News from the world of HER2-targeted treatment options

Breast carcinoma is the most common malignant tumor in women. The prognosis of patients is determined primarily by the stage and biology of the disease. Innovative therapeutics and new treatment regimens were key topics of this congress.

New developments of HER2-targeted therapies have already led to significant survival benefits in recent years. Several therapeutic regimens are now available for first-line therapy. The highest level of recommendation is a combination of docetaxel, trastuzumab, and pertuzumab and weekly paclitaxel in combination with trastuzumab and pertuzumab. In second-line therapy, the situation is already clearer. Here, after pretreatment with trastuzumab, the T-DM 1 treatment regimen is primarily recommended. Recent study results have now shown that the combination of trastuzumab and capecitabine can still have a positive impact on overall survival in pretreated patients compared to the combination of pertuzumab, trastuzumab and capecitabine. However, the combination of trastuzumab and lapatinib also showed significant overall survival benefits as second-line therapy. At least compared to lapatinib monotherapy.

The country needs new active ingredients

While a good response can be expected in early lines of therapy, this decreases in later lines of therapy. Here, acquired mutations, secondary resistance or, in triple-positive disease, endocrine resistance may occur. Moreover, due to toxicity, chemotherapy is not suitable as a combination partner in the long term. The question was whether – and if so, how – effective therapy can still be given in later lines of therapy. For example, by binding chemotherapy molecules to a HER2-targeted antibody, can chemotherapy be delivered directly to cells, increasing efficacy and reducing toxicity? How can brain metastases be treated effectively? And can HER2-targeted treatment work even if there is low or heterogeneous expression of the HER2 receptor? This is where antibody-drug conjugates (ADCs) come into play. The new class of cancer therapies combines the specificity of an antibody with the cytotoxicity of chemotherapy. Trastuzumab deruxtecan consists of a humanized anti-HER2 IgG1 monoclonal antibody that shares the same amino acid sequence as trastuzumab, an exatecan derivative, and a tetrapeptide-based cleavable linker. In a Phase II study, an ORR of 60.9% was achieved. Median overall survival had not been reached at the time of analysis, and progression-free survival (PFS) averaged 16.4 months. Patients with brain metastases had a PFS of 18.1 months.

Tyrosine kinase inhibitors promising

Previously pretreated patients with HER2-positive breast carcinoma were treated with a new, irreversible pan-HER tyrosine kinase inhibitor (TKI). Neratinib was studied together with capecitabine and loperamide vs. lapatinib and capecitabine. A statistically significant improvement was demonstrated in median progression-free survival (PFS), and a positive signal of stabilization was identified in overall survival (OS). In addition, those affected, who in principle have up to a 40% higher risk of brain metastases in the course of the disease, showed a statistically significant trend toward lower cumulative incidence or time delay of brain metastases in contrast to the comparison group.

The last-generation TKI tucatinib also showed encouraging results. It was compared together with trastuzumab and capecitabine against the combination of placebo, trastuzumab, and capecitabine. Outcome was significant improvement in PFS, improvement in objective remission rate, and benefit in OS. All observed subgroups benefited from this therapy regimen, including patients with brain metastases.

Source: DGHO 2020