Saliby R. M., Machaalani M., Zhong C., Alves Costa Silva C., Labaki C., Saad E., ...Daha Fazla
JOURNAL OF CLINICAL ONCOLOGY, cilt.43, sa.16_suppl, ss.1, 2025 (SCI-Expanded, Scopus)
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Yayın Türü:
Makale / Tam Makale
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Cilt numarası:
43
Sayı:
16_suppl
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Basım Tarihi:
2025
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Doi Numarası:
10.1200/jco.2025.43.16_suppl.4512
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Dergi Adı:
JOURNAL OF CLINICAL ONCOLOGY
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Derginin Tarandığı İndeksler:
Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, CAB Abstracts, CINAHL, Gender Studies Database, International Pharmaceutical Abstracts, Veterinary Science Database, Nature Index
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Sayfa Sayıları:
ss.1
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Ankara Üniversitesi Adresli:
Evet
Özet
4512
Background:
The gut microbiota modulates anti-cancer immune response and therefore benefit to immune checkpoint inhibitors (ICIs). Gut dysbiosis impacts the MadCAM-1/α4β7 axis leading to recirculation of immunosuppressive α4β7+Tr17 cells into tumors. From mechanistic insight to biomarker development, soluble MAdCMA-1 (sMAdCAM-1) is a circulating surrogate marker of gut dysbiosis. We aim to develop sMAdCAM-1 as a prognostic biomarker to ICI-based therapy in patients (pts) with mRCC.
Methods:
Using a Luminex assay, sMAdCAM-1 levels were measured in available plasma samples at baseline from 612 pts (69% of the intent-to-treat population) from the phase III JAVELIN Renal 101 trial (NCT02684006), which compared avelumab + axitinib with sunitinib in previously untreated mRCC pts. sMAdCAM-1 was examined on the original, per 10^4-scaled, and log-transformed scales. Linear assumption was visually checked by deviance residual and restricted cubic splines (RCS) plots. Optimal cut-off value was established based on the maximum log-rank statistic. Cox regression models were used to assess associations with progression-free survival (PFS) and overall survival (OS). The discrimination of the fitted model was assessed by time-dependent AUC index.
Results:
Higher sMAdCAM-1 levels were associated with improved PFS (median: 13.9 [11.3 - 6.6] vs 8.4 [6.0 - 9.9] months) and OS rate (at 18 months: 84.2% [80.2 - 87.4] vs 68.1% [59.2 - 75.5]). These associations remained after adjusting for IMDC risk groups (Table 1). The optimal cutoff was 180 ng/ml (25% percentile) based on the OS outcome in the whole population. Residual and RCS plots further confirmed a non-linear relationship of sMAdCAM-1 levels with OS and PFS. Median follow up was 18.9 months. The prognostic model incorporating IMDC + sMAdCAM-1 demonstrated a significant improvement in the AUC at 18 months compared to IMDC alone (0.72 vs 0.68; p=0.01). These associations were independent of study arm.
Conclusions:
Higher sMAdCAM-1 is associated with improved outcomes to 1
st
line regimens in mRCC. sMAdCAM-1 may have an added prognostic value to IMDC. As a diagnostic test of gut dysbiosis, it might guide the selection of pts eligible to microbiota-modulating strategies. The validation in two independent datasets and multi-omics correlation (i.e. fecal metagenomics) are ongoing under an international collaboration network.
Association of MAdCam-1 with clinical outcomes using Cox regression model.
Parameters
PFS HR (95% CI)
OS HR (95% CI)
Favorable
Ref
Ref
Intermediate
1.77 (1.31- 2.39)
<0.001
3.01 (1.60 - 5.66)
<0.001
Poor
2.88 (1.99 - 4.17)
<0.001
7.91 (4.02 - 15.56)
<0.001
sMAdCAM-1(high vs low)
0.75 (0.59 - 0.96)
0.021
0.59 (0.41 - 0.85)
0.004