Abstract 3827: Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer

Abstract Background: The oral vascular endothelial growth factor receptor (VEGFR) inhibitor fruquintinib, an innovative Chinese drug, has recently been approved by the U.S. Food and Drug Administration (FDA) for third-line treatment of metastatic colorectal cancer (mCRC) in adults. This study aims to investigate the efficacy and safety of radiotherapy (RT) combined with VEGFR-TKIs (such as fruquintinib) and PD-(L) 1 inhibitors in mCRC, and explore optimal sequence of RT with the systemic regimen. Methods: This retrospective study enrolled eligible patients with MSS/pMMR mCRC who had received RT in combination with anti-angiogenic drugs (Fruquintinib or Regorafenib) and immunotherapy (IT) between April 2018 and September 2023. Data on treatment response, progression-free survival (PFS), overall survival (OS), and adverse events were collected. Results: A total of 42 pts were analyzed. For Fru + IT + RT (n = 33) and Reg + IT + RT (n = 9), ORR were 21.2% (7/33) and 11.1% (1/9); DCR were 81.8% (27/33) and 88.9% (8/9), respectively. Median PFS were 6.4 mo and 5.0 mo (P=0.856) while median OS were 17.2 mo and 7.2 mo (P=0.578), respectively. In-depth analysis of Fru + IT + RT treated population, the PFS and OS of 3rd-line treatment were superior to later (≥ 4th) -line treatment (median: 6.7 vs 4.2 mo, P=0.02) and (median: 17.5 vs 8.9 mo, P=0.27), seemingly. Additionally, RT before initiation of Fru + IT demonstrated superior PFS compared to simultaneous/sequential RT with Fru + IT (median 7.1 vs 6.1 vs. 3.2 mo, p<0.001). Simultaneously, pts with interval time ≤1 month, received numerically benefit compared to interval time >1 month between RT and FRU+IT (mPFS: 6.2 vs. 3.8 mo, P=0.16; mOS: not reached vs. 7.65 mo, P=0.08). Further subgroup analysis revealed that men, age ≤56 years, ECOG PS score of 1, primary focal resection, recurrent metastatic disease, liver/pulmonary metastases, and metastatic involvement of organs ≥2, were more favorably treated with Fru for prolonged OS. Intriguingly, the 3rd-line treatment of Fru exhibited a tendency to prolong OS compared to Reg. Cox multivariate regression analysis suggested that the cycle of Fru/Reg combined with PD-1 inhibitor treatment was a common independent influencing factor for PFS and OS. Safety was consistent with previous reports, and the incidence of AE appeared to be lower in Fru + IT + RT than in Reg + IT + RT. Conclusion: In pts receiving RT of localized lesions, the addition of Fru combined with PD-1 inhibitor could prolong the pts' OS more than Reg plus PD-1 inhibitor. And radiotherapy sequential Fru + IT (interval time ≤1 mo) treatment is expected to be the optimal strategy for MSS/pMMR mCRC. Citation Format: Zhenyu Lin, Menglan Zhai, Tao Zhang. Optimizing the treatment schedule of radiotherapy combined with VEGFR-TKIs and PD-(L) 1 inhibitors in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3827.