Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient.

Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA.

Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting.

Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant.Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient.

Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA.

Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting.

Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant.

Citation Format: Takano T, Tsurutani J, Takahashi M, Yamanaka T, Sakai K, Ito Y, Fukuoka J, Kimura H, Kawabata H, Tamura K, Matsumoto K, Aogi K, Sato K, Nishio K, Nakagawa K, Saeki T. A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-14.