Abstract P5-16-13: Safety and efficacy of INT230-6, a potential first-in-class intratumoral therapy, in monotherapy and in combination with pembrolizumab: Results from the IT-01 study [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic breast cancer
Authors: Bedard Philippe , Siu Lillian L , Thomas Jacob , Hanna Diana , Olszanski Anthony J , Azad Nilofer , Whalen Giles , Ingham Matthew , Mahmood Syed , Bender Lewis H , Walters Ian B , El-Khoueiry Anthony 
Published: March 2022

Abstract
Background: INT230-6 is a novel formulation of cisplatin and vinblastine with an amphiphilic cell penetration enhancer that has been shown to enhance dispersion of the drug throughout tumors and allow diffusion into cells when given intratumorally. INT230-6 is being evaluated in monotherapy and in combination with immune checkpoint inhibitors (ICIs) in subjects with various advanced solid tumors, including advanced breast cancer. Methods: This phase 1/2 study evaluated INT230-6 in superficial and deep tumors with INT230-6 Q2W intratumoral injections for 5 doses alone or in combination with 200mg pembrolizumab IV Q3W for 2 years. Total INT230-6 injected in a subject ranged from 0.89 to 649 mL over 5 INT230-6 dosing sessions in each subject, except one subject who had only 2 dosing sessions. Subjects who had completed treatment in dose escalation cohorts were eligible for retreatment; and one subject was retreated with INT230-6 in multiple arms of the study. Advanced breast cancer subjects with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or below who have failed one or more approved therapies, or have no alternate approved therapy, were enrolled. Subjects must have adequate organ function and measurable disease by RECIST 1.1 criteria including one target tumor for injection. Tumor response using RECIST 1.1 was evaluated at 12 weeks from the first INT230-6 dose and then every 8 weeks. Tumor biopsies were taken prior to INT230-6 dosing on day 0 and on day 28 post dose. Results: 7 advanced triple negative breast cancer subjects (4 monotherapy, 3 pembrolizumab combination) were evaluable as of June 1, 2021. The median age was 56 (range 46-82) years old, with a median of 8 (2, 17) prior systemic therapies for metastatic disease. The intratumoral INT230-6 dose was up to 164 mL (82 mg of CIS, 16.4mg VIN) to tumors in a single dosing session. With INT230-6, 133-200% more volume is injected into the tumor and pharmacokinetics (PK) analysis shows that 95% of INT230-6 active agents remain in the tumor. Accordingly, assessment of tumor response using RECIST principles may be challenging, and even stable disease may represent a large decrease in viable tumor cells as indicated by biopsy evaluations. The most common (&gt;20%) related treatment related adverse events (AE) were localized tumor related pain (71%), nausea (57%), anemia (29%), fatigue (29%), neck pain (29%), and vomiting (29%). AEs were mostly low grade and only one subject experienced grade 3 anemia (13%). There were no related grade 4 or 5 AEs or serious AEs. Disease control rate (DCR), defined as the percent of patients with a complete response, partial response, or stable disease at the first radiologic assessment, was 57%. Median overall survival was 12 months. Pre- and post- biopsy at 28 days after two INT230-6 doses (n= 3 evaluable, monotherapy, and combination with pembrolizumab) showed a 55% decrease in Ki67 and 69% reduction in viable cancer cells. In addition, multiplex immunofluorescence (n= 3 evaluable, combination with pembrolizumab) showed an influx of activated CD4 and CD8 T cells and in some cases a reduction in FoxP3 T-reg cells.. Conclusion: INT230-6 is a potential first-in-class intratumoral therapy for advanced breast cancer being developed in monotherapy and in combination with ICIs. There is a favorable safety profile in this population, similar to the broader metastatic solid tumor population presented elsewhere. There are early signs of cancer cell death in injected tumors and immune activation in heavily pre-treated patients. A Phase 2 expansion cohort of INT230-6 in combination with ICIs is ongoing. In addition, INT230-6 in being studied in a separate randomized Phase 2 neoadjuvant breast cancer study.
Citation Format: Philippe Bedard, Lillian L Siu, Jacob Thomas, Diana Hanna, Anthony J Olszanski, Nilofer Azad, Giles Whalen, Matthew Ingham, Syed Mahmood, Lewis H Bender, Ian B Walters, Anthony El-Khoueiry. Safety and efficacy of INT230-6, a potential first-in-class intratumoral therapy, in monotherapy and in combination with pembrolizumab: Results from the IT-01 study [KEYNOTE-A10] in subjects with locally advanced, unresectable and metastatic breast cancer [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 P5-16-13.