Metastatic HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab: the impact of early response on patient survival

Lead Investigator: Evandro de Azambuja, Institut Jules Bordet
Title of Proposal Research:  Metastatic HER2-positive breast cancer treated with docetaxel, trastuzumab, and pertuzumab: the impact of early response on patient survival
Vivli Data Request: 7856
Funding Source: None
Potential Conflicts of Interest: Dr. Evandro de Azambuja reports: Honoraria and advisory board: Roche/GNE, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre and Lilly
travel grants: Roche/GNE, GSK/Novartis.
Research grant for his institute: Roche/GNE, AstraZeneca, Novartis, and Servier (outside the submitted work).
Research grants from governments or government agencies: None.
The disclosures will be announced in the research publication.
Dr. Debien reports: Grant from Fondation pour la Recherche Médicale
The disclosures will be announced in the research publication.

Summary of the Proposed Research:

Breast cancer (BC) is still the most frequent female cancer with 1 woman of 8 potentially affected by this disease. Breast cancer tumours are classified according to the expression of three main biomarkers: hormone receptors (estrogen and progesterone receptors) and a protein Human Epidermal growth factor Receptor 2 (HER2). The HER2-positive expression was associated with worse patient survival. Since early 2000, numerous progress has been achieved in HER2-positive BC management, by combining standard chemotherapy with anti-HER2 treatments. Despite the improvement in survival with combinations of anti-HER2 therapies, metastatic BC is still incurable.  Since the publication of the CLEOPATRA trial results, the combination of docetaxel, trastuzumab, and pertuzumab is a standard first-line strategy for patients with metastatic HER2-positive BC. The combination improves patients’ outcomes [progression-free survival (PFS) and overall survival (OS)]. However, such efficient treatment could be potentially toxic. Thus, optimising the treatment to reduce global toxicity without wasting efficacy is a major challenge. The initial tumour response, generally assessed after three months of treatment, could be a way to identify patients with improved survival, and in the end, explore the biomarkers related to early treatment response. In clinical trials, the efficacy of study treatment is evaluated based on imaging results. The response evaluation criteria in solid tumors (RECIST) distinguish four subgroups: complete response (CR), partial response (PR) ((≥30% decrease in the sum of diameter of target lesions without new lesions), stable disease (SD) (<20% increase in the sum of diameter of the target lesion or <30% decrease in them, without any new lesions), and progressive disease (PD) (≥20% increase in the sum of diameter of the target lesion and/or new lesions).

We hypothesized that the survival of patients would depend on the strength of the anti-tumour response based on the first tumour evaluation assessment by RECIST. To explore this hypothesis, we will analyze patients’ individual initial responses from CLEOPATRA and PERTAIN trials. Exploring patient-level data from clinical trials allows for having a more homogeneous population.

Statistical Analysis Plan:

Pooled analysis of individual data from CLEOPATRA (NCT00567190) and PERTAIN (NCT01491737) trials, treatment arm with a combination of docetaxel, trastuzumab, and pertuzumab.

To take into account the variability between studies due to their peculiar features (i.e. heterogeneity), the random effect model will be fitted to the data. This model allowed to estimate the amount of heterogeneity present in the data and accordingly provided suitable estimates of the standard errors of the fixed effects. So, the two studies will be evaluated jointly but each study will contribute its own specific weight to the results of the statistical analysis (Therneau, T. M., and P. M. Grambsch. 2000. Modeling Survival Data: Extending the Cox Model. New York: Springer).

CLEOPATRA trial evaluated the efficiency of the addition of pertuzumab to the induction chemotherapy by docetaxel and anti-HER2 monoclonal antibody trastuzumab. The experimental regimen in the CLEOPATRA trial is currently the standard of care for first-line metastatic HER2-positive breast cancer.
PERTAIN trial, patients with metastatic HER2-positive, HR-positive tumours received endocrine therapy and dual anti-HER2 blockade (trastuzumab and pertuzumab), and for some of them after induction chemotherapy based on docetaxel, as in the CLEOPATRA trial.
– There is no evidence about the prognostic impact of the initial tumour response on the patient’s outcome.
– The data provided from the clinical trial will allow having access to a more homogeneous dataset to assess the question.
– No research from other platforms
– The missing values will be excluded from analysis and will not be replaced.
– The outcome elements to be evaluated are the survival, the proportion of CR, PR, SD, and PD, and the range of TILs ( per range of 5%, if available)

• Study population:
The inclusion criteria:
O Patients ≥18 years old
o Diagnosed with HER2-positive metastatic breast cancer
o First-line therapy
o The tumour response by RECIST available at the first evaluation (usually at 8 to 12 weeks)
– The study arm from requested clinical trials: arm with pertuzumab
– Intent-to treat

The exclusion criteria:
O Hormone receptor status not available
O Absence of survival data

The primary objective is to compare the overall survival, in three groups of patients based on their tumour response defined by RECIST 1.1 assessment, patients with HER2-positive mBC, enrolled in the above-mentioned trials, receiving in first-line docetaxel chemotherapy and dual anti-HER2 blockade with trastuzumab and pertuzumab:
– Patients with complete or partial response at first tumour evaluation
– Patients with stable disease at first tumour evaluation.
– Patients with progressive disease at first tumour evaluation.

Survival curves for OS according to overall response evaluation use will be estimated using the Kaplan Meier method. Log-rank tests will be performed for the comparison of those curves.
The secondary objectives are:
– To assess OS in four groups (CR, PR, SD, PD)
– To assess PFS in three groups (CR, PR, and SD)
– To assess OS and PFS in three groups (CR, PR, and SD) according to subgroups of interest.

Subgroup analyses will be performed to evaluate the impact of CR, PR, or SD on survival outcomes (OS, PFS) according to (if the information is available and if feasible based on sample size):
• Age
• Menopausal status (premenopausal vs. postmenopausal);
• ECOG performance status (0 vs. 1 vs. 2);
• Body mass index (BMI) (</≥25kg/m2), if available
• Hormone receptor status (positive vs. negative)
• Type of metastatic disease: recurrence or de novo
• Sites of metastatic disease (visceral vs. non-visceral)
• PIK3CA mutations (mutated vs. not mutated), if available
• TILs, if available: To explore the correlation between TILs assessment (% of cells, continuous value) and type of tumour response (CR, PR, SD).

Note: If numbers are small, then CR and PR cohorts will be analysed together.
The requested data will provide the patients characteristics by type of early turmour response. The major advantage of having data from clinical trials is the homogeneous cohort. The tumour evaluation performed per protocol in the predefined timeframe, which is not necessarily applicable to the routine practice.

• Statistical analysis
A descriptive analysis of the patient population will be performed. The impact of tumour response (CD, PR , SD or PD for OS) on survival outcomes will be assessed in both univariate and multivariate Cox proportional hazards models. The variables included in the final multivariate models will be defined based on the results from the univariate model.
Survival curves for OS and PFS according to tumour response will be estimated using the Kaplan Meier method. Log-rank tests will be performed for the comparison of those curves. Results will be presented using the Kaplan-Meier survival plots.
Statistical analyses will be two-sided; p values of <0.05 will be considered statistically significant.

Requested Studies:

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT00567190
Sponsor ID: TOC4129g

A Randomized, Two-Arm, Open-Label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab Plus an Aromatase Inhibitor in First Line Patients With HER2-Positive and Hormone Receptor-Positive Advanced (Metastatic or Locally Advanced) Breast Cancer
Data Contributor: Roche
Study ID: NCT01491737
Sponsor ID: MO27775

Public Disclosures:

Debien, V., Agostinetto, E., Bruzzone, M., Ceppi, M., Molinelli, C., Branco, D.M., Jacobs, F., Marta, G.N., Lambertini, M. and de Azambuja, E., 2023. 228P The impact of initial tumor response to docetaxel, trastuzumab, and pertuzumab on survival outcomes of patients with HER2+ metastatic breast cancer: An exploratory analysis of the CLEOPATRA trial. ESMO Open, 8(1). doi: 10.1016/j.esmoop.2023.101417