Study Hints at Immunotherapy Benefit for Trastuzumab-Resistant HER2-Positive Breast Cancer
The addition of immunotherapy drugs to the treatment regimen for advanced HER2-positive breast cancer, may improve progression-free survival in women with oestrogen receptor-positive disease or with tumours carrying an immune protein called PD-L1.
Speaking at the European Society for Medical Oncology conference in May 2025, researchers presented early results from the DIAmOND study, which explored the effects of adding two types of checkpoint inhibitor drugs to standard treatment with trastuzumab; a drug commonly used to treat HER2-positive breast cancer.
The Australian study enrolled 72 patients with advanced HER2-positive breast cancer, whose disease was progressing despite treatment, and divided them into three treatment groups.
Two groups – one consisting of people with oestrogen receptor-positive (ER+) disease and one consisting of those with oestrogen-receptor negative (ER-) disease – received a combination of two checkpoint inhibitors, tremelimumab and durvalumab, plus trastuzumab.
The third group of people with ER+ or ER- disease received an initial single dose of tremelimumab, then continued treatment with durvalumab and trastuzumab.
At one year, those who received the initial priming dose of tremelimumab had the highest rate of progression-free survival, at 27%, followed by women with ER+ disease at 16%. However, in women with ER- disease, progression-free survival rates were just 8%.
The results also suggested that the immunotherapy approach was more effective in women with PD-L1+ disease, as progression-free survival rates were highest – 67% – in women with cancer that was both ER+ and PD-L1+.
Checkpoint inhibitors have been extraordinarily effective in treating lung and skin cancers, because they remove the tumour’s blockade of the immune system, and therefore allow it to attack the tumour.
Tremelimumab and durvalumab achieve this through different modes of action. Durvalumab interacts with the PD-L1 protein that is found on the surface of cancer cells, while tremelimumab targets another tumour protein called CTL-4, which works to suppress the immune response to the tumour. Researchers hoped that the combination of the two approaches would be more effective that one or the other by themselves.
Checkpoint inhibitors are associated with known side effects. Around two-thirds of those in group one and group two experienced severe adverse events, but the rate of severe events was slightly lower in the third group who received the initial priming dose of tremelimumab.
While the study is small, and the numbers of individuals in each treatment group even smaller, the researchers said the results suggest that targeting both CTLA-4 and PD-L1 with immunotherapy does have an effect in women with disease that was progressing despite trastuzumab therapy.
“Promising signals were seen in ER-positive and PD-L1 positive patients, and further investigation of dual checkpoint blockade plus HER2-targeted therapies is warranted,” they wrote.
Publication:
Loi S, Zdendowski N, Gebski V, Li I, Wilcken N, Morris M, Vatandoust S, Redfern AD, Blum FH, Stoodley I, Long S, Hay T, Hui R. Primary efficacy results of tremelimumab and durvalumab in combination with trastuzumab in trastuzumab resistant advanced HER2-positive breast cancer: BCT1703 DIAmOND. ESMO Open 2025; 10 (suppl 4) DOI: https://doi.org/10.1016/j.esmoop.2025.104873 301MO
