Chapters Transcript Video ESMO Breast Cancer 2026 Highlights: Saci-IO HR+ Harold Burstein, MD, PhD, and Ana C. Garrido-Castro, MD discuss results from the Saci-IO HR+ trial, which were presented at the 2026 ESMO Breast Cancer Congress. I'm Doctor Harold Burstein and welcome to Breast Cancer Breakthroughs. Today, we're talking about some of the highlights from the European Society of Medical Oncology Breast Cancer meeting which was just held in Berlin. Very excited to be joined by Doctor Ana Garrita Castro, one of our medical oncologists and a distinguished investigator already who's got her own data being presented. Uh, how was Berlin? a fun meeting. It certainly was a great meeting, great meeting. I think these European meetings become very fun and very popular. Tell us a little about this trial, the SassyIO trial that you were so integral in developing. Thank you so much. So this is a phase 2 study that's looking at the combination of a trope 2 directed antibody drug conjugate with a toposomerase 1 inhibitor payload. In combination with the immune checkpoint inhibitor pembrolizumab, there has been much interest in combining TA-1 inhibitor-based antibody drug conjugates such as stuzumab gobetecan with immune checkpoint inhibition because of the potential immunomodulatory effects that the DNA damage from the TPA-1 payload can induce in the tumor microenvironment, including activation of the sting pathway that can increase T cell infiltration into the tumor. And in fact what we know is that sattuzumab govetecan in its antibody drug conjugate construct carries a toposomerase 1 inhibitor payload. It targets trope 2, so binds to trope 2 on tumor cells that then gets internalized into the cancer cell, and the payload, the toposomerase 1 inhibitor payload, can then exert its anti-tumor effects within the cancer. Cell, but it can also exit that cancer cell and enter adjacent tumor cells that may not necessarily express trope 2 in the first place, and that's the bystander effect of the antibody drug conjugates. So here in this phase two study SassoHR positive, we explored the combination of saccetuzumab gobetecan with pembrolizumab versus SG alone. In a more immune cold setting, such as hormone receptor positive HER2 negative metastatic breast cancer, so we say immune cold, but you didn't actually, there's no test for that, right? We just sort of make the argument that historically in current practice. We're not using immunotherapy for advanced ER positive breast cancer. Exactly. We know that hormone receptor positive HER2 negative tumors have lower levels of PDL1 expression, lower levels of tumor infiltrating lymphocytes, um, and so the hypothesis here is that perhaps with these TOA-1 inhibitor ABCs we can increase that T cell infiltrate and make a more immune. tumor immune hot and that could perhaps synergize with pembrolizumab via combined restoration of T cell effector function. So there's a good rationale for this study. We want to take our pretty standard now ADC first or second line drug approach, and we're going to see if adding immunotherapy is going to help. What did we learn in this trial? So here in this phase. Study which enrolled patients with advanced hormone receptor positive HER2 negative breast cancer who had received prior endocrine therapy and 0 or 1 prior lines of chemotherapy, and there was a relatively even distribution between 0 versus 1 chemotherapy regimens. Here patients were randomized 1 to 1 to receive SG plus pembrolizumab or SG alone, and the primary endpoint here was progression-free survival in the overall patient population. The initial results were presented at ASCO 2024, and the median progression free survival end point was not met in the intent to treat patient population. There was no statistically significant difference in median PFS between treatment arms and also no significant difference in median overall survival in the overall patient population. So at Esmo Brest we presented these updated results. Now the final overall survival data from this trial, and again. Consistent with those initial results, we see no significant difference in median PFS and OS in the intent to treat population. But what was very interesting, and this initial signal was seen with the at the first PFS analysis, is that in the subgroup of patients with PDL1 positive tumors, which was about 40% of the patient population, and here PDL1 positivity was defined using the 22C3 assay and a combined positive score greater than or equal than 1. In this subgroup of patients with PD1 positive tumors, there does appear to be a signal towards improved outcomes with a combination of SG+ pembrolizumab, both for progression free and overall survival. What you can see here a delta for median PFS greater than 4 months and for median OS greater than 6 months. These are not statistically. Significant differences, and I would caution that these are subgroup analyses and sample sizes are small, but it is an interesting signal suggesting that perhaps there is a subgroup of patients with hormone receptor positive HER2 negative breast cancer who could benefit from immune checkpoint inhibition in combination with these ABCs. So it's a provocative study. Maybe there's a signal if the tumor is. EL1 positive. Take a step back with me though. To date, there's been a lot of effort to look at immunotherapy for ER positive breast cancer, and at best we've seen sort of provocative signals, but there's no standard indication. There's no FDA approval. What are we missing in these ER positive cancers that it's been so hard to move this class of drugs, the immunotherapy drugs forward? And secondly, Do we need to do these studies, for instance, if we're using all these ADCs, say, in triple negative or other settings, can we just add in the immunotherapy without having to study that? These are great questions. I think one of the challenges is that the the studies that have been conducted to date and ER positive HER2 negative breast cancer have looked at the addition of immune checkpoint inhibitor. To standard chemotherapy or endocrine backbones, and with chemotherapy it's been looked at in a pre-treated setting, and we know from, for example, other subtypes such as triple negative breast cancer that the benefit from immune checkpoint inhibition is seen in the first line setting, not in a more treatment refractory setting. So several trials have looked at the addition of immune checkpoint inhibitors to cytotoxic chemotherapy for advanced ER positive HER2 negative disease, but have not demonstrated significant improvements in outcomes. And I also think that patient selection is key. So whether it is PDL-1 levels of expression, levels of tumor infiltrating. Lymphocytes or other immune markers, we may need to find a more biomarker selected approach for immune checkpoint inhibition in the advanced setting, similar to triple negative breast cancer where also we've seen that immune checkpoint inhibition works in a subgroup of patients who have these higher levels of PDL-1 expression. Well, it's a nice demonstration of what a randomized phase two study can do. You've obviously generated a lot of important data. You've got some provocative signals. A lot to build on here, looking at the combination of antibody drug conjugate therapy and immunotherapy for ER positive metastatic disease. Thanks for being with us. Thank you so much. Published June 29, 2026 Created by Related Presenters Ana C. Garrido-Castro, MD Medical Oncology View full profile Harold Burstein, MD, PhD Medical Oncology View Full Profile