Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress)

TPS1127 Background: Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death ligand 1 (anti–PD-L1) agents with chemotherapy have shown promise in mTNBC. LV is an investigational antibody–drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-L1 activity. Preliminary results show LV delivered once every 3 weeks (Q3W) + pembrolizumab was tolerable with encouraging antitumor activity in patients with mTNBC (Han 2019). Additionally, interim results of weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with mTNBC who are PD-L1 low or negative, Part D will focus on this patient population. Methods: SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable locally advanced/mTNBC. Part D is currently enrolling ̃40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-L1 treatment, PD-L1 combined positive score < 10, measurable disease per RECIST v1.1 and an ECOG score ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 plus pembrolizumab 200 mg on Day 1 Q3W. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Clinical trial information: NCT03310957.