CheckMate-9ER Post-Hoc Analysis Seeks to Identify Efficacy Biomarkers for Nivolumab/Cabozantinib in RCC

David A. Braun, MD, PhD

A higher degree fucosylation and sialylation of serum proteins represent negative prognostic factors in advanced renal cell carcinoma (RCC) as they have been linked with worse clinical outcomes for nivolumab (Opdivo) plus cabozantinib (Cabometyx) and sunitinib (Sutent), according to findings from an exploratory post-hoc analysis of the phase 3 CheckMate-9ER study (NCT03141177).¹

The data, which were shared during the 2024 ESMO Congress, also suggested that serum glycoproteins involved in complement cascade and lipid metabolism could be predictive of response to the doublet vs sunitinib in this disease, according to David A. Braun, MD, PhD, assistant professor of medicine (Medical Oncology) and Louis Goodman and Alfred Gilman Yale Scholar at Yale School of Medicine, in New Haven, Connecticut. Specifically, high serum levels of CO3 glycopeptide are potentially predictive of favorable response to the nivolumab plus cabozantinib vs sunitinib, as are low serum levels of CFAH glycopeptide.

“We see that higher amounts of protein glycosylation, both sialylation and fucosylation, appear to be prognostic in this data set, and that specific protein glycosylation events related to lipid metabolism, but also related to the complement cascade, have the potential to [possibly] be predictive of response in anti–PD-1-based therapy, as opposed to sunitinib,” Braun said in a presentation of the data. “But I want to highlight this is really early exploratory work. I [believe] the main question is, is this an area for further investigation in biomarker development in RCC? And I [believe] the answer to that is, yes.”

CheckMate-9ER enrolled patients with previously untreated advanced RCC with a clear cell component. They could have disease of any risk by International mRCC Database Consortium (IMDC) criteria, but they needed to have tumor tissue available for analysis.

Patients were randomly assigned 1:1 to receive 240 mg of intravenous (IV) nivolumab every 2 weeks paired with 40 mg of oral cabozantinib once daily vs 50 mg of oral sunitinib on a cycle of 4-weeks-on/2-weeks-off. Treatment continued until disease progression by RECIST v1.1 criteria or intolerable toxicity. Stratification factors included IMDC risk score, tumor PD-L1 expression, and geographic region.

The primary end point of the study was progression-free survival (PFS) by blinded independent review committee (BICR) and RECIST 1.1 criteria. Secondary end points included overall survival (OS), objective response rate (ORR) by BICR and RECIST 1.1 criteria, as well as safety. Health-related quality of life served as an important exploratory end point.

In January 2021, the FDA approved nivolumab plus cabozantinib for the first-line treatment of patients with advanced RCC based on earlier data from CheckMate-9ER.² Data from the 55-month follow-up of the study shared during the 2024 Genitourinary Cancers Symposium showed that nivolumab plus cabozantinib continues to provide a meaningful improvement over sunitinib in PFS, OS, and ORR.³ In the intention-to-treat population, the PFS by BICR was 16.4 months (95% CI, 12.5-19.3) with the doublet vs 8.4 months (95% CI, 7.0-9.7) with sunitinib (HR, 0.58; 95% CI, 0.49-0.70). The median OS with nivolumab plus cabozantinib was 46.5 months (95% CI, 40.6-53.4) vs 36.0 months (95% CI, 29.2-42.8) with sunitinib (HR, 0.77; 95% CI, 0.63-0.95). The ORR by BICR was 55.7% with the doublet vs 27.7% with sunitinib.

“[Although] anti–PD-1–based therapy is really 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. Our group, and many others, have focused largely on the genomics and transcriptomics of the tumor itself, but we know that post-translational modifications of proteins themselves play an important role in those proteins’ function,” Braun said. “In fact, glycosylation of protein, altered glycosylation, is a hallmark of cancer and involved in many malignant processes. Hypersialylation in particular, engages sialic acid-binding immunoglobulin-like lectin receptors and is known to be immunomodulatory, potentially raising the idea that it could contribute to anti–PD-1 resistance.”

For the post-hoc analysis, Braun and colleagues evaluated the link between site-specific glycopeptide modifications with nivolumab plus cabozantinib/sunitinib response in patients with advanced RCC by leveraging pre-treatment serum samples. They used the InterVenn GlycoVision platform to conduct a glycoproteomic analysis, to understand if altered protein glycosylation is a possible avenue for biomarker studies in RCC. They identified 24 serum glycopeptides that were linked with PFS or OS with the doublet.

“The first question is, how are these regulated? Are they regulated in a coordinated fashion or not? We looked across patients for site-specific protein glycosylation, […and what] we can see is highly coordinated modules of altered protein glycosylation, [with] red piercing correlations across patients for these different site-specific glycosylations,” Braun said. “Now, in our initial study and our initial look at these particular proteins, we can see that these coordinated modules seem to be associated with altered PFS and OS with nivolumab plus cabozantinib, either positively or negatively. So, this gave us some initial insight for further study, that these are highly coordinated and potentially associated with clinical outcome.”

Braun added that the next question posed by the investigators was whether the total amount of glycosylation is important and if it plays a role in clinical outcomes. To that end, they examined the total amount of 2 forms of glycosylation: sialyation and fucosylation.

“We see basically an increasing amount of glycosylation, the number of amino acid residues that have a sialic acid or a fucose residue. As we can see, for both nivolumab [plus] cabozantinib and sunitinib, when you have more glycosylation, you have a higher hazard ratio, [which is] essentially worse PFS and OS with more protein glycosylation,” Braun explained. “This at least raises the potential that this could be prognostic and really reinforces prior studies seen in melanoma. So that’s a potential prognostic role.”

They then set out to evaluate whether this marker could be predictive for response to the doublet vs the monotherapy. When they look across several protein glycosylations, 2 patterns emerged, Braun noted. “One, proteins involved in lipid metabolism, and the second were members of the complement cascade,” he said. “One is CO3. And what we can see is that at low levels of protein glycosylation, there’s [essentially] no difference between nivolumab plus cabozantinib or sunitinib with respect to PFS, but at high levels of protein glycosylation, this is where we see tremendous benefit from nivolumab plus cabozantinib. This is hypothesis generating. This is a proinflammatory complement protein, so could this be mediating complement-induced antitumor activity?”

The opposite pattern was observed for CFAH glycopeptide. He noted that high levels of the checkpoint did not show benefit from the doublet whereas when the protein glycosylation was low, substantial benefit was observed with the combination. “The hypothesis is that this negative regulator of alternate complement activity, when it’s low, that’s when the immune therapy is able to act,” Braun said.

He concluded that the prognostic or predictive potential of glycopeptide biomarkers should be further examined in additional clinical trials.

Disclosures: Dr Braun shared that he has a non-CE consulting relationship with Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post/Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Scholar Rock, and NeoMorph. He serves on the advisory board for Exelixis, AVEO, Eisai, and Elephas, and has equity in Elephas and Fortress Biotech (subsidiary). He received research grants from National Institutes of Health/National Cancer Institute, DOD, KCA, Akoya, Exelixis, and AstraZeneca. Support for the current study was provided by Bristol Myers Squibb.

References

1. Braun DA, Vemula SV, Wang Y, et al. Novel serum glycoproteomic biomarkers predict response to nivolumab plus cabozantinib (nivo+cabo) versus sunitinib (suni) in advanced RCC (aRCC): analysis from CheckMate 9ER. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation 1694MO.
2. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed September 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery
3. Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for previously untreated advanced renal cell carcinoma: results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42 (suppl 4):362. doi:10.1200/JCO.2024.42.4_suppl.362