Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy
Status:
Active, not recruiting
Trial end date:
2022-01-01
Target enrollment:
Participant gender:
Summary
Breast cancer is the most common malignancy in the U.S. Targeted therapies such as tamoxifen
have been revolutionary in reducing tumor recurrences and mortality in early breast cancer.
Using this successful paradigm, there has been a continued search for other targeted biologic
therapies directed at receptors with known potential for promoting tumor growth.
The estrogen receptor (ER) and/or the HER signaling pathways are the dominant drivers of cell
proliferation and survival in the majority of human breast cancers. Molecular targets of
these pathways provide the most effective therapies in appropriately selected patients.
However, de novo and acquired resistance remain major obstacles to successful treatment, and
understanding the molecular pathways responsible for this resistance would enable the
discovery of new strategies to overcome it.
The superiority of multi-drug HER2-targeted therapy over single agent therapy has been
demonstrated in the preclinical setting using mouse xenografts. Trastuzumab, pertuzumab,
lapatinib, and gefitinib, represent a group of therapeutic agents that target the HER family
by different molecular mechanisms. Used as single agents in the MCF7/HER2-18 xenograft model,
these drugs restored or enhanced sensitivity to tamoxifen. However, tumor growth inhibition
lasted only 2-3 months before resistance to treatments occurred. However, when gefitinib, a
HER1 inhibitor, was added to the two-antibody (T+P) regimen to block signals from HER1
dimers, a complete disappearance of nearly all xenograft tumors was observed; moreover, there
was evidence of complete tumor eradication in 50% of the mice. The combination of lapatinib +
trastuzumab was also highly effective in eradication of tumor burden, with no evidence of
re-growth after 200 days. These xenograft models demonstrate that multi-drug HER2-targeted
therapy more effectively induces apoptosis and inhibits proliferation, thereby resulting in
tumor regression. Furthermore, HER2 combination therapy appears to more effectively reduce
levels of phosphorylated pAKT and MAPK, thus resulting in sustained tumor inhibition.
Phase:
Phase 2
Details
Lead Sponsor:
Baylor Breast Care Center
Collaborators:
GlaxoSmithKline Translational Breast Cancer Research Consortium