Abstract P5-18-06: Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: Diarrhea is a common side effect of many anti-cancer treatments, including chemotherapeutic agents, tyrosine kinase inhibitors, and pelvic radiotherapy. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib (an irreversible pan-ErbB inhibitor) to trastuzumab and docetaxel (pyrotinib arm) vs placebo, trastuzumab, and docetaxel (placebo arm) as neoadjuvant treatment in women with HER2+ early or locally advanced breast cancer (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of proactive diarrhea management (PDM) according to the recommendation from independent data monitoring committee. Methods: Between July 23, 2018 and January 8, 2021, 355 patients were enrolled and randomized, of whom 212 and 143 patients were randomized before and after the implementation of PDM strategy. The diarrhea management strategy was strengthened with the early identification and proactive management of diarrhea, including use of loperamide as first choice of antidiarrheal agents and strict application of loperamide recommended dose (4 mg initially and an additional 2 mg following each diarrhea stool, not exceeding 16 mg/day). Primary prophylaxis with loperamide was not allowed. The incidence, severity, onset, and duration of diarrhea were summarized. The data cutoff date was April 30, 2021. Results: Of all 178 patients with pyrotinib arm, there were 43 (40.6%) and 56 (77.8%) patients applied loperamide as the first choice of antidiarrheal agents before and after the PDM implementation, respectively. The incidence of grade 3 diarrhea has decreased from 50.0% before the PDM implementation to 36.1% after the PDM implementation (Table 1). During neoadjuvant treatment period, grade 3 diarrhea mainly occurred during the first cycle of treatment for both treatment arms (C1: 20.8%), showing a sharp decreased trend during the following cycles (C2: 8.7%; C3: 5.4%; C4: 4.5%). Furthermore, among patients with pyrotinib arm, the incidences of grade 3 diarrhea in the first, second cycle and thereafter were lower in patients enrolled after the implementation of PDM than those enrolled before the PDM implementation (C1: 29.2%. vs 44.3%; C2: 10.1% vs 21.8%; C3: 7.2% vs 14.1%; C4: 4.5% vs 11.1%). Among patients with pyrotinib, compared with those enrolled before the PDM implementation, the median duration per diarrhea episode (4 days [IQR, 2-9] vs 2 days [1-5]), median duration per grade 3 diarrhea episode (2 days [IQR, 2-3] vs 2 days [1-2]), and median cumulative duration of grade 3 diarrhea (6 days [IQR, 3-9] vs 2 [2-5] days) were shortened in those enrolled after the PDM implementation. During neoadjuvant treatment period, 31 (17.4%) patients experienced diarrhea leading to pyrotinib dose reduction, and only 1 (0.6%) patient discontinued study treatment due to diarrhea in the pyrotinib arm. Conclusion: Pyrotinib tolerability was improved with PDM, which reduced the incidence and duration of grade 3 diarrhea. Grade 3 diarrhoea occurred mainly during the first cycle of treatment and reduced in the second cycle and thereafter. Diarrhea in the pyrotinib group was characterized by early onset and short duration and was generally manageable. Table 1.Characteristics of treatment-emergent diarrheaBEFORE the implementation of PDMAFTER the implementation of PDMPyrotinib+Trastuzumab+Docetaxel(N=106)Placebo+Trastuzumab+Docetaxel(N=106)Pyrotinib+Trastuzumab+Docetaxel(N=72)Placebo+Trastuzumab+Docetaxel(N=71)Diarrhea incidence, n (%)All grade106 (100.0)57 (53.8)72 (100.0)36 (50.7)Grade 112 (11.3)32 (30.2)7 (9.7)28 (39.4)Grade 241 (38.7)18 (17.0)39 (54.2)6 (8.5)Grade 353 (50.0)7 (6.6)26 (36.1)2 (2.8)Cycle 147 (44.3)4 (3.8)21 (29.2)2 (2.8)Cycle 222 (21.8)2 (1.9)7 (10.1)0Cycle 314 (14.1)05 (7.2)0Cycle 411 (11.1)2 (1.9)3 (4.5)0Grade 4 or 50000Median time to the first onset, days (IQR)All grade4 (2 to 5)7 (4 to 28)3 (2 to 4)6 (5 to 12)Grade 39 (5 to 11)16 (7 to 24)9 (6 to 12)11 (6 to 16)Median duration per diarrhea episode, days (IQR)All grade4 (2 to 9)2 (2 to 4)2 (1 to 5)2 (1 to 3)Grade 32 (2 to 3)2 (2 to 2)2 (1 to 2)1 (1 to 1)Median cumulative duration, days (IQR)Grade 36 (3 to 9)2 (2 to 3)2 (2 to 5)1 (1 to 1)Median time since the first onset to recovery, days (IQR)All grade7 (3 to 12)2 (2 to 4)3 (1 to 10)2 (1 to 4)Note: PDM, proactive diarrhea management; IQR, interquartile range. Citation Format: Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Fei Wu, Shulin Liu, Xiang Lin, Jianjun Zou. Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-06.