1704P - Potential surrogate endpoints for overall survival (OS) in immunotherapy (IO)-treated metastatic renal cell carcinoma (mRCC): An International Metastatic Database Consortium (IMDC) study

Background

While OS remains the gold standard in first-line (1L) mRCC, surrogate endpoints that correlate with OS in the short term can be utilized to expedite drug testing and accelerate approval. We aimed to evaluate time-to-next therapy (TTNT) and best overall response (BOR) as potential intermediate endpoints (IEs).

Methods

We included all IMDC patients who received contemporary first-line IO-based-therapy from 2013 to 2023. The surrogacy of TTNT and BOR for OS was assessed using 3 methods: a Kendall’s Tau (KT) correlation between OS and TTNT across all follow-up (f/u) times; a linear regression between 18-month (mo) OS and TTNT rates at 6, 9 and 12 mo in 10 subgroups defined according to disease risk score (based on 18mo survival probability); and, a landmark analysis for OS based on BOR and TTNT rate at 6mo, using a multivariable Cox regression adjusting for IMDC risk groups; sites of metastases; histology type; age; nephrectomy status, stratified by therapy type and start year.

Results

1,667 patients were included in the analysis. Median age was 63yo, and 83% had clear-cell histology. Median f/u for OS was 15.4mo (IQR: 7.1-28.6). Across all timepoints, strong correlation (KT > 0.49) was observed between TTNT and OS (KT 0.67, 95%CI: 0.64-0.69). Across disease risk subgroups, 6mo TTNT explained 91% of the variance of OS at 18mo (R² 0.91, 95%CI: 0.64-0.95). 6mo landmark analysis showed adjusted HRs of 2.77 (95%CI: 2.16-3.55) for BOR and 2.82 (95%CI: 2.22-3.59) for TTNT (adj. p <0.0001 for all). Patients with an objective response as BOR had an 18-month OS rate of 91% (95%CI: 88%-93%) vs 74% (95%CI: 70%-78%) for those with no response at 6 months. Patients who received a second line of systemic therapy at 6 months had an 18-month OS rate of 63% (95%CI: 55%-69%) vs 87% (95%CI: 85%-90%) for those who didn’t.

Conclusions

BOR and TTNT appear to be strongly predictive of OS in IO-treated mRCC. Prospective validation is needed.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

W. Xie: Financial Interests, Personal, Other, Consulting: Convergent Therapeutics, Inc. E. Saad: Financial Interests, Personal and Institutional, Research Funding: Roche/Genentech. C. Labaki: Financial Interests, Personal and Institutional, Research Funding: Roche/Genentech. C. Suarez Rodriguez: Financial Interests, Personal, Invited Speaker: Astellas Pharma, Bristol Myers Sqquib (Inst), Ipsen, Hoffmann-La Roche Ltd, Merck; Financial Interests, Personal, Advisory Board: Bristol Myers Sqquib (Inst), Ipsen, Hoffmann-La Roche Ltd, Merck Sharp and Dohme, Eisai; Financial Interests, Institutional, Funding: Ipsen; Financial Interests, Institutional, Research Grant: Pfizer. J.M. Ruiz: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb (Mexico), Novartis; Financial Interests, Personal, Advisory Board: MSD, Asofarma; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb (Mexico, Ipsen. T.B. Powles: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Merck, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, MSD; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche, Pfizer, MSD, AstraZeneca, Ipsen; Financial Interests, Personal, Other, Sponsorship for Uromigos Podcast: Mashup Ltd; Financial Interests, Institutional, Other, honoraria: Gilead; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Ipsen, Merck, MSD, Seattle Genetics, Novartis, Pfizer, Merck Serono, Astellas, Johnson & Johnson, Eisai; Financial Interests, Institutional, Other, Honoraria: Gilead. L.A. Wood: Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, Bristol Myers Squibb, Merck; Non-Financial Interests, Personal, Advisory Board: BMS, Merck, AstraZeneca. G.A. De Velasco Oria: Financial Interests, Personal, Advisory Board: Pfizer, Astellas, BMS, MSD, Ipsen, Bayer, AstraZeneca, Eisai; Financial Interests, Personal, Invited Speaker: Pfizer, Astellas, BMS, MSD, Roche, Ipsen, Merck, Novartis, Janssen, Bayer; Financial Interests, Institutional, Research Grant: Roche. 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. D.Y.C. Heng: Financial Interests, Personal, Advisory Board: Pfizer, Merck, BMS, Ipsen, Novartis, AstraZeneca, Roche; Financial Interests, Personal, Steering Committee Member: Exilexis; Financial Interests, Institutional, Local PI: BMS, Pfizer, Ipsen. 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, 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. All other authors have declared no conflicts of interest.