A phase II study of docetaxel and pembrolizumab plus Interleukin-12 gene therapy in non-metastatic, anthracycline-refractory triple negative breast cancer (INTEGRAL)

Purpose: To evaluate the safety and efficacy of combining intra-tumoral IL-12 gene therapy with docetaxel and pembrolizumab in high-risk patients with early stage triple-negative breast cancer (TNBC) refractory to anthracycline-based neoadjuvant chemotherapy. Methods: In this single-arm, open-label phase II trial, patients with stage I-III TNBC and residual disease after anthracycline therapy received neoadjuvant docetaxel (100 mg/m2 IV) and pembrolizumab (200 mg IV) every three weeks for four cycles. Intra-tumoral injections of adenoviral-mediated interleukin-12 (ADV/IL-12) gene therapy were administered three days prior to cycles 2-4. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were safety and toxicity assessments. Correlative analyses included immune profiling and cytokine measurement. Results: Eight patients were enrolled; half received ADV/IL-12 at a starting dose of 5 x 1011 viral particles (VP) in 2mL volume, injected into the breast tumor. Owing to adverse events (AE's), the remaining 4 patients received 3 x 1011 viral particles. The trial was terminated early due to toxicity, with 87.5% of patients experiencing grade ≥3 AE's, including two treatment-related deaths. Only one patient (12.5%) who received a lower dose of ADV/IL-12 achieved a pCR. Elevation of CCL4 levels was observed exclusively in the patient who achieved pCR. Conclusions: The combination of docetaxel, pembrolizumab, and intratumoral ADV/IL-12 is associated with high systemic toxicity and minimal efficacy. These results underscore the need for cautious dose optimization and patient selection when integrating immuno-potentiating cytokines into neoadjuvant regimens. Translational insights from this study inform safer design of future IL-12-based strategies in immune-refractory TNBC.