Ana C. Garrido-Castro, MD, on Metastatic Breast Cancer: Trial Update on Sacituzumab Govitecan With or Without Pembrolizumab

Saci-IO HR+ was a randomized phase II investigator-initiated study to evaluate the efficacy of the trop2 directed antibody drug conjugate sacituzumab govitecan with or without the PD-1 inhibitor pembrolizumab in patients with metastatic hormone receptor-positive HER2 negative breast cancer. SG, sacituzumab govitecan, has demonstrated to improve median progression free and overall survival in patients with previously treated hormone receptor positive HER2 negative breast cancer who have received two to four prior chemotherapies for advanced disease as shown in the TROPiCS-02 study. We know that the payload of sacituzumab govitecan SN38 can enhance cytotoxic T-cell effector functions and deplete regulatory T-cells. It can also stimulate the cGAS-STING pathway increasing T-cell infiltration into the tumor, and thus we hypothesized that the combination of SG plus pembrolizumab would enhance the efficacy of SG alone in metastatic hormone receptor positive HER2 negative breast cancer. Saci-IO HR+ randomized patients one-to-one to receive SG plus pembrolizumab or SG alone in the metastatic hormone receptor positive HER2 negative setting. Patients had to have received prior endocrine therapy for advanced disease or progressed on or within 12 months of adjuvant endocrine therapy and they could have received 0 to 1 prior lines of chemotherapy in the advanced setting. The primary endpoint of the study was progression-free survival in the intent-to-treat population and key secondary endpoints were progression-free survival among patients with PD-L1 positive tumors defined using the 22C3 assay and a combined positive score greater than or equal than 1, and also overall survival in both the intent-to-treat and PD-L1 positive populations. The study demonstrated that the addition of pembrolizumab to sacituzumab govitecan did not significantly improve median progression-free survival in the intent-to-treat population. Median PFS with SG plus pembrolizumab was 8.1 months and median PFS with SG alone was 6.2 month, a hazard ratio of 0.81 and P-value of 0.37. In the intent-to-treat population at a median follow-up of 12.5 months, overall survival did not significantly differ between treatment arms. Median OS with SG plus pembrolizumab was 18.5 months versus 18 months with SG alone. And among patients with PD-L1 positive tumors which comprised about 39% of the patient population defined using the CPS cutoff greater than or equal than 1, there was a 4.4 month absolute difference in median progression-free survival between treatment arms favoring the combination that was not statistically significant. Median PFS with SG plus pembrolizumab was 11.1 months and 6.7 months with SG alone, a hazard ratio of 0.62, P-value of 0.23. Again at a median follow-up of 12.5 months, so overall survival data are not mature, among the patients with PD-L1 positive tumors there was a 6-month numerical increase in median OS with the addition of pembrolizumab to SG. Median OS with the combination was 18.5 months compared to 12.5 months with SG alone. Overall, the safety profile of SG plus pembrolizumab was similar to that reported with either agent and there were no new safety signals that were reported. In conclusion, Saci-IO HR+ is the first randomized trial to evaluate the efficacy of a topoisomerase 1 inhibitor ADC in combination with an immune checkpoint inhibitor in breast cancer. This study did not show a statistically significant difference in median progression free and overall survival among patients with metastatic hormone receptor positive HER2 negative breast cancer who had received up to one prior line of chemotherapy in the advanced setting. Overall survival data are not mature and additional follow-up is needed. Among the patients with PD-L1 positive tumors there was a non-significant 4.4 month numerical increase in median PFS and 6-month increase in median OS with the addition of pembrolizumab to SG, and so we do think that the results from this study support further investigation of the combination of SG plus pembrolizumab in patients with PD-L1 positive metastatic hormone receptor positive, HER2 negative breast cancer.