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The efficacy and safety of regorafenib/fruquintinib combined with PD-1/PD-L1 for metastatic colorectal cancer: a
Fan Yang1,2, Ying Mao2, Hanyu Huang1
1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China.
Objective:
The efficacy of regorafenib or fruquintinib in combination with PD-1/PD-L1 inhibitors for metastatic colorectal cancer (mCRC) treatment has not been elucidated. This study aims to systematically evaluate the efficacy and safety of this combination therapy.
Methods:
PubMed, Embase, Cochrane Library, and Web of Science were systematically retrieved until July 24, 2024. A meta-analysis was carried out for the overall objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the incidence of grade 3 or higher treatment-related adverse events (AEs). Non-overlapping 95% confidence intervals (CIs) were considered statistically significant.
Results:
26 studies encompassing 1,409 patients were analyzed. Pooled analysis revealed an ORR of 6% (95% CI: 3%-12%), a DCR of 62% (95% CI: 55%-68%), a median PFS of 3.84 months (95% CI: 3.19-4.49 months), a median OS of 13.08 months (95% CI: 10.17-16.00 months), and an incidence rate of grade 3-4 AEs of 21% (95% CI: 15%-28%). In subgroup analyses, the fruquintinib-based regimen demonstrated significantly superior efficacy compared to regorafenib-based therapy, with higher ORR (16% [95% CI: 13%-21%] vs 3% [95% CI: 1%-9%]), DCR (79% [95% CI: 72%-85%] vs 54% [95% CI: 47%-61%]), and median PFS (5.40 months [95% CI: 4.60-6.19] vs 3.00 months [95% CI: 2.47-3.52]). Median OS was numerically but not significantly longer with fruquintinib (14.35 months [95% CI: 10.68-18.02] vs 12.70 months [95% CI: 8.79-16.61]). Liver metastasis status strongly influenced outcomes, with significantly lower ORR (3% [95% CI: 1%-13%] vs 49% [95% CI: 32%-76%]) and shorter median PFS (2.37 months [95% CI: 1.77-2.96] vs 3.50 months [95% CI: 3.09-3.91]) in patients with liver involvement.
Conclusion:
The combination of regorafenib or fruquintinib with PD-1/PD-L1 shows moderate efficacy and acceptable safety in the treatment of mCRC. The fruquintinib-based regimen may be superior to the regorafenib-based regimen, and patients without liver metastasis may derive greater benefits. These findings offer new insights for treating mCRC, although they should be validated through large randomized controlled trials.
Systematic Review Registration:
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42024582268.
Insights
Combining regorafenib or fruquintinib with PD-1/PD-L1 inhibitors shows moderate efficacy for metastatic colorectal cancer (mCRC). Fruquintinib-based regimens appear superior, and patients without liver metastasis benefit most.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Metastatic colorectal cancer (mCRC) remains a significant challenge.
- The combination of targeted therapies like regorafenib or fruquintinib with immune checkpoint inhibitors (PD-1/PD-L1) is an emerging strategy.
- Efficacy and safety data for these specific combinations in mCRC are limited.
Purpose of the Study:
- To systematically evaluate the efficacy and safety of combining regorafenib or fruquintinib with PD-1/PD-L1 inhibitors in mCRC.
- To compare the outcomes between regorafenib-based and fruquintinib-based combination regimens.
- To identify patient subgroups that may benefit most from this combination therapy.
Main Methods:
- A systematic literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science.
- Meta-analysis was performed on data from 26 studies including 1,409 patients.
- Key endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs).
Main Results:
- The overall pooled analysis showed a 6% ORR, 62% DCR, median PFS of 3.84 months, median OS of 13.08 months, and 21% grade 3-4 AEs.
- Fruquintinib-based regimens demonstrated superior efficacy (ORR 16%, DCR 79%, PFS 5.40 months) compared to regorafenib-based regimens (ORR 3%, DCR 54%, PFS 3.00 months).
- Patients without liver metastasis showed significantly better outcomes (higher ORR, longer PFS) than those with liver involvement.
Conclusions:
- Regorafenib or fruquintinib in combination with PD-1/PD-L1 inhibitors offers moderate efficacy and acceptable safety for mCRC.
- Fruquintinib-based combinations may be more effective than regorafenib-based ones.
- Further validation through large randomized controlled trials is warranted, especially considering the impact of liver metastasis.
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