FEC-THP*	5-Flurouracil 600 mg/m^2, concurrent with epirubicin 90 mg/m^2, concurrent with cyclophosphamide 600 mg/m^2, concurrent with every 3 weeks *3 cycles, followed by Docetaxel 75 mg/m^2, concurrent with pertuzumab loading dose of 840 mg, followed by 420 mg, concurrent with trastuzumab 8 mg/kg loading dose, and then 6 mg/kg every 3 weeks *4 cycles, followed by trastuzumab alone 6 mg/kg every 3 weeks, to complete a total of 52 weeks of treatment
FECHP-THP*	5-Flurouracil 600 mg/m^2, concurrent with epirubicin 90 mg/m^2, concurrent with cyclophosphamide 600 mg/m^2, concurrent with pertuzumab loading dose of 840 mg, followed by 420 mg, concurrent with trastuzumab 8 mg/kg loading dose, and then 6 mg/kg every three weeks *3 cycles, followed by Docetaxel 75 mg/m^2, concurrent with pertuzumab loading dose of 840 mg, followed by 420 mg, concurrent with trastuzumab 8 mg/kg loading dose, and then 6 mg/kg every 3 weeks *4 cycles, followed by trastuzumab alone 6 mg/kg every 3 weeks, to complete a total of 52 weeks of treatment
P-TCH	Pertuzumab loading dose of 840 mg, followed by 420 mg, concurrent with trastuzumab 8 mg/kg loading dose, and then 6 mg/kg, concurrent with docetaxel 75 mg/m^2, concurrent with carboplatin AUC 6 every three weeks *6 cycles, followed by trastuzumab alone 2 mg/kg weekly or 6 mg/kg every 3 weeks, to complete a total of 52 weeks of treatment
Metastatic regimen
Pertuzumab and trastuzumab	Trastuzumab 8 mg/kg loading dose, followed by 6 mg/kg, concurrent with pertuzumab loading dose of 840 mg, followed by 420 mg, concurrent with docetaxel 75–100 mg/m^2 (at least 6 cycles) every 3 weeks

Notes:

* In the US, an Adriamycin–cyclophosphamide (AC) regimen is frequently used instead of an FEC regimen. However, there are no safety or efficacy data regarding the combination of an AC regimen with pertuzumab.

Abbreviation: AUC, area under curve.

Figure 4 Schema of personalized therapy selection based on molecular profiling of breast cancer.

Notes: The purpose of this figure to provide a conceptual framework of how trastuzumab and pertuzumab would form the backbone of personalized HER2-directed therapy. It is not meant to be inclusive of all possible therapies or combinations. The various inhibitors are being investigated in clinical trials, and are not currently the standard of care. *± Chemotherapy, and endocrine therapy if HR positive.
Abbreviations: PI3K, phosphoinositide 3-kinase; HER, human epidermal growth-factor receptor; FGFR, fibroblast growth-factor receptor; HR, hormone receptor.

RocheHoffmann-LaA Study of Pertuzumab in Addition to Chemotherapy and Herceptin (Trastuzumab) as Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer Available from: http://clinicaltrials.gov/show/NCT01358877 NLM identifier: NCT01358877Accessed December 10, 2013

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RocheHoffmann-LaA Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE) Available from: http://clinicaltrials.gov/show/NCT01120184 NLM identifier: NCT01120184Accessed December 10, 2013

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RocheHoffmann-LaA Study of a Combination of Trastuzumab and Capecitabine With or Without Pertuzumab in Patients With HER2-positive Metastatic Breast Cancer (PHEREXA) Available from: http://clinicaltrials.gov/show/NCT01026142 NLM identifier: NCT01026142Accessed December 10, 2013

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