A prospective, multicenter, single-arm clinical trial of PD-1 inhibitors in combination with radiotherapy and GM-CSF, sequentially followed by IL-2 (PRaG 2.0) therapy in advanced refractory solid tumors.
Authors: Xing Pengfei , Yang Jiabao , Kong Yuehong , Xu Meiling , Wang Jian , Wang Jianshe , Ma Yifu , Zhang Liyuan 
Published: June 2022

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Background: It’s been widely recognized that T cells play an essential role in immunotherapy of malignant tumors. Notably, in our previous PRaG trial, we observed that T cell decreasing occurred in some patients with advanced refractory solid tumors during PD-1 inhibitor combined with stereotactic body radiation therapy (SBRT) / hypo-fractionated radiotherapy (HFRT) and granulocyte macrophage-colony stimulating factor (GM-CSF) treatment which might be one of the reasons for their poor efficacy. To further improve the efficacy of immunotherapy combined with radiotherapy, we optimized the PRaG regimen and added interleukin-2 (IL-2), which amplifies and activates T cells. We conducted PRaG 2.0 trial to further explore the effect of T cells on efficacy. Methods: Patients with advanced refractory solid tumors who lacked or were intolerant to the available standard of care were enrolled to receive PRaG 2.0 regimen. A treatment cycle consisted of SBRT or HFRT (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 (d1-7), and then sequentially followed by IL-2 2million IU SC once daily for 7 days(d8-14). 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 primary endpoint was Progression-Free Survival (PFS). This trial was registered at www.clinicaltrials.gov with identifier number NCT04892498. Results: With the cutoff date of 31 December 2021, a total of 34 patients were enrolled, in which 28 patients (82%) completed at least 1 tumor assessment with a median follow-up time of 5.5 months (95%CI: 4.4, 6.6). Median PFS and overall survival (OS) were currently not reached. The objective response rate (ORR) was 21.4%, and the disease control rate (DCR) was 71.4% by RECIST1.1. Compared to baseline, no significant decrease of T cells, including CD3+, CD4+, and CD8+ T cells, have been observed in 19 patients who completed ≥ 4 treatment cycles. Treatment-related adverse events (TRAE) occurred in 28 of 34 (82.4%) patients, Grade ≥ 3 TRAEs occurred in three patients (8.8%). TRAEs leading to treatment interruption occurred in three patients (8.8%). Conclusions: These preliminary results of PRaG 2.0 trial demonstrate that PD-1 inhibitors in combination with radiotherapy, GM-CSF, and IL-2 could potentially maintain the T cells and improve clinical outcomes in patients with advanced refractory solid tumors with acceptable toxicity. Clinical trial information: NCT04892498.