Trastuzumab plus lapatinib or chemotherapy in patients with HER2-overexpressed advanced breast cancer: a randomized, phase II trial (GIM12-TYPHER).

Background: Trastuzumab combined with chemotherapy is a standard treatment for HER2-positive advanced breast cancer in later lines. Lapatinib and trastuzumab have also demonstrated efficacy. This study assessed the efficacy, toxicity, and quality of life (QoL) of trastuzumab plus lapatinib (with endocrine therapy for hormone receptor-positive cases) versus trastuzumab with physician-selected chemotherapy in patients previously treated with at least two anti-HER2 regimens.

Methods: In this open-label, multicenter phase II trial, 59 patients were randomized 1:1 to receive either trastuzumab and lapatinib (Arm A) or trastuzumab with chemotherapy (Arm B). The primary endpoint was clinical benefit rate (CBR), defined as confirmed complete response, partial response, or stable disease for ≥24 weeks. Secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), QoL, and safety.

Results: With a median follow-up of 57.5 months, the CBR was 20.7% in Arm A and 26.7% in Arm B (p=0.76). The ORR was 13.8% vs. 20.0% (p=0.73), and median PFS was 3.6 months in Arm A vs. 6.1 months in Arm B (HR 0.63; p=0.08). Median OS was 29.9 vs. 31.1 months (HR 1.07; p=0.82). Adverse events occurred in 86.2% (Arm A) and 66.7% (Arm B) of patients, with grade 3-4 events in 24.1% and 13.3%, respectively. QoL favored Arm A (p=0.03). Due to early study closure and limited sample size, all results should be considered exploratory and not powered to assess definitive treatment effects.

Conclusion: While efficacy differences were not significant, trastuzumab with lapatinib showed better QoL despite higher adverse event rates, suggesting it may be a viable chemotherapy-free option for pretreated HER2-positive advanced breast cancer.