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Abstract SP086: Rationale for combination therapies

There has been a lot of emerging clinical data in the treatment of early and late stage breast cancer with PD-1/PD-L1 inhibitors in the last 12 months. We have learnt several important points relevant for future development in breast cancer patients. Most important of these is the observation that early-stage disease has a different immune context to advanced disease. This is evidenced by study results that in the neoadjuvant settings PD-(L)1 inhibitors have efficacy in both PD-L1 positive and negative populations, whereas in the advanced setting, efficacy has only been reported in PD-L1 positive patients. It has been hypothesized that chemotherapy, or certain types of chemotherapy, may be more “immunogenic” than others, but thus far, there is scant evidence to support this. Rather it is more likely that the immune context is important. In the early-stage setting, many primary breast cancers (triple negative and HER2-positive) are highly infiltrated with immune cells, the cancers has received no prior treatment, and cancer burden is low, confined to the breast and ultimately completely removed. In contrast, in the advanced setting, the immune infiltrate is low to non-existent, patients often have higher disease burden, hostile tumor microenvironments in multiple organs sites, and have received prior treatment, implying that the cancer has evolved to become treatment resistant, as well as more efficient at suppressing or evading host immune detection. Hence, in the setting of recurrent disease, and likely also in the locally advanced setting, despite chemotherapy usage and objective tumor shrinkage, it is the pre-existing immunity that ultimately dictates the chances of benefit from PD-(L)1 inhibitors. What combinations are likely therefore to be effective in the advanced setting where immunity does not exist? Targeted therapies such as MEK and AKT inhibitors are being evaluated in clinical trials, thus far have proven disappointing. New antibody drug conjugates (ADCs) such as Sacituzumab Govetecan and DS-8201a have shown impressive anti-tumor activity in the advanced setting. However, given their proven cytotoxic bystander effects on nearby cells, it will be essential to evaluate ADCs and immunotherapy sequencing approaches to ensure that the scant amount of pre-existing local TIL is also not destroyed. Interestingly a recent study in advanced HER2-positive breast cancer (KATE2) reported benefit of atezolizumab to trastuzumab emantasine also in only PD-L1 positive patients. Notably T-DM1 does not have prominent bystander effects. Other possibilities to create immunity in the advanced setting include radiotherapy, more potent anti-HER2 agents, as well as genetically engineered T cell receptor or chimeric antigen receptor T cells, and agents targeting T regulatory cells. This task is likely to be a very challenging as it will require more than making “cold” tumors “hot”, as is probable that we will need to find the means that can re-invigorate the whole host immune system in the context of advanced breast cancer. Citation Format: S Loi. Rationale for combination therapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP086.