1694MO - Novel serum glycoproteomic biomarkers predict response to nivolumab plus cabozantinib (NIVO+CABO) versus sunitinib (SUN) in advanced RCC (aRCC): Analysis from CheckMate 9ER

Background

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.

Editorial acknowledgement

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

D.A. Braun: Financial Interests, Personal, Invited Speaker, Speaker on innovation in oncology and clinical trial design: LM Education/Exchange Services; Financial Interests, Personal, Other, Consulting: Octane Global, Defined Health, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, Insight Strategy, Catenion, PWW Consulting, Haymarket; Financial Interests, Personal, Advisory Board, Advisory Board: Exelixis, Aveo; Financial Interests, Personal, Invited Speaker: Aptitude Health, AbbVie, ASCO Post RCC Roundtable, Targeted Oncology, Pfizer, Medscape; Financial Interests, Personal, Other, Advisor: Fortress Biotech (subsidiary), DLA Piper; Financial Interests, Personal, Other, Co-Founder: CurIOS; Financial Interests, Personal, Advisory Board: Elephas Bio, Merck, Eisai, Compugen, Link Cell Therapies, Scholar Rock, Neomorph; Financial Interests, Personal, Other, Medical education: Accolade 2nd.MD; Financial Interests, Personal, Other, stock options: Elephas; Financial Interests, Personal, Research Grant: AstraZeneca, Exelixis; Non-Financial Interests, Advisory Role: Bristol Myers Squibb; Non-Financial Interests, Member: ASCO. A. Yu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. C. Pickering: Financial Interests, Institutional, Full or part-time Employment, Lead clinical data scientist: InterVenn Biosciences. D. Serie: Financial Interests, Institutional, Officer, I am the Chief Data Officer of InterVenn Biosciences: InterVenn; Financial Interests, Personal, Stocks/Shares, I own stock in InterVenn: InterVenn Biosciences. T.K. Choueiri: Financial Interests, Personal, Advisory Board, Advice on GU/RCC drugs: BMS, Pfizer, Merck, Exelixis, AstraZeneca; Financial Interests, Personal, Advisory Board, Advice on Onc drugs: Lilly, EMD Serono, Infinity; Financial Interests, Personal, Advisory Board, Advice on RCC drug: Calithera; Financial Interests, Personal, Invited Speaker, RCC drug: Ipsen; Financial Interests, Personal, Advisory Board, Advice on GU Onc drugs: Surface Oncology; Financial Interests, Personal, Other, Consultant on onc drugs: Analysis Group; Financial Interests, Personal, Invited Speaker, CME, ww2.peerview.com: Peerview; Financial Interests, Personal, Invited Speaker, CME, gotoper.com: PER; Financial Interests, Personal, Invited Speaker, CME, researchtopractice.com: ResearchToPractice; Financial Interests, Personal, Invited Speaker, National Association of Managed Care: NAMC; Financial Interests, Personal, Invited Speaker, ASCO-related event: ASCO-SITC; Financial Interests, Personal, Other, Grant review to Orien Network ($400): ORIEN; 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Financial Interests, Personal, Advisory Board, GU cancer drug development: alkermes, Gilead; Financial Interests, Personal, Other, Study section reviewer. $200.00 per day for 1 day: National Cancer Institute; Financial Interests, Personal, Other, Cancer Center Grand Rounds: Cleveland Clinic; Financial Interests, Personal, Advisory Board, Advisory Board/month: CURESPONSE; Financial Interests, Personal, Advisory Board: Tempest, Precede Bio (not publicly traded)); Financial Interests, Personal, Member of Board of Directors, unpaidhttps://www.accru.org/main/public/index.xhtml: ACCRU; Financial Interests, Personal, Member of Board of Directors, Unpaidhttps://kidneycan.org: KidneyCan; Financial Interests, Personal, Other, External Advisory Board Member: Gustave Roussy; Financial Interests, Personal, Stocks/Shares, advisor: Pionyr (not publicly traded), Tempest (publicly traded), Osel (not publicly traded), Precede Bio (not publicly traded)), CURESPONSE (not publicly traded), Inndura; Financial Interests, Personal, Stocks/Shares: Primium; Financial Interests, Personal, Royalties, For writing and updating chapters in GU Oncology: Up-To-Date online textbook; Financial Interests, Institutional, Funding, National Chair: BMS, Merck, Exelixis, AstraZeneca, Takeda, Tracon; Financial Interests, Institutional, Local PI, National Chair: Roche; Financial Interests, Institutional, Funding, National co-chair: Pfizer, EMD-Serono; Financial Interests, Institutional, Funding, Chair of trial: Lilly; Financial Interests, Institutional, Local PI: Surface Oncology, GSK; Financial Interests, Institutional, Funding, SC member: Eisai; Financial Interests, Institutional, Funding, National co-chair on 3 ongoing trials: ALLIANCE Cooperative Group; Financial Interests, Institutional, Research Grant, for GU oncology translational research through IION program: BMS; Financial Interests, Institutional, Research Grant, for GU oncology translational research: Exelixis; Financial Interests, Institutional, Research Grant, For Health outcomes research: Roche; Financial Interests, Institutional, Local PI, leads trials as PI: Nikang; Non-Financial Interests, Leadership Role, Co-Chair of the meeting, 2019- current and BOD member (unpaid): Kidney Cancer Research Summit of KidneyCAN; Non-Financial Interests, Principal Investigator, Trial Global and National PI with GU Cancers, mostly Kidney Cancer: Multiple Academic and Industry entities; Non-Financial Interests, Personal, Other, Track Leader/Session chair/Speaker/Discussant: ASCO; Non-Financial Interests, Personal, Other, Speaker/Discussant/Track Leader: ESMO; Non-Financial Interests, Institutional, Other, Access to genomic database: Foundation Med, Guardant, Invitae; Non-Financial Interests, Personal, Other, Grants reviewers: AACR; Non-Financial Interests, Personal, Other, Reviewer of papers: Various journals (e.g. NEJM, Lancet, JCO); Non-Financial Interests, Personal, Other, Medical writing and editorial assistance support (e.g. ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, Pharmagenesis, and others). However, first draft frequently initiated by myself when I am 1st author: Medical Communication; Non-Financial Interests, Member: ASCO, AACR; Non-Financial Interests, Other, Political vote usually as “independent”, not a member of any political party. I am an issue voter: General US Politics; Other, Employee at DFCI. Please see https://www.dana-farber.org/ for mission statement (non-profit hospital). I am also the past President of Medical Staff at DFCI 2015-2018: Dana-Farber Cancer Institute (DFCI); Other, Professor at HMS, Please see https://hms.harvard.edu/ for mission statement (non-profit school): Harvard Medical School (HMS); Other, The institution filed patents related to biomarkers of immune checkpoint blockers, and circulating tumor DNA. No money made and some patents were abandoned: Filed patents. W. Xu: Financial Interests, Personal, Advisory Board: Exelixis, Xencor, Jazz; Financial Interests, Personal, Other, Consulting: Aveo, Merck; Financial Interests, Institutional, Research Grant, Research funding paid to institution: Oncohost; Financial Interests, Institutional, Local PI: CRISPR Therapeutics. S.V. Vemula: Financial Interests, Personal, Full or part-time Employment: BMS; Financial Interests, Personal, Stocks/Shares: BMS. S. Gupta: Financial Interests, Personal, Full or part-time Employment, Employed at Bristol Myers Squibb: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Non-Financial Interests, Member: ASCO, SITC. All other authors have declared no conflicts of interest.