Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.

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

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).