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Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (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 approximately 4 molecules of 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-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed 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 unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design 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 LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score < 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤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 every 21 days 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. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. 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) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-06.

Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.