A Phase Ⅱ Trial of Multisite Stereotactic Radiation Therapy (SRT) or Stereotactic Body Radiation Therapy (SBRT) with PD-1 Inhibitor and GM-CSF for the Treatment of Chemo-Refractory Metastatic Solid Tumors

Abstract

Although accumulated evidences have demonstrated the patients with some types of tumors benefit from anti-programmed death-1 (PD-1) monoclonal antibody, the possible synergistic effect of combination of PD-1 inhibitor and radiotherapy still needs to be explored. A phase Ⅱ trial was conducted to assess the clinical efficacy and safety of multisite stereotactic radiation therapy (SRT) or stereotactic body radiation therapy (SBRT) combined with PD-1 inhibitor and GM-CSF for the treatment of chemo-refractory patients. Participants had multi-metastatic solid tumors progressing beyond at least first-line chemotherapy. They were treated with SRT/SBRT (3 doses of 8Gy) for one metastatic site. On the second day after radiotherapy, PD-1 inhibitor 200 mg once was intravenously administered and GM-CSF 200 μg daily was subcutaneously injected for 2 weeks. This course was repeated every 3 weeks, targeting a second metastatic site. Triple-combination therapy was given for at least 2 cycles. After the combination therapy, maintenance with PD-1 inhibitor was administered until disease progression or unacceptable toxicity. The primary end points included safety, toxicity, progression-free survival (PFS) and overall survival (OS). A total of 15 patients were enrolled. The median number of metastatic lesions was 8(95%CI, 5.5 to 20.5) and the median sum of the longest diameter of all measurable lesions was 158.0mm (95%CI, 98.9 to 287.3mm). All patients completed two cycles or more of the triple-combination therapy. Some remarkable tumor regression was observed at both the irradiated focus and distant metastatic sites at the time of evaluation. The median PFS was 3.3 months (95%CI, 2.3 to 7.2months). Treatment-related adverse events of any grade occurred in 13 (86%) patients, and grade 3 and higher adverse event like pneumonitis occurred in 2 (13.0%) patients. A combined therapy consisting of SRT/SBRT, GM-CSF and PD-1 inhibitor is well tolerated. With the new chemo-free regimen, myelosuppression hasn’t been detected and gastrointestinal side effects remained low. Our data suggest triple-radioimmunotherapy could result in greater synergistic efficacy. They are considered as a new treatment option for patients with chemotherapy- refractory metastatic solid tumors.