In CheckMate 9ER trial (NCT03141177) NIVO+CABO demonstrated superior PFS, OS, and ORR versus SUN in patients with previously untreated aRCC, however not all patients experience a sustained response. Therefore, there is need to identify patients who are most likely to benefit from NIVO+CABO treatment, as predictive biomarkers are currently lacking in aRCC. The post-translational modification of proteins with carbohydrate groups plays an important role in regulating immune responses. Therefore, we investigated the protein glycosylation as predictive and prognostic biomarkers of response to NIVO+CABO or SUN in aRCC using a novel, liquid biopsy-based glycoproteomic platform.
Methods
Serum samples collected from 189 aRCC patients treated with NIVO+CABO or SUN from CheckMate 9ER were tested using InterVenn GlycoVision™ platform, that combines high resolution mass spectrometry with artificial intelligence (AI) and advanced machine learning (ML). Validation was performed on an additional 93 aRCC patient samples from the same study.
Results
We identified 24 glycopeptides that showed association with PFS or OS in the NIVO+CABO arm, while 64 glycopeptides showed association with PFS or OS in the SUNI arm. Subjects with higher number of glucosyl modifications including fucosylation and sialylation had worse PFS and/or OS following treatment with NIVO+CABO and SUN indicating their potential prognostic value (q-value: <0.05). Glycoproteins involved in complement cascade (complement factor H, complement component 3) and lipid metabolism (apolipoprotein C3, apolipoprotein D, and zinc-alpha-2-glycoprotein) were predictive of PFS response to NIVO+CABO vs SUN in Cox regression analysis (p-value: <0.01). Among patients within the high serum levels of complement protein 3 glycan at baseline, there was improved PFS with NIVO+CABO vs SUN HR=0.32 (0.14-0.69, p-value:0.0025).
Conclusions
Our results indicate potential role for protein fucsosylation and sialylation mechanisms in driving resistance to NIVO+CABO and SUN in aRCC. Serum glycoproteins involved in complement cascade and lipid metabolism were predictive of response to NIVO+CABO vs SUN in aRCC.
Clinical trial identification
NCT03141177.