A Phase II Trial of PD-1 Inhibitors Combined With Multisite Radiotherapy and GM-CSF (PRaG Regimen) for the Treatment of Chemo-Refractory Metastatic Solid Tumors

Abstract

Advanced cancer patients refractory to chemotherapy have a poor prognosis and few therapeutic options. Evidences have shown that radiotherapy can induce a systemic anti-tumor immune response, which may potentially sensitize PD-1 inhibitors. Immunomodulatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) may have a synergistic effect with radiotherapy or anti-PD-1 therapy. A phase Ⅱ trial was conducted to assess the clinical efficacy and safety of stereotactic body radiation therapy (SBRT) or hypofractionated radiotherapy (HFRT) combined with PD-1 inhibitor and GM-CSF (PRaG regimen) for the treatment of chemo-refractory solid tumor patients.Subjects with multi-metastatic solid tumors and progressed beyond at least first-line chemotherapy were enrolled. In a PRaG cycle, SBRT or HFRT (3 × 8 Gy or 3 × 5 Gy) was delivered for one metastatic site, GM-CSF 200 µg was subcutaneously injected daily for 2 weeks after radiotherapy, and sindilimab 200 mg or toripalimab 240 mg was intravenously administered once within one week after completion of SBRT or HFRT. PRaG was repeated every 21 days for at least 2 cycles. After discontinuation of PRaG and patient had no disease progression, sindilimab or toripalimab monotherapy was given until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS). This trial is registered in chictr.org.cn (No. ChiCTR 1900020175).By February 2021, a total of 48 patients were enrolled. Forty-three patients (89.6%) completed at least two cycles of the triple-combination therapy, and the remaining five patients received one cycle of the triple therapy and continued treatment. Treatment-related adverse events (TRAE)of any grade occurred in 35 (72.9%) patients. The common adverse events were fatigue 52.1%, anorexia 47.9%, thyroid dysfunction 29.2%, liver dysfunction 18.8% and rash 14.6%. Two patients (4.2%) experienced Gr3 and higher TRAE. Both patients had lung lesions irradiated during PRaG and one patient experienced Gr3 pneumonia and another patient experienced Gr4 pneumonitis. Forty-one patients completed at least one efficacy evaluation, seven patients had confirmed partial response (PR), and the objective response rate (ORR) was 14.6% (RECIST 1.1). The median PFS was 5.2 months (95% CI, 4.3-6.1).The PRaG regimen is well tolerated with acceptable toxicity. Our data suggest that SBRT or HFRT can sensitize the anti-tumor effects of anti-PD-1 therapy and produce a great synergistic efficacy. The PRaG regimen could contribute to a promising salvage treatment for patients with chemotherapy-refractory metastatic solid tumor.