ESMO Immuno-Oncology 2025 | How are ADC and ICI combinations redefining breast cancer treatment?

Several ADCs have been approved in all breast cancer subtypes. First, it was with T-DM1 in the advanced setting of HR2 positive breast cancer. Then T-DM1 moved to the adjuvant setting for patients with residual disease after neoadjuvant chemotherapy. Then we had the approval of TDXd in advanced HR2 breast cancer. And then more recently, Sacituzumab Govitecan in triple-negative breast cancer. And now more recently in luminal breast. Immune checkpoint blockers in breast, it’s only approved in triple-negative breast cancer, both in the advanced setting, but also in the early setting. The combination that has been already reported at ASCO in June is with Sacituzumab Govitecan and Pembrolizumab. So in advanced triple-negative breast cancer, patients with PD-L1 positive tumors in first line are treated with a combination of chemo and Pembrolizumab. In second line, it is Sacituzumab Govitecan as monotherapy that is the recommended treatment. So in the ASCENT trial, they evaluate in first line the combination of Sacituzumab Govitecan, the ADC targeting TROP2, and the anti-PD-1 Pembrolizumab. So patients were randomized between Sacituzumab Govitecan and Pembrolizumab to chemo-Pembrolizumab. Of note, only a few patients that were included received Pembrolizumab in the neoadjuvant setting. So as you know, now Pembrolizumab is used in stage 2, stage 3, early TNBC. So here in the ASCENT trial, while the approval arrives during the trial, only 4% to 5% of the patients included received this neoadjuvant Pembrolizumab. So in these patients that were immunonaive in first line with PD-L1 positive, two-thirds were recurrent, one-third were de novo disease. The trial demonstrates an increased PFS from 7.8 months for chemo-Pembrolizumab to 11.2 months for Sacituzumab Govitecan and Pembrolizumab. Overall survival is immature, but already this PFS advantage is really encouraging. Of note, patients that progress in the control arm were allowed to receive Sacituzumab Govitecan in second line as it is recommended. So with this crossover, overall survival will be difficult to really demonstrate in this trial. So there are other combinations of ADC and an immune checkpoint blocker that are under evaluation in breast cancer, both TNBC, but also in the luminal, also in HR2 disease, and also the combination moves to the neoadjuvant setting. So in the neoadjuvant setting, the goal is to achieve a pCR. Patients with complete pathological or complete response, we are more moving in the mood of de-escalation of treatment to opt for immunotherapy because we know that patients that achieved a complete response have a very good outcome, while patients with residual disease, even if they receive immunotherapy, they have a high chance, they have a high risk of relapse. And in this setting, there are some trials evaluating the combo of ADC with immunotherapy as rescue therapy, and we are waiting for the results. They are also trials evaluating the combination in the neoadjuvant setting to improve the pCR rate.

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