Serum glycoproteins may predict response to nivolumab/cabozantinib in aRCC
On Cox regression analysis, glycoproteins were predictive of PFS response to nivolumab plus cabozantinib vs sunitinib (P < .01).
Serum glycoproteins involved in complement cascade and lipid metabolism may serve as potential biomarkers that are predictive of response to nivolumab (Opdivo) plus cabozantinib (Cabometyx) vs sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC), according to a post-hoc exploratory analysis of the CheckMate 9ER trial (NCT03141177) presented at the 2024 European Society for Medical Oncology Congress in Barcelona, Spain.1
David A. Braun, MD, PhD
In CheckMate 9ER, the combination of nivolumab and cabozantinib demonstrated superior progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs sunitinib in patients with advanced RCC.2 The trial included 651 patients with previously untreated advanced RCC with a clear cell component with a median follow-up of 55.6 months.
“The CheckMate 9ER trial showed the benefit of nivolumab plus cabozantinib over sunitinib for advanced RCC. While anti–PD-1 based therapy is the standard for first-line RCC, we still lack effective biomarkers to figure out which patients are likely to respond and which tumors are likely to be resistant to therapy,” explained presenting author David A. Braun, MD, at the ESMO Congress. Braun is an assistant professor of medicine (medical oncology) and of pathology and urology at Yale School of Medicine in New Haven, Connecticut.
For the study, the investigators tested serum samples from 189 patients with advanced RCC who were enrolled in CheckMate 9ER. Samples were tested with the InterVenn GlycoVision platform, which “combines high-resolution mass spectrometry with artificial intelligence (AI) and advanced machine learning,” according to the authors. Validation was conducted with additional samples from 93 patients with advanced RCC in the trial.
The investigators were able to identify 24 serum glycopeptides that showed an association with altered PFS or OS in patients who were treated with nivolumab plus cabozantinib. Additionally, 64 glycopeptides were shown to be associated with PFS or OS in patients treated with sunitinib.
Patients who had a higher number of glucosyl modifications––including fucosylation and sialylation, 2 forms of protein glycosylation––demonstrated a higher hazard ratio, and therefore worse PFS and/or OS following treatment with nivolumab plus cabozantinib and sunitinib. According to the authors, this finding indicates the potential prognostic value (q-value, < .05) of protein glycosylation for treatment response.
The investigators then sought to assess whether altered protein glycosylation could be predictive of response to treatment. On Cox regression analysis, glycoproteins involved in complement cascade (complement protein 3 [CO3], complement factor H [CFAH]) and lipid metabolism (apolipoprotein C3, apolipoprotein D, and zinc-alpha-2-glycoprotein) were predictive of PFS response to nivolumab plus cabozantinib vs sunitinib (P < .01).
Specifically, high levels of CO3 glycopeptide at baseline was associated with improved PFS with nivolumab plus cabozantinib vs sunitinib (HR, 0.32; CI, 0.14-0.69; P = .0025), whereas low levels showed no difference in PFS (P = .67). According to the authors, this may be due to pro-inflammatory signaling mediated by CO3.
Conversely, low serum levels of CFAH glycopeptide were associated with favorable response to nivolumab plus cabozantinib vs sunitinib (P = .0012), whereas high levels showed no difference in PFS (P = .97). The authors suggest that this may be because CFAH is a negative regulator of alternative complement activity, so when it’s low, the immune therapy is able to act.
Braun concluded in the presentation, “We see that higher amount of protein glycosylation, both sialylation and fucosylation, appear to be prognostic in this dataset, and that specific protein glycosylation events related to lipid metabolism [and] also related to the complement cascade have the potential to be predictive of response in anti–PD-1 based therapy, as opposed to sunitinib. But I want to highlight that this is really early exploratory work. I think the main question is, is this an area for further investigation in biomarker development in RCC? And I think the answer that is ‘yes.’ "
References
1. Braun DA, Wang Y, Yu A, et al. Novel serum glycoproteomic biomarkers predict response to nivolumab plus cabozantinib (NIVO+CABO) versus sunitinib (SUN) in advanced RCC (aRCC): Analysis from CheckMate 9ER. Presented at: 2024 European Society for Medical Oncology Congress. September 13-17, 2024. Barcelona, Spain Abstract 1694MO. https://esmocongress.esmo.org/esmo/esmo2024/en-GB/presentation/644700
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829-841. doi:10.1056/NEJMoa2026982
