PD-1 inhibitors combined with radiotherapy and GM-CSF, sequentially followed by IL-2 regimen in advanced refractory solid tumors: A prospective, multicenter clinical trial.

Abstract

2616 Background: Low frequency of durable responses in patients treated with immune checkpoint inhibitors demands for taking complementary strategies in order to boost immune responses against cancer. Our previous PRaG1.0 trial also demonstrated that PD-1 inhibitors in combination with radiotherapy and granulocyte macrophage-colony stimulating factor (GM-CSF) could improve clinical response in patients with advanced refractory solid tumors (ChiCTR1900026175). In an effort to further enhance efficacy, we conducted this PRaG2.0 trial (ClinicalTrials.gov: NCT04892498) and optimized the PRaG1.0 regimen by incorporating interleukin-2 (IL-2). Methods: The PRaG 2.0 regimen was administered to patients with advanced refractory solid tumors who lacked or were unable to tolerate standard-of-care treatments. A treatment cycle consisted of radiotherapy (5 or 8Gy×2-3f) delivered for one metastatic lesion, PD-1 inhibitor dosing within one week after completion of radiotherapy, GM-CSF 200μg subcutaneous (SC) injection once daily for 7 days, and then sequentially followed by IL-2 2million IU SC once daily for 7 days. PRaG 2.0 regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose of normal tissues. Patients who could not continue radiotherapy and had not yet developed progression disease (PD) allowed PD-1 inhibitors to be continued as maintenance therapy until PD or unacceptable toxicity but no more than one year. The endpoints were Progression-Free Survival (PFS), objective response rate (ORR) and overall survival (OS). Results: As of 31st October 2024, 66 patients were enrolled in the study. The median Progression-Free Survival (PFS) was 4.3 months, and the median overall survival (OS) was 10.3 months. The objective response rate (ORR) was 22.7%, and the disease control rate (DCR) was 56.1% according to RECIST version 1.1. Treatment-related adverse events (TRAE) experienced in 57 (86.4%) patients, with 6 patients (9.1%) experiencing Grade ≥ 3 TRAEs. We found that in the period prior to disease progression, the absolute count of Treg cells increased compared to baseline, while the percentage of CD8+PD-1+/CD8+ cells decreased compared to baseline. Conclusions: The PRaG 2.0 trial demonstrates that PD-1 inhibitors in combination with radiotherapy, GM-CSF, and IL-2 could be a potential treatment regimen for patients with advanced refractory solid tumors. The decrease in the CD8+PD-1+/CD8+% ratio and the increase in the absolute count of Treg cells may suggest potential tumor progression in patients. Clinical trial information: NCT04892498 .