Abstract GS3-02: Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer

Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2 and HER4) plus capecitabine significantly improved progression-free survival (PFS) compared with that for lapatinib plus capecitabine in women with HER2-positive metastatic breast cancer after treatment with trastuzumab and taxanes in the interim analysis of the PHOEBE trial (NCT03080805; Xu et al. Lancet Oncology, 2021). In this report, we present an updated analysis of the overall survival data from this trial. Methods: This PHOEBE trial enrolled patients with HER2-positive metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) to receive either oral pyrotinib 400 mg or lapatinib 1250 mg once daily, combined with oral capecitabine 1000 mg/m² twice daily on days 1-14 of each 21-day cycle. Stratification factors were hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative) and previous lines of chemotherapy for metastatic disease (≤1 vs 2). The primary endpoint was PFS assessed by masked independent central review. Data cutoff for the updated overall survival analysis was March 31, 2021. Results: Between July 31, 2017 and October 30, 2018, 267 eligible patients were enrolled and randomized to either pyrotinib plus capecitabine (pyrotinib group) or lapatinib plus capecitabine (lapatinib group). 134 patients in pyrotinib group and 132 in lapatinib group started the assigned treatment. At data cutoff, the median follow-up duration was 33.2 months (95% CI 31.4-34.2) in the pyrotinib group and 31.8 months (95% CI 31.2-34.1) in the lapatinib group. 78 (58.2%) patients in the pyrotinib group and 98 (74.2%) patients in the lapatinib group received post-discontinuation therapy, with trastuzumab (60 [44.8%] in the pyrotinib group and 65 [49.2%] in the lapatinib group) being the most common. As of data cutoff date, 54 (40.3%) of 134 patients randomly assigned to the pyrotinib group and 69 (52.3%) of the 132 patients randomly assigned to lapatinib group had died. Median OS was not reached (95% CI 34.0-not reached) in the pyrotinib group and 26.9 months (22.4-not reached) in the lapatinib group (HR 0.69 [95% CI 0.48-0.98]; P=0.019). Kaplan-Meier estimated OS at 24 months was 66.6% (95% CI 57.7-74.0) and 58.8% (95% CI 49.7-66.7), respectively. 99 (73.9%) patients in the pyrotinib group and 121 (91.7%) in the lapatinib group had disease progression or had died. Pyrotinib plus capecitabine significantly improved PFS assessed by investigator compared with that for lapatinib plus capecitabine (12.5 months [95% CI 9.8-13.8] vs 5.6 months [95% CI 5.5-7.0]; HR 0.48 [95% CI 0.37-0.63]; P<0.0001). The benefits of pyrotinib plus capecitabine were observed in most clinically relevant subgroups for the updated analysis of both OS and PFS (Table 1). Conclusion: With extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant OS improvement compared with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. This updated analysis of overall survival in the PHOEBE trial reaffirmed pyrotinib plus capecitabine as an established treatment option in this patient population. Table 1.Subgroup analysis of OS and PFS per investigator.HR for OSHR for PFSAll Patients0.69 (0.48-0.98)0.48 (0.37-0.63)Trastuzumab therapy for metastatic disease<3 months0.67 (0.33-1.35)0.34 (0.17-0.69)3-6 months0.78 (0.34-1.76)0.66 (0.32-1.34)≥3 months0.79 (0.37-1.66)0.44 (0.26-0.75)Trastuzumab resistanceNo0.60 (0.39-0.91)0.44 (0.32-0.61)Yes0.94 (0.48-1.85)0.58 (0.35-0.98)HER2 amplification by FISH0.76 (0.39-1.51)0.57 (0.35-0.92)Pathological gradingII0.65 (0.33-1.28)0.51 (0.31-0.85)III0.82 (0.41-1.65)0.51 (0.31-0.83)Unknown0.70 (0.41-1.21)0.45 (0.29-0.70)Visceral lesionsVisceral0.59 (0.40-0.88)0.45 (0.33-0.62)Non-visceral1.28 (0.55-2.95)0.57 (0.31-1.04)ECOG performance status00.72 (0.40-1.29)0.42 (0.26-0.66)10.67 (0.43-1.04)0.50 (0.36-0.71)Estrogen and progesterone receptor statusPositive0.74 (0.44-1.25)0.58 (0.39-0.86)Negative0.64 (0.39-1.04)0.41 (0.28-0.60)Previous lines of chemotherapy for metastatic disease00.72 (0.38-1.35)0.47 (0.30-0.74)10.73 (0.44-1.22)0.49 (0.32-0.73)20.56 (0.24-1.32)0.56 (0.28-1.08)Data are median (95% CI). HRs are from unstratified analyses. Citation Format: Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer [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 GS3-02.