Trastuzumab and pertuzumab in hemodialysis: A case report

Introduction

Trastuzumab is a humanized recombinant monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). ¹ In HER2-positive early-stage breast cancer, it has been the backbone of HER2-directed therapy for over a decade. Pertuzumab is a recombinant humanized monoclonal IgG1κ antibody that inhibits HER2 dimerization, resulting in more complete inactivation of HER2 signaling. ² For HER2-positive early-stage breast cancer, it is currently approved by the United States Food and Drug Administration in combination with trastuzumab and chemotherapy in both the neoadjuvant and adjuvant settings for patients meeting disease-specific criteria. ³

Both trastuzumab and pertuzumab have similar, large molecular weights, 150 kDa and 148 kDa, respectively, and clearance involves the reticuloendothelial system. ¹ , ³ , ⁴ Per the prescribing information for trastuzumab and pertuzumab, no dose adjustments are necessary for patients with mild to moderate renal impairment based on a population pharmacokinetic study. ³ , ⁵ No specific dose adjustment recommendations are available for severe renal impairment due to limited or lack of pharmacokinetic data. ³ , ⁵

A PubMed search was conducted using the terms “trastuzumab and dialysis”, “pertuzumab and dialysis”, “trastuzumab and hemodialysis”, “pertuzumab and hemodialysis”, “trastuzumab and continuous renal replacement therapy”, and “pertuzumab and continuous renal replacement therapy”. ⁶ At present, a total of six cases have been reported that detail the use of trastuzumab in dialysis. ⁴ ,^7–10 In contrast, only one reported case on the use of pertuzumab in dialysis has been identified to date. One of the trastuzumab cases included a complete pharmacokinetic evaluation via obtainment of blood samples and determination of trastuzumab serum concentrations. ⁴ The authors determined that trastuzumab is not removed by hemodialysis and concluded in this case that the pharmacokinetic profile of trastuzumab is comparable between patients receiving hemodialysis and those without evidence of renal impairment. ⁴ A recent case is the first to describe a patient on peritoneal dialysis, who received both the intravenous and subcutaneous formulations of trastuzumab. ⁷ Pharmacokinetic monitoring revealed similar trastuzumab exposure compared to patients with normal renal function, and no toxicity was noted. In all cases, change in cardiac function was either not identified or reported. ⁴ ,^7–9 We herein add a further case on the use of trastuzumab in patients with end-stage renal disease, and provide one of the first published reports that we are aware of on the use of pertuzumab in hemodialysis. Patient consent for publication was obtained.

Case description

A 51-year old female was diagnosed with a clinical T2N1M0, grade 3, hormone receptor-negative, HER2-positive, invasive ductal carcinoma of the left breast. Her past medical history was significant for several comorbidities including hypertension, morbid obesity, and end-stage renal disease for which she received hemodialysis three times per week. Baseline echocardiogram revealed a left ventricular ejection fraction (LVEF) of 55–59%. Due to a recent procedure, she received one cycle of trastuzumab alone at a loading dose of 8 mg/kg. She then went on to receive six cycles of neoadjuvant TCHP at standard dosing – docetaxel 75 mg/m², carboplatin area under the plasma concentration-time curve (AUC) 6, trastuzumab 6 mg/kg, and pertuzumab 840 mg loading dose followed by 420 mg every 21 days - while continuing her hemodialysis sessions. She tolerated the treatment extremely well and her course was relatively uneventful, with primary complaints of fatigue, mild diarrhea, and grade 2 peripheral neuropathy per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 necessitating 20% dose reduction of both docetaxel and carboplatin with cycle six. LVEF was monitored via echocardiogram approximately every 8–10 weeks throughout the treatment course. Cardiac function remained stable and no significant changes in LVEF were noted. Following a partial mastectomy and axillary node dissection, pathology revealed that she had achieved a pathologic complete response (pCR).

Given her pCR, she subsequently resumed trastuzumab and pertuzumab in the adjuvant setting. Every 8–10 week echocardiogram monitoring continued. She received six cycles of trastuzumab plus pertuzumab in the adjuvant setting before a routine repeat echocardiogram identified a grade 2 decline in LVEF to 45–49%. The patient remained asymptomatic. Therapy was held and the cardio-oncology service was consulted. She was initiated on daily lisinopril for cardioprotection, in addition to her previously prescribed carvedilol, and her dose of furosemide, administered on non-dialysis days, was increased after pro-BNP was found to be elevated. Change from transthoracic echocardiogram with strain imaging to multigated acquisition (MUGA) scan was also recommended. In this obese patient with technically difficult images, where accuracy of LVEF estimation was critical in medical decision making, change to MUGA was preferred due to lower inter-observer variability and reproducibility of LVEF results. LVEF improved within 3.5 weeks, with recovery to 57% on MUGA scan. Given her excellent response to neoadjuvant therapy, lack of data in hemodialysis, and extrapolation from the APHINITY trial ¹¹ for continuation of pertuzumab in addition to trastuzumab in the adjuvant setting, the decision was made to forgo further pertuzumab. Patient resumed therapy with trastuzumab alone, which she continued to complete a total of one year of HER2-targeted therapy. Cardiac function continued to improve, with LVEF of 60% noted on follow-up echocardiogram four months later, approximately two months after completion of therapy. Of note, there were no changes to patient comorbidities or medications that may have contributed to this decline in LVEF.

Treatment was administered on a non-dialysis day per recommendations in the literature, with carboplatin dose calculated via target AUC 6 × 25 and docetaxel at full dose 75 mg/m², and hemodialysis occurring the following day. ¹²

Discussion

This report is, to our knowledge, one of the first published cases describing the use of pertuzumab in a patient receiving hemodialysis. Though previously published cases reporting on the use of trastuzumab in hemodialysis did not note any cardiotoxicity, our patient did experience a reversible decline in LVEF following twelve cycles of combination trastuzumab and pertuzumab. This is important given a previous study has identified that a lower glomerular filtration rate is associated with a higher risk of developing cardiotoxicity in patients receiving trastuzumab in the adjuvant setting for early-stage breast cancer. ¹³ Our patient was able to complete neoadjuvant therapy containing both trastuzumab and pertuzumab, with LVEF remaining stable, and subsequently achieve a pCR. Reversible decline in LVEF was observed upon continuation of both trastuzumab and pertuzumab in the adjuvant setting. We monitored LVEF every 8–10 weeks in our patient, which is more frequent than currently advised by the trastuzumab and pertuzumab prescribing information, and we recommend more frequent monitoring in this setting. Furthermore, our scheduling of trastuzumab differs from other previously reported cases on the administration of trastuzumab in hemodialysis. In two cases, the patients received trastuzumab during the last 90 minutes of the hemodialysis session. ⁸ In a third case, hemodialysis was done at 48, 96, and 168 hours after trastuzumab administration. ⁴

Our report is limited in that we did not obtain blood samples to complete a pharmacokinetic assessment of pertuzumab in hemodialysis. Though our patient did not complete the total planned course of pertuzumab, this case does demonstrate the relatively safe and effective use of pertuzumab in a patient with end-stage renal disease undergoing hemodialysis, as well as lend additional support to the use of trastuzumab in this particular patient population.