Clinical trialPhase 3Breast cancer

Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer

N Engl J Med · 2015Not stated in the abstract

Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. N Engl J Med. 2015. 372:724-734

Study type: Clinical trial
Study name: CLEOPATRA
Phase: Phase 3
Design: Randomised, placebo-controlled trial (prespecified final overall survival analysis, median follow-up 50 months)
Sample size: Not stated in the abstract
Source: N Engl J Med · 2015
Trial registration: NCT00567190

In plain words

This study was in women with advanced HER2-positive breast cancer who had not yet had drug treatment for advanced disease. Adding the drug pertuzumab to trastuzumab and docetaxel helped patients typically live about 15.7 months longer (56.5 months versus 40.8 months). Most side effects happened while docetaxel was being given, and heart side effects over the long term were acceptable.

Key results

56.5 months vs 40.8 months

Median overall survival

Difference 15.7 months; 95% CI 49.3 to upper limit not reached vs 35.8–48.3

0.68

Hazard ratio for death

95% CI 0.56–0.84; P<0.001; analysis not adjusted for crossover between groups (conservative)

6.3-month improvement in the pertuzumab group

Median progression-free survival (investigator assessment)

Hazard ratio 0.68; 95% CI 0.58–0.80

7.7-month increase with pertuzumab

Median duration of response (independent assessment)

Drugs in this study:Docetaxel (Taxotere)Pertuzumab (Perjeta)Trastuzumab (Herceptin)

Dose and schedule cards

THP (pertuzumab + trastuzumab + docetaxel; CLEOPATRA)

HER2-positive metastatic disease, first-line (no prior anti-HER2 therapy or chemotherapy for metastatic disease)Cycle length: Every 21 daysOn the page “Breast cancer” · Advanced HER2-positive and HER2-low disease

HER2-positive metastatic disease, first-line (no prior anti-HER2 therapy or chemotherapy for metastatic disease)

Drug	Dose	Route	Schedule
Pertuzumab	Loading dose 840 mg, then 420 mg	IV	Day 1
Trastuzumab	Loading dose 8 mg/kg, then 6 mg/kg	IV	Day 1
At least 6 cycles
Docetaxel	75 mg/m² (up to 100 mg/m² if tolerated)	IV	Day 1

Cycle length: Every 21 days
Duration: Docetaxel for at least 6 cycles; pertuzumab and trastuzumab until progression or unacceptable toxicity

Baseline LVEF of at least 50%, monitored about every 12 weeks; LVEF below 40%, or 40 to 45% with a decrease of 10 points or more: withhold for at least 3 weeks. NCCN (version 4.2026) considers THP the preferred first-line approach for most patients.

On the page “Breast cancer” · Advanced HER2-positive and HER2-low disease

THP — pertuzumab + trastuzumab + docetaxel (CLEOPATRA)

HER2-positive metastatic breast cancer, first line (no previous anti-HER2 therapy or chemotherapy for metastatic disease)Cycle length: Every 3 weeksOn the page “Pertuzumab (Perjeta)” · Standard doses: with trastuzumab and chemotherapy (FDA label)

HER2-positive metastatic breast cancer, first line (no previous anti-HER2 therapy or chemotherapy for metastatic disease)

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
Docetaxel	75 mg/m² (up to 100 mg/m² if tolerated)	IV, after pertuzumab and trastuzumab	Day 1 every 3 weeks

Cycle length: Every 3 weeks
Duration: Until disease progression or unacceptable 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

Combination of pertuzumab, trastuzumab and docetaxel.

Pertuzumab loading dose 840 mg (day 1 of cycle 1) then 420 mg IV every 3 weeks; trastuzumab loading dose 8 mg/kg (day 2 of cycle 1) then 6 mg/kg every 3 weeks; docetaxel 75 mg/m² every 3 weeks (up to 100 mg/m² if tolerated) for at least 6 cycles and thereafter at the discretion of the patient and physician. Pertuzumab and trastuzumab until progression or unmanageable toxicity.

2Placebo group

Combination of placebo, trastuzumab and docetaxel.

Placebo every 3 weeks + trastuzumab (8 then 6 mg/kg every 3 weeks) + docetaxel 75 mg/m² every 3 weeks for at least 6 cycles.

Source of the regimen details: ClinicalTrials.gov NCT00567190 and the FDA label for Perjeta (DailyMed, section 14.1)

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 HER2-positive metastatic breast cancer who had not previously received chemotherapy or anti-HER2 therapy for metastatic disease.

Endpoints

Secondary endpoints reported in this paper: overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety. Sensitivity analyses were adjusted for patients who crossed over from the placebo group to pertuzumab after the interim analysis.

Safety and side effects

Most adverse events occurred during docetaxel administration in both groups, and long-term cardiac safety was maintained. Exact figures for grade 3 or higher adverse events are not given in the abstract.

Clinical significance and place in guidelines

This final analysis showed that adding pertuzumab to trastuzumab and docetaxel in first-line treatment of HER2-positive metastatic breast cancer significantly prolongs overall survival, with long-term cardiac safety maintained. Drug approval status and formal guideline recommendations should be checked separately, as they are not given in the abstract.

Limitations

Some patients in the placebo group crossed over to pertuzumab after the interim analysis; the main analysis was not adjusted for this crossover (conservative), and sensitivity analyses showed consistent results. Overall survival and the other endpoints reported in this paper were secondary. The study was funded by the drug manufacturers.

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.