Clinical trialBreast cancer

Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer

N Engl J Med · 20174805 patients (2400 in the pertuzumab group and 2405 in the placebo group)

von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. N Engl J Med. 2017. 377:122-131

Study type: Clinical trial
Study name: APHINITY
Design: Randomised, placebo-controlled trial
Sample size: 4805 patients (2400 in the pertuzumab group and 2405 in the placebo group)
Source: N Engl J Med · 2017
Trial registration: NCT01358877

In plain words

This study looked at whether adding the drug pertuzumab to the usual treatment after surgery (chemotherapy and one year of trastuzumab) in HER2-positive breast cancer lowers the risk of the disease coming back. Adding this drug slightly reduced the risk of recurrence, and this benefit was seen mostly in patients whose lymph nodes were affected. The more common side effect of this drug was diarrhoea, which happened mostly during chemotherapy; serious heart problems were rare in both groups.

Key results

171 patients (7.1%) vs 210 patients (8.7%)

Disease recurrence

Hazard ratio 0.81; 95% CI 0.66–1.00; P=0.045

94.1% vs 93.2%

3-year invasive-disease-free survival rate (all patients)

Pertuzumab vs placebo

92.0% vs 90.2%

3-year invasive-disease-free survival rate (node-positive)

Hazard ratio 0.77; 95% CI 0.62–0.96; P=0.02

97.5% vs 98.4%

3-year invasive-disease-free survival rate (node-negative)

Hazard ratio 1.13; 95% CI 0.68–1.86; P=0.64

9.8% vs 3.7%

Grade 3 or higher diarrhoea

Pertuzumab vs placebo; almost exclusively during chemotherapy

Drugs in this study:Carboplatin (Paraplatin)Cyclophosphamide (Endoxan)Docetaxel (Taxotere)Doxorubicin (Adriamycin)Paclitaxel (Taxol)Pertuzumab (Perjeta)Trastuzumab (Herceptin)

Dose and schedule cards

After surgery (adjuvant; APHINITY)

Early HER2-positive breast cancer at high risk of recurrenceCycle length: Every 3 weeksOn the page “Pertuzumab (Perjeta)” · Standard doses: with trastuzumab and chemotherapy (FDA label)

Early HER2-positive breast cancer at high risk of recurrence

Drug	Dose	Route	Schedule
Pertuzumab	Initial dose 840 mg, then 420 mg	IV infusion; initial 60 minutes, then 30 to 60 minutes	Day 1 every 3 weeks
Trastuzumab	Initial dose 8 mg/kg, then 6 mg/kg (or subcutaneous 600 mg fixed dose)	IV; initial 90 minutes, then 30 to 90 minutes	Day 1 every 3 weeks
Standard anthracycline- and/or taxane-containing chemotherapy	As per regimen	IV	—

Cycle length: Every 3 weeks
Duration: Start on day 1 of the first taxane-containing cycle; 1 year in total (up to 18 cycles) or until recurrence or unmanageable toxicity

On the page “Pertuzumab (Perjeta)” · Standard doses: with trastuzumab and chemotherapy (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pertuzumab group

Pertuzumab added to standard adjuvant chemotherapy plus 1 year of trastuzumab.

Pertuzumab loading dose 840 mg then 420 mg + trastuzumab loading dose 8 mg/kg then 6 mg/kg, IV every 3 weeks from day 1 of the first taxane-containing cycle, for a total of 52 weeks (maximum 18 cycles). Chemotherapy at the investigator's choice: 3 or 4 cycles of FEC (fluorouracil 500–600, epirubicin 90–120, cyclophosphamide 500–600 mg/m²) or FAC (doxorubicin 50 mg/m²) followed by 3 or 4 cycles of docetaxel (75 to 100 mg/m² every 3 weeks) or 12 doses of weekly paclitaxel 80 mg/m²; or 4 cycles of AC (doxorubicin 60, cyclophosphamide 500–600 mg/m²) or EC (epirubicin 90–120) every 3 weeks or every 2 weeks with G-CSF, followed by docetaxel or 12 doses of weekly paclitaxel 80 mg/m²; or 6 cycles of docetaxel 75 mg/m² + carboplatin AUC 6 (anthracycline-free regimen). After chemotherapy, radiotherapy and/or endocrine therapy at the investigator's discretion.

2Placebo group

Placebo added to standard adjuvant chemotherapy plus 1 year of trastuzumab.

Pertuzumab placebo + trastuzumab (8 then 6 mg/kg every 3 weeks) for 1 year (maximum 18 cycles) with the same chemotherapy options.

Source of the regimen details: FDA label for Perjeta (DailyMed, section 14.3, APHINITY) and ClinicalTrials.gov NCT01358877

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with operable HER2-positive breast cancer, with node-positive disease or with node-negative but high-risk disease. In the trial population, 63% of patients had node-positive disease and 36% had hormone receptor-negative disease.

Endpoints

The primary endpoint assessed was invasive-disease-free survival. In the study design, the 3-year invasive-disease-free survival rate was assumed to be 91.8% with pertuzumab and 89.2% with placebo. Cardiac events (heart failure, cardiac death and cardiac dysfunction) and diarrhoea were also reported.

Safety and side effects

Heart failure, cardiac death and cardiac dysfunction were rare in both treatment groups. Grade 3 or higher diarrhoea occurred almost exclusively during chemotherapy and was more common with pertuzumab than with placebo (9.8% versus 3.7%).

Clinical significance and place in guidelines

According to the abstract, adding pertuzumab to trastuzumab and adjuvant chemotherapy improved invasive-disease-free survival in early HER2-positive breast cancer; the benefit was more evident in node-positive patients, and no difference was seen in node-negative patients. The status of regulatory approval and clinical guideline recommendations should be checked separately, as they are not mentioned in the abstract.

Limitations

The absolute benefit in the 3-year invasive-disease-free survival rate in the overall population was small (94.1% versus 93.2%) and the upper limit of the confidence interval of the hazard ratio was 1.00. No significant difference was seen in node-negative patients. Grade 3 or higher diarrhoea was more common with pertuzumab. The study was funded by the manufacturer.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.