Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group

Summary

Background

Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer.

Methods

We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0–3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed.

Findings

Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2–60·7) with trastuzumab and pertuzumab versus 73·4% (56·6–84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio [HR] 0·65 [95% CI 0·37–1·12], p=0·12). At a median follow-up of 20·7 months (IQR 12·5–30·4), the median progression-free survival was 5·6 months (95% CI 3·6–16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7–24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3–4 adverse events were hypertension (in six [15%] of 39 patients in the trastuzumab and pertuzumab group vs five [12%] of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four [10%] vs five [12%]), dyspnoea (two [5%] vs four [10%]), fatigue (three [8%] vs two [5%]), pain (two [5%] vs two [5%]), and a thromboembolic event (0 [0%] vs four [10%]). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure.

Interpretation

Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population.

Funding

F Hoffmann-La Roche.

Introduction

Worldwide, nearly a third of breast cancer cases occur in patients older than 65 years, and in high-income countries this proportion rises to more than 40–50%.¹ Despite the high incidence of cancer and its related mortality in the older population, our knowledge about ageing and cancer and about optimal treatment for older patients is far from adequate. The International Society of Geriatric Oncology (SIOG) has established guidelines on breast cancer treatment in older patients, but confirms that solid evidence is absent in many areas.2, 3 This is largely because of a paucity of evidence-based data for older patients with breast cancer as a result of their under-representation in clinical trials.⁴ Many breast cancer clinical trials have tended to exclude older individuals on the basis of age, comorbidity, or both. However, older patients are just as willing as younger patients to participate in clinical trials if given the opportunity.⁵

HER2-positive metastatic breast cancer is an aggressive disease if left untreated, but important advancements in HER2-directed drug development have led to substantial improvements in outcomes. In the phase 3 CLEOPATRA study, addition of pertuzumab to trastuzumab and docetaxel significantly improved median progression-free survival (from 12·4 months to 18·5 months; hazard ratio [HR] 0·65 [95% CI 0·54–0·78]; p<0·001) and median overall survival (from 40·8 months to 56·5 months; HR 0·68 [0·56–0·84]; p<0·001] with limited additional toxicity, establishing a new first-line standard of care for this population.⁶ The addition of adjuvant pertuzumab to trastuzumab and chemotherapy has shown a small benefit in patients with early HER2-positive disease.⁷

Docetaxel is a chemotherapeutic agent with well known and clinically relevant toxicity, including alopecia, neutropenia, neuropathy, and fatigue, affecting quality of life. Because of age-related changes in drug pharmacokinetics and pharmacodynamics,⁸ tolerance of chemotherapeutic drugs such as docetaxel might decrease in the older population⁹ and affect quality of life.¹⁰ In a palliative setting such as metastatic breast cancer, maintenance of quality of life and avoidance of substantial toxicity might be as important as improving survival. Introduction of HER2-directed therapies to classical chemotherapy raises the question of whether it is possible to treat patients with HER2-positive metastatic breast cancer with HER2-directed regimens without classical chemotherapy. In the neoadjuvant setting, the dual blockade of HER2 with pertuzumab plus trastuzumab has shown substantial antitumour activity.¹¹ Metronomic chemotherapy refers to treatment at regular, close intervals without prolonged breaks at doses substantially lower than the maximum tolerated dose.¹² Metronomic chemotherapy regimens, including oral cyclophosphamide, have been tested in metastatic breast cancer13, 14 and showed clear antitumour activity with minimal toxicity. Trastuzumab emtansine is an antibody–drug conjugate targeting HER2 by trastuzumab binding, followed by intracellular delivery of the cytotoxic agent emtansine, which has become the standard second-line therapy after the combination of a taxane plus trastuzumab with or without pertuzumab in patients with metastatic breast cancer based on major antitumour activity with minimal toxicity.15, 16 Although the above mentioned regimens without classical chemotherapy are not age-specific, the fact that they are associated with clear antitumour activity and manageable toxicity makes them suitable for older patients.

One of the major characteristics of older patients with cancer treated in clinical practice is the major heterogeneity observed among patients of the same chronological age. Geriatric assessment is a procedure developed by geriatricians to evaluate older patients' functional and global health status, to identify and manage age-related problems, allowing clinicians to select patients more appropriately for therapy and to avoid futile therapy or overtreatment as well as undertreatment.¹⁷ The present study integrates geriatric assessment to better define the study population, to evaluate the prognostic capacity of geriatric assessment, and to evaluate geriatric functional evolution during therapy.

Given the need to develop new treatment strategies with limited toxicity for older patients with breast cancer, we aimed to examine the safety and activity of dual anti-HER2 treatment with or without metronomic chemotherapy in this population.