The antibody-drug conjugate trastuzumab deruxtecan is approved for various therapeutic indications. Since March 2023, it can also be used as monotherapy for the treatment of adults with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy at this disease stage or developed disease recurrence early after adjuvant chemotherapy. Treatment with trastuzumab deruxtecan is the first approved therapy for patients with HER2-low breast cancer. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in an early benefit assessment whether the antibody-drug conjugate offers an added benefit for these patients in comparison with the appropriate comparator therapy.
The (German-language) report was published in May 2023, an English translation in October 2023.
IQWiG sees a hint of major added benefit of trastuzumab deruxtecan in comparison with treatment of physician's choice for patients without visceral disease (i.e. without disease of the internal organs), and a hint of considerable added benefit for patients with visceral disease. Advantages in overall survival are decisive for this positive assessment.
It remains unclear whether the observed effects can be transferred to male patients because only two men participated in the decisive study.
New category: HER2-low tumors
Breast cancer is called "HER2-positive" when the tumor cells have a very large number of HER2-type receptors onto which growth factors dock, stimulating cell division. Until recently, breast cancers with low HER2 expression were classified as HER2-negative and therefore not included in studies on anti-HER2 targeted therapy. However, patients with HER2-low tumors were now also included in the DESTINY-Breast04 study, where trastuzumab deruxtecan showed an effect also for these patients, leading to the corresponding extension of the approval.
The early benefit assessment was based on the approval study DESTINY-Breast04, a randomized controlled trial (RCT) with 555 female and 2 male patients, which compared trastuzumab deruxtecan with treatment of physician's choice (here: capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel).
Longer overall survival and better quality of life
In the DESTINY-Breast04 study, the advantage of treatment with trastuzumab deruxtecan in patients with HER2-low tumors was shown in overall survival in particular: The median survival of patients in the intervention group was six months longer (23.4 versus 16.8 months). Since the observed effect was greater in patients without visceral disease than in patients with visceral disease, the extent of added benefit varies: It is major for patients without visceral disease, and considerable for patients with visceral disease.
A relevant advantage of trastuzumab deruxtecan in comparison with the comparator group was also shown in most recorded aspects of health-related quality of life (physical, cognitive, social, and role functioning). There were also positive effects in severe side effects, especially in the overall rate of severe adverse events of major extent. However, there are also negative effects in several specific adverse events (including severe nausea, serious infections, or severe platelet deficiency).
The fact that IQWiG only derived hints from the DESTINY-Breast04 study (i.e. it assessed the certainty of conclusions as low) results from uncertainties in the implementation of the appropriate comparator therapy, in the selection and dosing of chemotherapies in the comparator arm, and from missing information on the pretreatment of the study participants.
Overall, IQWiG sees mainly advantages of treatment with trastuzumab deruxtecan for female patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy: In comparison with treatment of physician's choice, there is a hint of considerable added benefit of trastuzumab deruxtecan for patients with visceral disease, and a hint of major added benefit for patients without visceral disease.
"The results from the DESTINY-Breast04 study are very relevant for practice," emphasizes Katrin Nink from IQWiG's Drug Assessment Department. "We now know that trastuzumab deruxtecan can also be used in the treatment of breast cancer with low HER2 expression. This substantially expands the population of patients who benefit from this drug."
G‑BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the Federal Joint Committee (G‑BA). After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.
You can find an overview of the results of IQWiG's benefit assessment in an English extract. In addition, the website informedhealth.org published by IQWiG provides easily understandable information on this benefit assessment.
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