ESMO Breast 2025 | Post-ADC treatment strategies in HER2+ breast cancer

The presentation was on the post-ADC field. So basically the question was, are there any specific clinical factors or any biomarkers that would direct which treatment we would usually choose? So starting with the clinical features, well of course there is the brain metastasis question. And traditionally brain metastasis was something we have been treating with local therapy. But recently it was shown that systemic treatment can have great activity also in brain metastasis of HER2-positive breast cancer and the initial focus in clinical research that was with the small molecule tyrosine kinase inhibitors. The reason for that is obviously because we have believed that the TKIs have specific activity there because due to the molecular size, they may be able to pass the blood-brain barrier. And the latest iteration of that paradigm, of course, that’s the triple combination of tucatinib, the third generation TKI, trastuzumab, and capecitabine. And we’ve seen large activity there. We’ve seen a response rate in the range of 50% and compared with the former potential standard of capecitabine/trastuzumab, we’ve seen a doubling of overall survival. Now, more recently, we have also learned that ADCs have specific activity, and especially T-DXd. And the reason for that, again, is that at the metastatic site in the brain itself, the blood-brain barrier is partially substituted with a more permeable blood-tumor barrier. and ADCs such as trastuzumab deruxtecan, so third generation ADCs, they have a bystander effect and this seems to be specifically important in the context of brain metastasis because the breakdown of the blood-brain barrier is not uniform so conventional cytotoxic they have a heterogeneous uptake into the brain metastasis that is overcome by the bystander effect and then also the interaction between the tumor cells and the brain cells in the brain that is targeted by the targeting of the microenvironment with the bystander effect and that results in this extremely high response rates that we’ve been seeing several Phase II trials among the DESTINY-Breast01 but also more recently in the DESTINY-Breast12 trial. Now, overall I would believe that in patients with brain metastasis, if local therapy is not indicated, second-line standard treatment is T-DXd, of course, with tucatinib being the third-line option. Of course, if prevention is the question, we come back to the tyrosine kinase inhibitors because here it’s believed that there may be some preventive properties given with small molecule tyrosine kinase inhibitors while by large molecules such as ADCs they don’t have any preventive properties at all. So this is not a proven concept at the moment but this is something to remember perhaps. Right so first line standard of care still those taxane trastuzumab pertuzumab for the majority of our patients and second line that’s T-DXd today that may change with the ASCO meeting when the data from the DESTINY-Breast09 trial will be presented first line T-DXd and once patients progress on T-DXd the evidence from prospective trials that is that is really something that’s really scarce. So that kind of becomes the art of oncology. Usually we do trastuzumab, capecitabine and tucatinib in the third line setting but the ESMO guidelines also suggest T-DM1 as a reasonable treatment option here. Problem is that we know after T-DXd that all the other HER2-directed treatment options they have limited activity. So this is really a field where future research is necessary. There are many trials ongoing in the setting with novel TKIs. There are trials ongoing in the setting with biparatopic antibodies such as zanidatamab. But at the moment our evidence what treatment to choose that is really limited. So first of all we need to ask ourselves the question is the disease still HER2 positive after T-DXd and there is some down regulation of HER2 expression in patients who in the tumor in patients who progress on prior T-DXd. Then of course the question is this a homogeneously a HER2 positive disease or are there different clones present? So are the HER2 negative and HER2 positive clones present? And of course over time and under treatment the HER2 status can also change so it makes sense to reassess this. The issue with T-DM1 is that obviously there are relevant resistance mechanisms in patients who progress on T-DXd that can relate to the heterogeneity of the disease, that can relate to the lysosomal function, so the alterations in the internalization of the antibody antigen complex and uptake not into the lysosome but in submembranous punctae which are basically caveolar endocytic compartments with neutral pH so there is no degradation of the antibody therefore the cytotoxic is not released in the intracellular compartment. There’s also the issue of rapid recycling so the rapid recycling of the early endosome to the surface and also no lysosomal degradation of the antibody. So in the end there are several mechanisms of resistance to T-DM1 which we have tried to overcome either with a kind of biparatopic approach so combining T-DM1 and pertuzumab which was not superior to T-DM1 alone in the MARIANNE trial. Otherwise, we could also try to stabilize the HER2 expression of the cell membrane by combining T-DM1 with a small molecule, TKI, because Lapatinib and Tucatinib, we have the data that they stabilize HER2 expression, the cell membrane. Again, HER2-CLIMB-02 combination of tucatinib and T-DM1 only a bit superior to T-DM1 alone. So clinically highly interesting approaches, but clinically of limited activity. Then, of course, HER3 expression might be something that is relevant in this context, we know tumors co-express HER2 and HER3 have  poor survival. It appears that HER3 up regulation results in resistance to HER2 directed treatment. So that is something that, that suggests that some hyperopic approach uh targeting also the, the heterodimerization of HER2 and HER 3 which are the most potent inducers of HER2 signaling. That this might be reasonable. And then of course there are 3 directed ADCs in clinical development such as patritumab deruxtecan. RB2 mutations are relatively rare and HER2 positive breast cancer, but they exist and, they may still be, may still be sensitive to irreversible TKI such as neratinib and tucatinib but there’s relative resistance to lapatinib reported, targeting PIK3CA that hasn’t been so successful in HER2 positive breast cancer. So the role of pathway inhibitors, or PIK3CA inhibitors, MTOR inhibitors, that is, that is unclear, but, we have learned is that it’s important in the luminal B HER2 positive subset of breast cancer to target both the estrogen receptor and HER2. And that has been successful. We’ve, we’ve uh seen that the triple combination of just of endocrine therapy and the CDK46 inhibitor in the PATINA trial, for example. Yields interesting, highly interesting uh progression free survival rates of, of 44 months. And they also know that in pre-treated patients, the triple combination of abemaciclib and trastuzumab is superior to trastuzumab and chemotherapy. So that was the MONARCH trial in the pre-treated population. The problem is that these patients of course has not received prior T-DXd and still I believe even outside of, of the approval for opalcycline, this is an interesting option in, in the patients who progress on prior treatment if they have hormone receptor positive or HER2 positive metastatic breast cancer. So in the end, we, we try to individualize treatment based upon the clinical factors and the biomarkers available. TKIs and such as tucatinib and TDM1 are an option. Patients progressing on prior T-DXd but have limited activity. The rare case of an OB2 mutation, irreversible TKIs are preferred and in hormone receptor positive/HER2 positive breast cancer, I believe this. Parallel inhibition of HER2 anti-estrogen receptors clinically relevant and even though the CDK4/6 inhibitors are not approved in this setting, it makes perfect sense to combine the drug uh the CDK4/6 inhibit to do this combination if, if clinically possible. But in the end, all the options we have available at the moment will not solve the problem. And uh we, we need novel options in this setting because especially the T-DXd now will make it to the first line I think after ASCO when, when we will have the results of Destiny-Breast09 online. So highly exciting times, we, we have had a massive impact on the outcome of patients with, with HER2 positive metastatic breast cancer with the normal treatment options, but now we need to define the best way to go on once the patient progresses on T-DXd.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.