PD-1 Inhibitor Combined with Radiotherapy and GM-CSF with or not IL-2 (PRaG regimen) in Patients with Microsatellite Stable Metastatic Colorectal Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Immunotherapy has improved outcomes for metastatic colorectal cancer(mCRC) patients with MSI-H/dMMR but has not been effective in MSS/pMMR tumors, which comprise 95% of mCRC. Radiotherapy is able to stimulate tumor specific immune response and improve the efficacy of PD-1/PD-L1 inhibitors in metastatic cancers. The synergistic effects of radiotherapy and PD-1/PD-L1 inhibitors can be reinforced by adding cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2(IL-2). Our previous PRaG trial demonstrated that radiotherapy in combination with PD-1 inhibitors and GM-CSF could improve clinical response in patients with advanced refractory solid tumors, which was presented at the ASTRO congress 2021. We found that mCRC patients with MSS/pMMR could also benefit from the PRaG regimen. <h3>Materials/Methods</h3> Patients of mCRC with MSS/pMMR were collected from the PRaG trial and PRaG 2.0 trial. A treatment cycle consisted of radiotherapy (5 or 8 Gy × 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 14 days(d1-14), or GM-CSF 200μg (d1-7), and then sequentially followed by IL-2 200 million IU SC once daily for 7 days(d8-14). PRaG regimen was repeated every 21 days for at least 2 cycles until no appropriate lesions for irradiation or reached the tolerance dose. Pooled analysis of response rate (ORR), median progression-free survival (PFS), and treatment-related adverse events were calculated. The PRaG trial was registered in chictr.org.cn (No. ChiCTR1900020175) and the PRaG 2.0 trial was registered in clinicaltrials.gov (NCT04892498). <h3>Results</h3> With the cutoff date of 15 February 2022, a total of 12 mCRC patients with MSS/pMMR were enrolled. All of the patients completed at least 2 cycles of PRaG therapy and one evaluation. The median follow-up was 7.0 months (95%CI, 4.7, 9.3). The ORR was 25%, and the disease control rate (DCR) was 58.3%. The median PFS was 4.7 months (95%CI, 0.9 to 8.5). One patient got complete remission, with PFS over 18 months. Treatment-related adverse events (TRAE) occurred in 10 of 12 (83.3%) patients. One patient (8.3%) occurred Grade3 TRAE of renal insufficiency. <h3>Conclusion</h3> Our preliminary results suggest that the PRaG regimen could improve clinical outcomes in mCRC patients with MSS/pMMR with acceptable toxicity. Radiotherapy could have radiosensitization effect on immunotherapy of mCRC with MSS/pMMR.