An exploratory post-hoc analysis of the phase 3 CheckMate-9ER study (NCT03141177) has identified potential biomarkers that may predict the efficacy of nivolumab (Opdivo) plus cabozantinib (Cabometyx) in patients with advanced renal cell carcinoma (RCC). The findings, presented at the 2024 ESMO Congress, suggest that the degree of fucosylation and sialylation of serum proteins could serve as negative prognostic factors, while specific serum glycoproteins involved in complement cascade and lipid metabolism may predict response to the doublet therapy versus sunitinib (Sutent).
David A. Braun, MD, PhD, from Yale School of Medicine, highlighted that while anti-PD-1-based therapy is standard for first-line RCC, effective biomarkers to predict patient response are lacking. The study explored post-translational modifications of proteins, particularly glycosylation, as a potential avenue for biomarker discovery.
Glycoproteomic Analysis Details
The researchers leveraged pre-treatment serum samples from CheckMate-9ER participants and used the InterVenn GlycoVision platform for glycoproteomic analysis. This analysis aimed to determine if altered protein glycosylation could serve as a biomarker in RCC. The analysis identified 24 serum glycopeptides linked with progression-free survival (PFS) or overall survival (OS) with the nivolumab plus cabozantinib combination.
The study revealed coordinated modules of altered protein glycosylation associated with PFS and OS. Specifically, higher amounts of protein glycosylation, including sialylation and fucosylation, correlated with worse PFS and OS in both the nivolumab plus cabozantinib and sunitinib arms, suggesting a potential prognostic role.
Predictive Markers for Combination Therapy
Further analysis indicated that proteins involved in lipid metabolism and members of the complement cascade could predict response to the nivolumab plus cabozantinib doublet versus sunitinib monotherapy. High serum levels of CO3 glycopeptide potentially predicted a favorable response to the combination therapy, suggesting complement-induced antitumor activity. Conversely, low serum levels of CFAH glycopeptide, a negative regulator of alternate complement activity, also indicated substantial benefit with the combination.
CheckMate-9ER Trial Background
CheckMate-9ER enrolled patients with previously untreated advanced RCC with a clear cell component, irrespective of their International mRCC Database Consortium (IMDC) risk score. Patients were randomized 1:1 to receive either 240 mg of intravenous nivolumab every 2 weeks combined with 40 mg of oral cabozantinib once daily, or 50 mg of oral sunitinib on a 4-weeks-on/2-weeks-off cycle. The primary endpoint was PFS, with secondary endpoints including OS and objective response rate (ORR).
In January 2021, the FDA approved nivolumab plus cabozantinib for first-line treatment of advanced RCC based on CheckMate-9ER data. Follow-up data presented at the 2024 Genitourinary Cancers Symposium demonstrated continued improvements in PFS, OS, and ORR with the combination compared to sunitinib. The median PFS was 16.4 months with the doublet versus 8.4 months with sunitinib (HR, 0.58; 95% CI, 0.49-0.70), and the median OS was 46.5 months versus 36.0 months (HR, 0.77; 95% CI, 0.63-0.95). The ORR was 55.7% with the combination versus 27.7% with sunitinib.
Implications and Future Directions
Dr. Braun concluded that the prognostic and predictive potential of these glycopeptide biomarkers warrants further investigation in additional clinical trials. These findings offer a potential avenue for developing more effective biomarkers to personalize treatment strategies in advanced RCC and improve patient outcomes.
