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Published on: August 19, 2025
Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as
Angelo Di Leo1, Henry L Gomez, Zeba Aziz
1Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy 59100. adileo@usl4.toscana.it
Purpose:
Lapatinib, a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR/ErbB1) and human epidermal growth factor receptor 2 (HER-2/ErbB2), is effective against HER-2-positive locally advanced or metastatic breast cancer (MBC). This phase III trial evaluated the efficacy of lapatinib in HER-2-negative and HER-2-uncharacterized MBC.
Patients And Methods:
Women with MBC were randomly assigned to first-line therapy with paclitaxel 175 mg/m(2) every 3 weeks plus lapatinib 1,500 mg/d or placebo. A preplanned retrospective evaluation of HER-2 status was performed using fluorescence in situ hybridization and immunohistochemistry. The primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), and overall survival (OS).
Results:
In the intent-to-treat population (n = 579), there were no significant differences in TTP, EFS, or OS between treatment arms, although differences in ORR and CBR were noted. In 86 HER-2-positive patients (15%), treatment with paclitaxel-lapatinib resulted in statistically significant improvements in TTP, EFS, ORR, and CBR compared with paclitaxel-placebo. No differences between treatment groups were observed for any end point in HER-2-negative patients. The most common adverse events were alopecia, rash, and diarrhea. The incidence of diarrhea and rash was significantly higher in the paclitaxel-lapatinib arm. The rate of cardiac events was low, and no difference was observed between treatment arms.
Conclusion:
Patients with HER-2-negative or HER-2-untested MBC did not benefit from the addition of lapatinib to paclitaxel. However, first-line therapy with paclitaxel-lapatinib significantly improved clinical outcomes in HER-2-positive patients. Prospective evaluation of the efficacy and safety of this combination is ongoing in early and metastatic HER-2-positive breast cancer patients.
Insights
Lapatinib plus paclitaxel did not benefit patients with HER-2-negative metastatic breast cancer (MBC). However, this combination significantly improved outcomes for HER-2-positive MBC patients.
Area of Science:
- Oncology
- Pharmacology
Background:
- Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER-2.
- It is effective in HER-2-positive locally advanced or metastatic breast cancer (MBC).
Purpose of the Study:
- To evaluate the efficacy of lapatinib in combination with paclitaxel for HER-2-negative and HER-2-untested MBC.
- To compare outcomes against paclitaxel plus placebo.
Main Methods:
- Phase III trial with 579 women with MBC randomly assigned to paclitaxel plus lapatinib or placebo.
- Retrospective HER-2 status evaluation using FISH and IHC.
- Primary endpoint: time to progression (TTP). Secondary endpoints: objective response rate (ORR), clinical benefit rate (CBR), event-free survival (EFS), overall survival (OS).
Main Results:
- No significant differences in TTP, EFS, or OS in the overall intent-to-treat population.
- In 86 HER-2-positive patients, paclitaxel-lapatinib significantly improved TTP, EFS, ORR, and CBR compared to paclitaxel-placebo.
- No differences observed in HER-2-negative patients.
- Increased incidence of diarrhea and rash in the lapatinib arm; low cardiac event rate.
Conclusions:
- Adding lapatinib to paclitaxel does not benefit patients with HER-2-negative or HER-2-untested MBC.
- First-line paclitaxel-lapatinib significantly improves outcomes in HER-2-positive MBC.
- Ongoing prospective trials evaluate this combination in HER-2-positive breast cancer.
