PracticeUpdate Oncology Best of 2018

EDITOR’S PICKS 10

Pertuzumab and Trastuzumab With or Without Metronomic Chemotherapy for Older Patients With HER2-Positive Metastatic Breast Cancer The Lancet Oncology

COMMENT By Reshma L. Mahtani DO T he goal of treatment in metastatic breast cancer patients is palliation, and when considering treatments, we must balance risks of toxicity with benefit. This is especially true in elderly patients who often have comorbidities and poorer tolerance to treatment. For patients with HER2-positive disease, the availability of HER2-directed therapies has dramatically improved outcomes. Many of these thera- pies, such as trastuzumab and pertuzumab, are very well tolerated. In the neoadjuvant setting, these agents have demonstrated significant activity in combination, with- out the use of concomitant chemotherapy. Therefore, there is interest in examining approaches that include less toxic therapies in combination with HER2-directed treat- ments, especially in older patients. In the current analysis, the authors report improvements in PFS with the addition of metronomic oral cyclophosphamide to trastuzumab and pertuzumab in older and frail patients. The toxicity profile was acceptable and is improved when compared with docetaxel, which was used in the CLEOPATRA trial. This study is therefore helpful in supporting the use of a less toxic chemotherapy partner for some patients, as we move towards a more personalized approach to treatment. By Lillie D. Shockney RN, BS, MAS C learly, cardiac toxicity is of concern when taking care of patients with HER2-pos- itive metastatic disease, especially when treating elderly patients with poorer performance function. This study demonstrated that considerable additional time was gained with metronomic chemo along with biologic targeted agents. Given the physical condition of these patients, however, based on age and/or comorbid conditions, it is important to know how the patient's time was spent during the addi- tional months achieved by taking these drugs. Was she able to attend and enjoy her grandson's graduation or was she home, feeling too ill to go? Did she get to her granddaughter's wedding and reflect back on that event with a smile that she was able to participate in that special day? We must always look at quality of life and tol- erance of drug therapies through the eyes of the patient and no one else's. Although we may believe we can judge how the patient is feeling and how well she is physi- cally doing, when comparisons are made, usually the patient is not doing as well as we hoped. These are all important when measuring trial outcomes as well as in daily care, whether the patient is participating in a study or not. • Among older patients with HER2-positive metastatic breast cancer, the addition of metronomic oral cyclophosphamide to treatment with trastuzumab plus pertuzumab provided a significant survival benefit without any added safety concerns. The use of this regimen may delay or reduce the need for taxane chemotherapy. Neil Majithia MD Take-home message • In this phase II multicenter trial, older patients with HER2-positive metastatic breast cancer were randomized to receive the combination of pertuzumab and trastu- zumab alone (n=39) or in conjunction with metronomic chemotherapy with oral cyclophosphamide (n=41). After a median follow-up of 20.7 months, the addition of metronomic cyclophosphamide provided a progression-free survival benefit of around 7 months over placebo (12.7 months vs 5.6 months). The most common grade ≥3 adverse events were hypertension, diarrhea, dyspnea, and fatigue, and the rates of adverse events were similar in the two groups.

Abstract BACKGROUND Despite the high incidence of met- astatic 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 with- out metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer. METHODS We did a multicentre, open-label, ran- domised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologi- cally proven, HER2-positive metastatic breast cancer, without previous chemotherapy for met- astatic 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 per- formance 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 tras- tuzumab 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 base- line geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evalu- ation 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. FINDINGS Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screen- ing G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated pro- gression-free survival at 6 months was 46·2% (95% CI 30·2-60·7) with trastuzumab and pertu- zumab versus 73·4% (56·6-84·6) with trastuzumab

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