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.