Abstract PS4-10-15: Accelerating an Anthracycline-Free Future: A New Drug in Clinical Testing Offers Patients Hope for Safer, More Effective Breast Cancer Therapy Combinations

Abstract Background: Doxorubicin is used in several chemotherapy regimens for many breast cancer subtypes, including triple-negative breast cancer (TNBC) and HER2-positive breast cancer before surgery (neoadjuvant). Doxorubicin can also be used in early-stage breast cancer in adjuvant therapy, after surgery, or in metastatic breast cancer. Patients refer to this drug as the “red devil.” It earns this moniker not just for its harsh red color, but for its side effects: fatigue, nausea, hair loss, and, far worse, permanent heart damage. Some patients die from neoadjuvant treatment itself. TNBC is an aggressive breast cancer subtype that affects 420,000 women worldwide and 56,000 in the US. Patients agree to intense neoadjuvant immunochemotherapy (Keynote-522), hoping to achieve a pathologic complete response (pCR), which means no cancer left at the time of surgery. Achieving pCR is strongly linked to an increase in event-free survival (EFS) and can serve as an endpoint to expedite FDA drug approvals. The SCARLET phase III trial, led by the National Cancer Institute, is studying whether an anthracycline-free regimen (NeoPACT) can remove doxorubicin in early-stage TNBC. While this trial gives patients hope, the EFS results are not expected until 2033 or 2034. Many patients are unable to wait so long, especially in the adjuvant or metastatic settings. Current Research Objectives and Rationale: INT230-6 is a new drug consisting of two potent cytotoxic chemotherapy agents (cisplatin and vinblastine sulfate) formulated with a diffusion and cell penetration enhancer (SHAO) in a single vial. The product candidate is designed for intratumoral injection. INT230-6 kills cancer cells locally and stimulates the immune system to recognize and attack cancer systemically. The drug, after being injected into the tumor, attacks the entire tumor. In early studies, the drug has been shown to cause up to 95% tumor necrosis in tumors as large as 4.4 cm. The ongoing INVINCIBLE-4 trial (NCT06358573) is a two-cohort randomized controlled study testing INT230-6 dosed before the standard Keynote-522 regimen, which includes doxorubicin (cohort A), and the KN-522 regimen alone (cohort B). The goal of INVINCIBLE-4 is to enhance initial tumor destruction and immune priming, thereby improving pathological complete response (pCR) rates over KN-522. With higher pCR rates and strong immune activation, a regimen without anthracyclines may become possible. Phase 3 Study Design and Rationale: If the results from the Phase 2 INVINCIBLE-4 study show a clinically meaningful increase in pCR using INT230-6 before KN-522, the next step would be a pivotal phase III trial design with three treatment arms in neoadjuvant TNBC: 1. INT230-6 followed by full KEYNOTE-522 regimen 2. INT230-6 followed by KEYNOTE-522 without anthracycline. 3. Standard KEYNOTE-522 regimen alone (with anthracycline) With pCR as the first primary endpoint for accelerated approval and enrolling sufficient TNBC patients for the endpoint of EFS, the three-arm 1:1:1 randomized study design comparing cohorts 1 or 2 separately to cohort 3 could enable a significantly faster approval pathway (for cohort 2). pCR results could be available years before the SCARLET study data. However, EFS will be required for full approval of INT230-6 with an anthracycline-free regimen. Citation Format: C. W. Handy, J. R. Rodrigues, K. A. Guedes, I. B. Walters, L. H. Bender. Accelerating an Anthracycline-Free Future: A New Drug in Clinical Testing Offers Patients Hope for Safer, More Effective Breast Cancer Therapy Combinations abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-15.