Prof.  Ruihua  Zhao
The First Affiliated Hospital of Zhengzhou Universit y,  China

Title: The Efficacy Comparison of Fruquintinib, Regorafenib Monotherapy or Combination with PD-1 Inhibitors in the Treatment of Microsatellite Stable Metastatic Colorectal Cancer

Abstract:

Background: Regorafenib and fruquintinib are the standard third-line regimens for colorectal cancer (CRC) according to the NCCN guideline, but both of them have limited efficacy. Several phase 2 trials have indicated that regorafenib or fruquintinib combined with immune checkpoint inhibitors (ICIs) can reverse the immunosuppressive and achieve promising efficacy for microsatellite stable or proficient mismatch repair (MSS/pMMR) CRC. However, due to the lack of studies comparing the efficacy among fruquintinib (F), regorafenib (R), fruquintinib plus PD-1 inhibitors (FP), and regorafenib plus PD-1 inhibitors (RP), it is still unknown whether the combination therapy is more effective than monotherapy, and which of the four regimens has the best efficacy remain uncertain. Methods: A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital, and 313 MSS/pMMR metastatic CRC (mCRC) patients were finally included. Results: 313 eligible patients were divided into F (n=70), R (n=67), FP (n=95) and RP (n=81) groups. The key clinical characteristics were well-balanced among groups. The median PFS of the F, R, FP, and RP groups were 3.5 (95%CI, 2.9-4.1) months, 3.6 (95%CI, 2.5-4.7) months, 4.9 (95%CI, 3.0-6.8) months, and 3.0 (95%CI, 2.0-4.1) months. The median OS was 14.6 (95%CI, 7.3-21.9) months, 15.7 (95%CI, 9.8-21.6) months, 16.7 (95%CI, 11.1-22.3) months, 14.1 (95%CI, 8.9-19.3) months. FP regimen had an improved DCR (P =0.044), 6-month PFS (P =0.014) and exhibited a better trend in PFS (P =0.057) compared with F, and it was also significantly better in PFS than RP (P= 0.030). RP did not confer a significant survival benefit, instead, the R group had a trend towards greater benefit with OS (P =0.080) compared with RP. No significant differences were observed between the R and F group whether in PFS or OS (P >0.05). Conclusions: FP is superior to F in achieving 6-month PFS and DCR, while RP is not better than R. FP has an improved PFS and 6-month PFS compared with RP, but F and R had a similar clinical efficacy. Therefore, FP is a highly promising strategy in the treatment of MSS/pMMR mCRC.

Biography:

Basic research: In recent years, I have been committed to the research of the expression, function and mechanism of non-coding RNAs such as long-chain non-coding RNA (LncRNA) and microRNA (miRNA) in malignant tumors. So far, I have achieved the following results: 1. It was found that the expression levels of MALAT1, BC200 and H19 in esophageal squamous cell carcinoma tissues were significantly higher than those in adjacent tissues, and the postoperative disease-free survival (DFS) and overall survival (OS) of patients with high expression of MALAT1, BC200 and H19 were significantly shortened, suggesting that the expression levels of MALAT1, BC200 and H19 can be used as prognostic predictors for patients with esophageal squamous cell carcinoma who received radical surgery, and further confirmed LncRNA BC200 Promotes Esophageal Squamous Cell Cancer Migration and Invasion and Can Regulate ATF4 Expression. 2. We found that the plasma expression level of miR-221 in breast cancer patients was significantly higher compared to that of healthy volunteers, and those with high miR-221 expression tended to exhibit negative hormone receptor (HR) expression. Additionally, patients with high miR-221 expression demonstrated increased tolerance towards chemotherapy. Furthermore, the levels of miR-221, HR status, HER2 status, and Topo II expression were identified as independent predictors for chemotherapy drug response. These findings suggest that the expression level of miR-221 could serve as a predictive marker for resistance to neoadjuvant chemotherapy primarily consisting of taxanes and anthracyclines. 3. We confirmed that miR98 promotes invasion and metastasis in breast cancer cells,. Our study also revealed that CCL18, an important component within the breast cancer microenvironment, can down-regulate the expression of miR98 through the N-Ras/c-myc/lin28 pathway. Consequently, this down-regulated state leads to increased N-Ras protein expression via post-transcriptional regulation which subsequently activates the c-myc/lin28 pathway- thereby maintaining continuous reduction in miR98 levels and forming a positive feedback loop. 4. Low expression levels of miR-34b were found to be indicative of poor prognosis among osteosarcoma patients; this observation was further validated through in vitro experiments where sirolimus was shown to interact with PAK1 and ABCB1 by up-regulating miR-34b. As a result, sensitivity towards anti-cancer drugs improved while multidrug resistance reversed in osteosarcoma cells. 5 We synthesised Novel Pt(IV) complexes to overcome multidrug resistance in gastric cancer by targeting P-glycoprotein and Novel indole–chalcone platinum(IV) complexes as tubulin polymerization inhibitors to overcome oxaliplatin resistance in colorectal cancer.

Clinical studies: As a member of the multidisciplinary team specializing in digestive tract tumors and breast cancer at our hospital, I have actively participated in numerous national speech contests and MDT competitions and achieving outstanding results. Additionally, I have been involved in several sponsored clinical studies initiated by researchers. Notably, our team's clinical study on the combination of anlotinib with sintilimab as second-line treatment for advanced biliary tract cancers has received commendation from CSCO biliary system guidelines. Currently, I am leading two ongoing clinical studies: (1) An open-label, single-center phase II clinical study evaluating the efficacy of Surufatinib combined with Chidamide and fFulvestrant for unresectable/metastatic HR-positive breast cancer; (2) An exploratory clinical study investigating short-term radiotherapy followed by sequential administration of sintilimab, anlotinib combined with XELOX neoadjuvant treatment for locally advanced MSS/pMMR rectal cancer.