Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab

Abstract

Background: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies.

Patients and methods: Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data.

Results: The incidence of all-grade diarrhea across studies was generally greater for pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%-54%; grade 2, 8%-37%; grade 3, 0%-12%; grade 4, 0%). Incidence was highest during the first pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among pertuzumab-treated patients with diarrhea, 47%-67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with pertuzumab had a higher incidence of grade 3 diarrhea than patients <65 years (19% versus 8%). All-grade diarrhea occurred at greater frequency among pertuzumab-treated Asian versus white patients with metastatic breast cancer (74% versus 63%); the corresponding rates in the control arm were 53% and 45%, respectively.

Conclusions: In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon.

Clinicaltrials.gov identifiers: NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).

Keywords: EGFR; HER2; breast cancer; diarrhea; docetaxel; pertuzumab.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Study designs of (A) CLEOPATRA, (B) NeoSphere, and (C) TRYPHAENA. (A) In CLEOPATRA [6, 7], patients with HER2-positive MBC were randomized to receive first-line trastuzumab and docetaxel plus pertuzumab or placebo until unacceptable toxicity or disease progression. Docetaxel treatment was recommended for a minimum of six cycles, after which patients were permitted to continue to receive HER2-targeted therapies. (B) In NeoSphere [8], patients with HER2-positive early-stage breast cancer were randomized to one of four neoadjuvant treatment regimens: trastuzumab + docetaxel (Arm A), pertuzumab + trastuzumab + docetaxel (Arm B), pertuzumab + trastuzumab (Arm C), or pertuzumab + docetaxel (Arm D) for four cycles. While adjuvant therapy regimens were also designated in NeoSphere, these regimens did not contain pertuzumab and were not included in the present analysis. (C) Similar to NeoSphere, TRYPHAENA [9] evaluated pertuzumab in the neoadjuvant setting only. Patients were randomized to receive six cycles of one of the following: 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) + pertuzumab + trastuzumab for three cycles, followed by pertuzumab + trastuzumab + docetaxel for three cycles (Arm A); FEC for three cycles, followed by pertuzumab + trastuzumab + docetaxel for three cycles, in which the first pertuzumab-containing cycle was cycle 4 (Arm B); or docetaxel + carboplatin + trastuzumab + pertuzumab for three cycles (Arm C). The sample sizes for the intent-to-treat populations are shown. BC, breast cancer; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; PD, progression of disease; q3w, every 3 weeks.

Figure 2.

Incidence of diarrhea by treatment cycle in (A) CLEOPATRA, (B) NeoSphere, and (C) TRYPHAENA. Percentages were calculated using the number of patients receiving treatment per arm and per cycle as denominators. aCycle 4 was the first pertuzumab-containing cycle. D, docetaxel; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; IQR, interquartile range; P, pertuzumab; H, trastuzumab; TCH, docetaxel (T), carboplatin (C), trastuzumab (H).