RC48-ADC combined with radiotherapy and immunotherapy as salvage therapy for advanced solid tumors with HER2 expression: A multicenter, phase II trial.

3032 Background: Antibody-drug conjugates (ADC) have demonstrated efficacy in treating tumors with HER2 over expression. However, the clinical benefits of ADCs are limited in tumors with lower HER2 expression. The combination of ADCs, radiotherapy, and immunotherapy has shown promising feasibility with HER2-expressing tumors across various cancer types. This approach can enhance spatial and physicochemical synergistic effects, resulting in a more diverse and increased release of tumor antigens. Subsequently, PD-1 inhibitors activate effector T cells, generating a robust immune response that targets and eliminates tumor cells. A single-arm, multicenter phase II trial was initiated to evaluate the clinical efficacy of RC48-ADC combined with radiotherapy and immunotherapy, in HER2-expressing advanced solid tumors. The findings from this trial may establish a new salvage treatment strategy for tumors with low HER2 expression. Methods: This study enrolled patients with advanced, HER2-expressing (IHC 1+, 2+, or 3+) solid tumors that had progressed following standard therapies or due to intolerance. Participants received RC48 (disitamab vedotin, 2.0 mg/kg on day 1), followed by radiotherapy every other day (2-3 fractions of 5-8 Gy), GM-CSF 200 μg on days 3-7), sequential IL-2 (2 million IU on days 8-12), and a PD-1 inhibitor administered within one week after completing radiotherapy. This regimen was repeated every three weeks. The primary endpoint was the objective response rate (ORR). Results: As of the cutoff date (December 31, 2024), 52 patients were enrolled, including 10 with gynecological cancers, 10 with pancreatic cancer, and 32 with various other tumor types (including breast, gastric and colorectal cancers). All participants had evaluable data. According to RECIST 1.1, the overall ORR was 36.5%, with two patients achieving a complete response (CR) that lasted nearly two years, maintaining minimal residual disease negative status. The ORRs for patients with HER2 expression of 1+, 2+, and 3+ were 29.0%, 43.4%, and 60.0%, respectively. The median progression-free survival (PFS) for all patients was 5.9 months (95% CI: 4.1–9.7 months). The median overall survival (OS) for all patients was 14.3 months (95% CI: 8.6–15.7 months).Treatment-related adverse events were predominantly mild (grade 2 or lower), including fatigue, hair loss, nausea, fever, and rash. Only three patients (5.8%) experienced grade 3 adverse events. Conclusions: The results indicate promising efficacy and manageable safety, with a favorable short-term tumor response rate. This suggests that the combination of RC48-ADC, radiotherapy, and immunotherapy could serve as an effective salvage therapy option for patients with HER2-expressing advanced solid tumors. The combination therapy appears to enhance the synergistic effects of radiotherapy and immunotherapy. Clinical trial information: NCT0511550 .