Therapeutic: datopotamab deruxtecan for breast cancer

With the cancer cells having no oestrogen or progesterone receptors, and no overexpression of HER2, many potential drug treatments are ruled out.

Less than half of patients with metastatic triple negative breast cancer (TNBC) respond to currently available first-line treatment options, including chemotherapy, either alone or in combination with immunotherapy.

If there is a response to initial treatment, the disease will typically progress within 2 years and the average overall survival is just 12–18 months. Another potential treatment, datopotamab deruxtecan, is being developed by AstraZeneca and Daiichi Sankyo.¹

It is an antibody-drug conjugate with the antibody part targeting trophoblast cell surface antigen 2 (TROP2), which is associated with increased tumour progression and poor survival.

TROP2 is broadly expressed in several solid tumours, including TNBC. The deruxtecan payload is a topoisomerase I inhibitor. A first-in-human dose escalation and dose expansion study was done in non-small cell lung cancer and it showed both promising efficacy and a manageable safety profile.²

Numerous clinical trials are under way in TNBC and a meta-analysis has been done to evaluate adverse events at all grades and dose reductions in TNBC patients treated with the ADC in clinical trials.³

This showed that although adverse events were common, grade 3–4 events were fairly infrequent and most instances involved stomatitis. Updated results of an ongoing Phase Ib/II trial have been released.⁴

The open-label, two-part, multicentre trial is looking at the efficacy of datopotamab deruxtecan in combination with the PD-L1 inhibitor, durvalumab, in patients with high levels of PD-L1 expression.

Subjects with previously untreated, unresectable, locally advanced or metastatic TNBC were given 6 mg/kg of the ADC plus 1120 mg of the antibody.

Of the 62 patients given the combination, most of whom had tumours with low PD-L1 expression, there was an objective response rate of 79%, including six complete responses and 43 partials.

Responses were seen regardless of PD-L1 expression level. The median progression-free survival was 13.8 months and the median duration of response was 15.5 months.

Grade 3 or higher treatment-emergent adverse events occurred in 57% of patients, with the most common being increased amylase and stomatitis. Trials continue, including two Phase III studies in TNBC and further studies in non-small cell lung cancer.

References

1. D. Okajima, et al., Mol. Cancer Ther. 20, 2329 (2021).
2. T. Shimizu, et al., J. Clin. Oncol. 41, 4678 (2023).
3. G. Gadaleta-Caldarola, et al., Cancer Treat. Res. Commun. 37, 100775 (2023).
4. P. Schmid, et al., Annals Oncol. 34(Suppl. 2), S337 (2023).