PD-1 Inhibitor Combined with Radiotherapy and GM-CSF with or not IL-2 (PRaG Regimen) for Advanced Metastatic Non-Small Cell Lung Cancer

Abstract

<h3>Purpose/Objective(s)</h3> PD-1/PD-L1 immunotherapy has greatly changed the treatment paradigm of lung cancer and has made good progress in the treatment of lung cancer with high PD-L1 expression. However, there are limited therapeutic options for patients after failure of standard therapy or after failure of immunotherapy. And there has been evidence of possible synergistic effects of radiotherapy combined with PD-1 inhibitors or GM-CSF. This study retrospectively analyzed the clinical efficacy and safety of PD-1 inhibitors in combination with large split radiotherapy and GM-CSF in combination with IL-2 (PRaG2.0 regimen) or without IL-2 (PRaG1.0 regimen) for patients with advanced metastatic lung cancer. <h3>Materials/Methods</h3> A combined analysis of non-small cell lung cancer enrolled in PRaG 1.0 and 2.0 was performed in patients with definite recurrent metastatic advanced lung cancer that had progressed using guideline-recommended first- and second-line systemic therapy and had measurable metastatic lesions (>1 cm), allowing enrollment of patients who had previously failed with PD-1 inhibitors. The treatment modality was PRaG regimen triple therapy with large fractionated radiotherapy (planned dose of PTV 24Gy/8Gy/3f) for one metastatic lesion, subcutaneous GM-CSF 200ug for fourteen consecutive days 24 hours after the end of radiotherapy or subcutaneous GM-CSF 200ug for seven consecutive days sequential IL-2 2million IU for seven consecutive days, administered within 1 week after the end of radiotherapy with PD-1 inhibitor for 21 days for one cycle and triple therapy for 2 or more consecutive cycles. This was followed by maintenance treatment with PD-1 inhibitors until disease progression or intolerable toxicity. Assessment was performed using RECIST1.1 criteria. Toxic reactions were observed and recorded according to CTC4.0 criteria. <h3>Results</h3> From 03/2019 to 12/2021, 14 patients were effectively enrolled in this study. The objective remission rate was ORR:14.3% (2/14), disease control rate was 50% (7/14), median disease-free survival was:4.33 months 95%CI (2.251-6.409 months), median overall survival was:10.47 months 95%CI (8.088-12.852 months). Eight patients (57.1%) experienced treatment-related adverse reactions, with no patient experiencing grade 3 or higher adverse reactions. One patient who had failed previous immunotherapy achieved CR, and another patient with PD-L1 CPS 0 achieved PR. <h3>Conclusion</h3> The treatment model of large split radiotherapy and PD-1 inhibitor and GM-CSF combined with or without IL-2 (PRaG treatment) was tolerable in terms of toxic side effects, and better clinical efficacy was observed. The Bragg treatment modality is expected to be a salvage treatment for patients with refractory advanced metastatic non-small cell lung cancer after failure of standard therapy and is expected to be a re-challenge regimen after failure of PD-1/PD-L1 inhibitor therapy.