Abstract P2-14-06: Durable responses with intratumoral electroporation of plasmid interleukin-12 plus pembrolizumab in patients with advanced triple-negative breast cancer: Cohort 1 update from KEYNOTE-890
Authors: Telli Melinda L. , Wapnir Irene , Devitt Bianca , Cuff Katharine , Soliman Hatem , Vinayak Shaveta , Canton David A. , Twitty Christopher G. , Xie Sunny , Lu Ying , Bannavong Donna , O'Keeffe Bridget , Aung Sandra , Joshi Rohit 
Published: March 2022

Abstract
BACKGROUND: Electroporated plasmid interleukin-12 (tavokinogene telseplasmid; TAVO-EP) delivered to accessible tumors by intratumoral injection induces sustained local expression of IL-12. IL-12 is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells, promoting anti-tumor immune responses. TAVO-EP has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Anti-PD1 monotherapy has just over 5% overall response rate (ORR) in the second-line or later (2L+) treatment setting for advanced TNBC. New antibody-directed conjugate (ADC) chemotherapy has increased rates of responses compared with prior standard chemotherapy in 2L+ advanced TNBC; however, short duration of response (DOR), and toxicity are issues of concern. Therapies that can induce durable responses with limited toxicity are needed. METHODS: Cohort 1 of this Phase 2, open-label, multicenter study assessed the safety and efficacy of TAVO-EP in combination with pembrolizumab as 2L+ treatment for advanced TNBC. Eligible patients had at least 1 line of prior systemic therapy for advanced or metastatic disease, measurable disease by RECIST v1.1, and ≥1 lesion accessible for TAVO-EP treatment. Patients received pembrolizumab (200 mg IV) every 3 weeks and TAVO-EP (0.5 mg/mL at dose volume of ~1/4 lesion volume) on Days 1, 5, and 8 every 6 weeks. Tumor assessments were performed every 12 weeks. The primary endpoint was RECIST v.1.1 ORR by investigator review. Secondary endpoints included safety and tolerability, DOR, progression-free survival (PFS), immune-related RECIST (iRECIST) ORR and PFS, disease control rate, and overall survival (OS). ClinicalTrials.gov: NCT03567720. RESULTS: Between 01Nov2018 and 30Jan2020, 26 patients were enrolled and received at least one dose of study treatment (median follow up of 11.1 months). Patients had a median of 2 prior lines of systemic therapy for advanced disease (range 1-5). Among 23 patients evaluable for response, the ORR was 17.4% (4 with partial response [PR]). One responder with centrally confirmed PD-L1-negative disease and chest wall and bulky liver metastases had a sustained PR and an iRECIST complete response (CR). One responder had near complete regression of a large fungating chest wall skin lesion. The median DOR was 16.6 months. Median OS was 11.0 months (range 0.6-27.5+). The most common treatment-related adverse events (TRAEs) (all grades) were administration site pain and fatigue. Grade 3 TRAEs were reported in 6 patients (23%) including fatigue (11.5%); acute kidney injury, enterocolitis, and myocarditis (3.8% each). There were no Grade 4 or 5 TRAEs. CONCLUSIONS: The combination of TAVO-EP and pembrolizumab in pretreated patients with advanced TNBC resulted in durable RECIST v1.1 responses, including in PD-L1-negative disease, and was well tolerated. This novel immunotherapeutic regimen warrants further evaluation in 2L+ advanced TNBC. Cohort 2 exploring TAVO-EP + pembrolizumab + chemotherapy in frontline TNBC is currently enrolling.
Citation Format: Melinda L. Telli, Irene Wapnir, Bianca Devitt, Katharine Cuff, Hatem Soliman, Shaveta Vinayak, David A. Canton, Christopher G. Twitty, Sunny Xie, Ying Lu, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Durable responses with intratumoral electroporation of plasmid interleukin-12 plus pembrolizumab in patients with advanced triple-negative breast cancer: Cohort 1 update from KEYNOTE-890 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-06.