Swain S M, Schneeweiss A, Gianni L, Gao J J, Stein A, Waldron-Lynch M, Heeson S, Beattie M S, Yoo B, Cortes J, Baselga J
Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.
National Center for Tumor Diseases, University Hospital Heidelberg, Germany.
Ann Oncol. 2017 Apr 1;28(4):761-768. doi: 10.1093/annonc/mdw695.
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 (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.
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.
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).
帕妥珠单抗可破坏人表皮生长因子受体2（HER2）与表皮生长因子受体（EGFR）、HER3及HER4之间的异二聚化。因此，帕妥珠单抗可能导致与EGFR拮抗剂类似的不良事件，如腹泻。我们报告了在CLEOPATRA、NeoSphere和TRYPHAENA研究中观察到的帕妥珠单抗所致腹泻的发生率及严重程度。
患者（n = 1443）患有转移性[CLEOPATRA（n = 804）]或早期乳腺癌[NeoSphere（n = 416）和TRYPHAENA（n = 223）]。根据接受的治疗分析腹泻的发生率及严重程度。还评估了腹泻并发发热性中性粒细胞减少的发生率以及既往存在的胃肠道合并症的影响。使用CLEOPATRA数据进行亚组分析。
在各项研究中，基于帕妥珠单抗的治疗中所有级别的腹泻发生率总体上更高，范围为28%至72%（1级，21% - 54%；2级，8% - 37%；3级，0% - 12%；4级，0%）。发生率在首个含帕妥珠单抗的周期中最高，随后周期降低。因腹泻导致的剂量延迟或停药很少见，范围为0%至8%。在接受帕妥珠单抗治疗且发生腹泻的患者中，47% - 67%接受了药物干预，最常用的是洛哌丁胺。腹泻与发热性中性粒细胞减少的重叠情况不常见，范围为0%至11%。未观察到既往存在的胃肠道合并症与腹泻之间的关联。在CLEOPATRA研究中，接受帕妥珠单抗治疗的≥65岁患者3级腹泻的发生率高于<65岁的患者（19%对8%）。在接受帕妥珠单抗治疗的转移性乳腺癌亚洲患者与白人患者中，所有级别的腹泻发生率更高（74%对63%）；对照组相应的发生率分别为53%和45%。
在转移性和早期乳腺癌治疗中，腹泻在所有含帕妥珠单抗的治疗方案中都很常见，但可控制。腹泻发作主要为低级别，最常发生在首个治疗周期。与腹泻相关的药物延迟或停药不常见。
NCT00567190（CLEOPATRA），NCT00545688（NeoSphere），NCT00976989（TRYPHAENA）。
