1716P - Primary resistance to front-line immune-based combinations in patients with advanced renal cell carcinoma (ARON-1)

Background

The recent therapeutic advancements based on immune-oncology (IO) combinations have revolutionized the renal cell carcinoma (RCC) management. However, a subset of patients, termed "primary refractory (P_ref)", faces dismal outcomes. Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of P_ref metastatic RCC patients.

Methods

This study collected data from 72 centers across 22 countries worldwide, involving patients aged ≥18 with metastatic clear cell RCC. All enrolled patients were treated with first-line IO combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors 1.1 criteria. Statistical analyses employed Kaplan-Meier, Cox proportional hazard models, logistic regression, and receiver operating characteristic curve analysis.

Results

Among 1709 patients, 19% exhibited primary refractoriness. Nivolumab/ipilimumab showed the highest P_ref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). P_ref patients demonstrated significantly lower median overall survival (OS) (7.6 months) compared to non-P_ref patients (55.7 months) (p<.01). Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium (IMDC) risk, no nephrectomy, sarcomatoid de-differentiationand and increased risk of P_ref. At the multivariate analysis nephrectomy, sarcomatoid de-differentiation, intermediate/poor IMDC risk, bone and brain metastases emerged as significant predictors of OS for P_ref RCC patients. Stratification based on clinical-pathological features emphasized the negative impact of IMDC (intermediate/poor), metastatic sites (bone and brain), Neutrophil-to-Lymphocyte ratio (≥4), and the number of metastatic sites (≥2) on the P_ref outcomes.

Conclusions

The ARON-1 study provides valuable insights into P_ref mRCC patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Buti: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Ipsen, Merck, Eisai, MSD, Novartis, Pfizer; Financial Interests, Personal and Institutional, Research Funding: Novartis, Pfizer. F. Massari: Financial Interests, Personal, Invited Speaker: Astellas, BMS, Janssen, Ipsen, MSD, Pfizer. E. Grande: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGa, Pfizer, Roche, Dr. Reddy's, Adium; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, ONCODNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, Nanostring Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Coordinating PI, Independent research grant: IPSEN; Non-Financial Interests, Other, Ad Board member: ENETS; Non-Financial Interests, Member of Board of Directors: GETNE, Guard Consortium, Grupo Centro de Tumores Genitourinarios. J. Kucharz: Financial Interests, Personal and Institutional, Research Funding: Angelini, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, Merck, Novartis, MSD, Pfizer. O. Fiala: Financial Interests, Personal, Invited Speaker: Novartis, MSD, Janssen, Merck, Pierre Fabre, BMS, Pfizer. T. Buchler: Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Astellas, Janssen, Ipsen, Merck; Financial Interests, Personal, Advisory Board: Bayer, Bristol Myers Squibb, Ipsen, Merck, Servier, Eli Lilly, Pfizer, Accord; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Merck, Bayer, Exelixis, Eisai, Eli Lilly, Roche, MSD; Financial Interests, Personal and Institutional, Coordinating PI: AstraZeneca. Z.W. Myint: Financial Interests, Personal, Research Funding: Merck. A. Bamias: Financial Interests, Personal, Invited Speaker: Ipsen, Debiopharm; Financial Interests, Personal, Advisory Board: BMS, MSD, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Roche, BMS, MSD; Financial Interests, Institutional, Funding: AstraZeneca, Pfizer; Financial Interests, Personal, Steering Committee Member: MSD; Non-Financial Interests, Other, Steering Committee member: Roche; Non-Financial Interests, Institutional, Proprietary Information, Access to data from SAUL trial for substudies (published): Roche; Non-Financial Interests, Leadership Role: Hellenic GU Cancer Group. M. Santoni: Financial Interests, Personal, Sponsor/Funding: Janssen, BMS, Ipsen, MSD, Astellas, Bayer. All other authors have declared no conflicts of interest.