Three New Drugs in HER2-Positive Metastatic Breast Cancer Made Their Mark on the Oncology Agenda

Attended by approximately 8000 scientists working on breast cancer from all over the world, the San Antonio Breast Cancer Symposium began on 10 December 2019 in Texas, USA. Studies that will change our daily clinical practice were presented at the congress.

Among these studies, metastatic (stage 4) HER2 receptor-positive breast cancer patients were the focus of results for three newly developed anticancer agents that made their mark on the day.

Approximately 15-20% of breast cancer patients have the type we call HER2 positive . In addition, approximately 10% of all patients with breast cancer present with metastatic disease at diagnosis. Among patients diagnosed at an early stage, 30% develop metastases during follow-up. In metastatic disease, our aim is to prolong survival rather than to achieve a complete cure.

The presence of the HER2 receptor is very important in planning the selected breast cancer treatment. Among the targeted drugs developed against this receptor, trastuzumab (Herceptin), pertuzumab (Perjeta) and T-DM1 (Kadcyla) have received approval from the American Food and Drug Administration (FDA) and entered standard use. Patients may develop resistance to these drugs over time. With increasing survival, new drugs are needed.

On the other hand, one of the most important problems in our patients with HER2-positive metastatic breast cancer is the possible development during long-term follow-up of brain metastases in these patients. In patients whose disease has spread to the brain, not every drug may have the desired effect because of the blood-brain barrier.

Presented on the second day of the congress, demonstrating the effectiveness of new drugs developed for this patient group, 3 important studiesmade their mark on the oncology agenda.

Phase III HER2CLIMB study and tucatinib

Tucatinib is an agent with high sensitivity specific to the HER2 receptor, an oral tyrosine kinase inhibitor . In patients who have received multiple lines of treatment, we routinely use the chemotherapy agent capecitabine together with the targeted drug trastuzumab. This study examined the effect on treatment response of adding tucatinib to this combination, a phase III clinical trial that enrolled a total of 612 patients.

Approximately half the patients enrolled had brain metastases. In 60%, in addition to the HER2 receptor, hormone receptors were positive.

Looking at the entire patient group in the study results, the 1-year progression-free survival (PFS, the time from the start of the new treatment until disease worsening) was an additional 21% better in those using tucatinib (33% versus 12%), and median PFS was 2.2 months longer (7.8 months versus 5.6 months).

The 2-year overall survival with tucatinib use was 22% better (45% vs 27), while median survival was 5 months longer (22 months versus 17 months).

The treatment benefit rate was shown to increase by 18% (41% versus 23%).

Subgroup evaluations showed that tucatinib benefited all patient groups.

In particular, it was shown to make a major contribution to PFS in patients with brain metastases (1-year PFS 25% versus 0%).

Regarding drug-related side effects the most common were diarrhea, redness of the hands and elevated liver enzymes. However, there was no significant difference between the groups in side effects leading to drug discontinuation.

This study was published in NEJM, one of the important journals in oncology, on the same day it was presented.

In conclusion, although patients enrolled in this study had previously used many treatment options such as T-DM1, pertuzumab and trastuzumab, adding tucatinib to standard treatment was shown to reduce the risk of death by 1/3 in all patients and by 50% in those with brain metastases in particular, and to increase the treatment benefit rate 2-fold.

This treatment agent appears likely to take an important place in HER2-positive metastatic disease in the coming period.

Phase III SOPHIA study: margetuximab

Margetuximab is an agent developed against the HER2 receptor. Its structure differs slightly from that of trastuzumab, which we routinely use. Its sensitivity to the HER2 receptor is approximately 5 times greater than that of trastuzumab.

This study evaluating the effectiveness of margetuximab enrolled patients who had received multiple lines of treatment (particularly our standard treatments developed against HER2: trastuzumab, pertuzumab and T-DM1), a total of 536 patients. One group received chemotherapy with trastuzumab, while the other received chemotherapy with margetuximab.

The study results showed:

• Progression-free survival was 1.3 months better in the margetuximab arm (PFS: 5.7 versus 4.4 months).
• The treatment benefit rate (ORR) was 30% better in patients receiving margetuximab (ORR 67 versus 37%).
• An additional improvement of 1.8 months in overall survival (OS) was demonstrated (OS: 21.6 versus 19.8 months). 
• No difference in drug-related side effects was found between the groups.

Trastuzumab deruxtecan

This drug has a structure similar to T-DM1, which we routinely use. It consists of a chemotherapy agent linked to a HER2 receptor-directed monoclonal antibody .

This phase II study presented at the congress enrolled patients who had previously received multiple lines of treatment (a median of 6 lines), a total of 180 patients.

With trastuzumab deruxtecan, the overall response rate (ORR) was 60%, while the disease control rate was 97% in the study.

Progression-free survival was 16 months. Although median overall survival data were not yet available, the 1-year overall survival rate was 86.4%, which was found to be a high rate.

In the subgroup evaluation of the study, brain metastases were present in 24 patients, whose median time until disease worsening was 18 months.

Drug-related side effects: nausea, fatigue and neutropenia were observed, but these side effects were manageable.

As a serious side effect (grade 3 and 4), lung toxicity was observed in 3 patients. This side effect was managed with cortisone treatment.

A phase III study comparing this treatment with capecitabine-trastuzumab, the current standard treatment arm, is ongoing.

Summary of new studies in metastatic HER2-positive breast cancer

• In first-line treatment, the combination of pertuzumab-herceptin-chemotherapy,
• and in second-line treatment, T-DM1, are our standard approaches.
• It now appears that we have different treatment options in the third line. What remains unclear today is which treatment combination will be more effective in which patient subgroup. I believe that new study results to be announced in the coming period will provide the answer.

In conclusion, we observe that the three new drugs whose successful results were announced at the San Antonio Breast Cancer Symposium have launched a promising new period in breast cancer treatment. These three different new drugs, which we believe will receive FDA approval in the near future for HER2-positive metastatic breast cancer in patients receiving multiple treatments, will make important contributions to the breast cancer treatment process. We believe that breast cancer treatment will be one of the most gratifying areas of oncology.

*

*