Preliminary Outcomes of an Innovative Therapeutic Model Based on SBRT Targeting HER-2 Expression Advanced Solid Tumors (PRaG3.0 Regimen).

The effectiveness of radiotherapy, particularly stereotactic radiotherapy (SBRT), in modulating tumor phenotypes, enhancing antigen presentation, and provoking a systemic immune response has gained wide acceptance. This creates a solid foundation for combining radiotherapy with immunotherapy (iRT). The PRaG therapy, a novel iRT approach, utilizes SBRT, PD-1/L1 inhibitors, and GM-CSF to activate the immune response and alter the tumor microenvironment, aiming for an abscopal effect. RC48-ADC, an anti-HER2 antibody-drug conjugate, induces immunogenic cell death and a broad release of cancer cell antigens, thereby enhancing the effect of immunotherapy through the activation of effector T-cells. This study aims to evaluate the efficacy and safety of combining RC48-ADC with radiotherapy, PD-1/L1 inhibitors, GM-CSF, and IL-2 (PRaG3.0 regimen) in treating HER2-expressing advanced solid tumors. This study enrolled participants with advanced, confirmed HER2-expressing (IHC3+, 2+, or 1+) solid tumors that had progressed following standard treatments or due to intolerance. In the cycle, participants received RC48-ADC (2.0 mg/kg on day 1, every 3 weeks), followed by SBRT (2-3 doses of 5-8 Gy) targeting one metastatic lesion every other day. This was followed by GM-CSF (200 μg on days 3-7), sequential IL-2 (2 million IU on days 8-12), and a PD-1/L1 inhibitor administered within one week after completing HFRT. After at least 6 cycles of RC48-ADC combined with PD-1/L1 inhibitor, GM-CSF, and IL-2, maintenance therapy with a PD-1/L1 inhibitor continued until disease progression or unacceptable toxicity was observed. The primary endpoint was the objective response rate (ORR). As of January 31, 2024, 29 patients had been enrolled at this center. According to RECIST 1.1 criteria, the overall objective response rate (ORR) was 41.4%, with two patients achieving complete response (CR) for nearly two years and maintaining minimal residual disease (MRD) negative status. The disease control rate (DCR) stood at 72.4%. Notably, the ORR for patients with low HER-2 expression (1+) was 47.4%, compared to 30% for those with high HER-2 expression (2+ to 3+). The median progression-free survival (PFS) for all patients was 6.3 months (95% CI: 4.5, 8.1). Treatment-related adverse events were predominantly mild (grade 2 or below), including fatigue, hair loss, nausea, fever, and rash. Only 2 patients (6.8%) experienced grade 3 side effects, which were abnormal liver function and skin itching. The preliminary results of the PRaG 3.0 regimen demonstrate promising efficacy and manageable safety profiles, suggesting that this treatment plan could be a viable salvage therapy option for patients with HER2-expressing advanced solid tumors, irrespective of HER-2 expression levels. It also potentially enhances the synergistic effect of radiotherapy combined with immunotherapy. However, further validation in a larger patient cohort is required. [ABSTRACT FROM AUTHOR]