188 - RC48-ADC Combined with Radiotherapy and Immunotherapy as Salvage Therapy for Advanced Solid Tumors with HER2 Expression: A Multicenter, Phase II Trial

08:00am - 08:10am PT

Room 22/23

Presenter(s)

Meiling Xu, MD, PhD, RT - The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu

M. Xu Jr¹, Y. Kong², P. Xing³, J. Zhang⁴, X. Zhao¹, and L. Zhang⁵; ¹Center for Cancer Diagnosis and Treatment, The Second Af?liated Hospital of Soochow University, Suzhou, China, ²Center for Cancer Diagnosis and Treatment,The Second Affiliated Hospital of Soochow University, Suzhou, China, ³Department of Radiotherapy & Oncology, The Second Affiliated Hospital of Soochow University; Institute of Radiotherapy & Oncology, Soochow University; Suzhou Key Laboratory for Radiation Oncology, Suzhou, China, ⁴Center for Cancer Diagnosis and Treatment, The Second Affiliated Hospital of Soochow University, Suzhou, China, ⁵Center of PRaG therapy, The Second Affiliated Hospital of Soochow University, Suzhou, China

Purpose/Objective(s): Recent advancements in combined radiation and immunotherapy have shown substantial promise in clinical practice. Radiotherapy activates systemic immune responses by releasing tumor antigens, stimulating immune cell activation, and inducing pro-inflammatory cytokines, which in turn modify the immune microenvironment. Our research team has developed a prospective, hypofractionated radiation therapy combined with PD-1 inhibitors and GM-CSF based comprehensive treatment protocol, termed PRaG therapy. In this approach, the primary role of radiotherapy is not local tumor control, but rather the exposure of tumor antigens to enhance systemic immune responses. RC48-ADC, a HER2-targeted antibody-drug conjugate, selectively induces cytotoxic effects on HER2-positive tumor cells. By leveraging the spatial and physicochemical synergy between radiotherapy and RC48-ADC, we can enhance the tumor antigen exposure, further amplifying the efficacy of PRaG therapy. This strategy aims to improve outcomes for patients with advanced HER2-expressing tumors. We hypothesize that combining RC48 with PRaG therapy will yield better results for these patients.

Materials/Methods: This multicenter phase II trial enrolled patients with advanced HER2-expressing (IHC 1+, 2+, or 3+) solid tumors that had failed standard therapies or were intolerant to them. Participants received RC48-ADC (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 objective response rate (ORR).

Results:

As of the cutoff date (Dec 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 patients had evaluable data. According to RECIST 1.1, the overall ORR was 36.5%, with two patients achieving a complete response 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 PFS for all patients was 5.9 months (95% CI: 4.1–9.7 months). The median OS was 14.3 months (95% CI: 8.6–15.7 months). Treatment-related adverse events were generally mild (grade 2 or lower), including fatigue, hair loss, nausea, fever, and rash. Only three patients (5.8%) experienced grade 3 adverse events.

Conclusion:

The results suggest that the combination of RC48-ADC, radiotherapy, and immunotherapy offers promising efficacy and manageable safety, with a favorable short-term tumor response rate. This combination approach appears to enhance the synergistic effects of radiotherapy and immunotherapy, providing a potential effective salvage therapy for patients with HER2-expressing advanced solid tumors.