Saci-IO HR+: Randomized phase II trial of sacituzumab govitecan (SG) +/- pembrolizumab in PD-L1+ hormone receptor-positive (HR+) / HER2- metastatic breast cancer (MBC).

TPS1102 Background: Immune checkpoint inhibitors (ICIs) have not yet benefited most patients with MBC. In HR+ MBC, the first randomized trial combining an ICI with chemotherapy demonstrated no clinical benefit with the addition of pembrolizumab to eribulin.1 The optimal ICI combination agent to overcome primary resistance in HR+ MBC is unknown. One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.5 months in HR+ MBC refractory to endocrine therapy.2 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.3 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.4 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,5 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors. Methods: This is a multi-center 1:1 randomized phase II trial to investigate whether the addition of pembrolizumab (200 mg IV every 3 weeks) to SG (10 mg/kg IV days 1+8 every 21 days) improves PFS compared to SG alone in HR+ HER2- MBC that is PD-L1+ by central assessment with 22C3 combined positive score (CPS) ≥ 1 (NCT04448886). Key eligibility criteria include at least 1 prior hormonal therapy and no more than 1 prior chemotherapy for HR+ MBC. Eligible patients must have evaluable disease, and previously treated brain metastases are permitted. Exclusion criteria include prior treatment with SG, irinotecan, and PD-1/L1 inhibitors. Based on a sample size of 110 patients, the trial has 80% power to detect a 3-month difference in median PFS from 5.5 months in the SG-alone cohort to 8.5 months in the SG + pembrolizumab cohort with a one-sided alpha of 0.1. Participants undergo mandatory baseline and on-treatment research biopsies if their disease is safely accessible. Tumor biopsies will be evaluated for Trop-2, immune cells, inhibitory checkpoints, transcriptomic signatures, and genomic alterations. Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed. The trial is currently open and enrolling patients. References: 1) Tolaney SM et al. JAMA Oncol 6, 1598-1605 (2020). 2) Kalinksy K et al. Ann Oncol 12, 1709-1718 (2020). 3) Cardillo TM et al. Bioconjug Chem 26, 919-931 (2015). 4) Iwai T et al. Oncotarget 9, 31411-31421 (2018). 5) Hibino S et al. Cancer Res 78, 3027-3040 (2018). Clinical trial information: NCT04448886 .