A post-hoc analysis of the phase 3 CheckMate-9ER study (NCT03141177) has identified potential serum glycoproteomic biomarkers that may predict response to nivolumab (Opdivo) plus cabozantinib (Cabometyx) versus sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC). The findings, presented at the 2024 ESMO Congress, suggest that the amount of glycosylation, specifically sialylation of serum proteins, is crucial, with higher levels associated with worse clinical outcomes.
Glycosylation and Clinical Outcomes
The study found that increased glycosylation, sialylation, and fucosylation were linked to poorer progression-free survival (PFS) and overall survival (OS) in patients treated with either nivolumab plus cabozantinib or sunitinib monotherapy. This indicates that the overall level of protein glycosylation might serve as a prognostic indicator for tumor aggressiveness in advanced RCC.
Predictive Glycopeptides
Importantly, the analysis identified specific glycopeptides related to lipid metabolism and the complement cascade that could potentially distinguish response to nivolumab plus cabozantinib versus sunitinib. Notably, CO3 and CFAH, involved in the complement cascade, showed altered levels that correlated with differential responses to the two treatment regimens.
According to Dr. David A. Braun, MD, PhD, assistant professor of medicine at Yale School of Medicine and lead author of the study, these findings offer a promising avenue for identifying patients likely to benefit from nivolumab plus cabozantinib. "Despite the clinical importance of nivolumab plus cabozantinib as a standard of care, we still don't have good tools to distinguish which patients are likely to respond and which patients, unfortunately, have resistant tumors. That's where the idea of effective biomarkers comes along."
Biological Significance of Glycosylation
Altered protein glycosylation is recognized as a hallmark of cancer, influencing various malignant processes, including immune modulation. High levels of sialylation, for instance, can lead to immune suppression and potential resistance to PD-1 blockade. This underscores the importance of investigating glycosylation patterns in the context of immunotherapy response.
Next Steps
Dr. Braun emphasized the need for validation in independent cohorts to confirm the predictive value of these glycoproteomic biomarkers. "We have some interesting hypothesis-generating findings, but the next step is to validate. In other cohorts with similar types of treatment, [we need to be able to] say, ‘[These data] are not just a one-off. This is something where we can consistently see specific glycopeptides that are altered and prognostic or potentially predictive of response in IO-based therapy.’"
Further research will focus on elucidating the biological mechanisms through which altered protein glycosylation impacts treatment outcomes and exploring potential strategies to modify glycosylation and improve therapeutic efficacy.
