Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)

Background: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (P), face dismal outcomes.

Objective: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of P patients.

Methods: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve.

Results: In our study, the P rate was 19%. Nivolumab/ipilimumab showed the highest P rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-P patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for P patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of P. This study presents limitations, mainly because of its retrospective design.

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

Citing Articles

Immune-Based and Novel Therapies in Variant Histology Renal Cell Carcinomas.

Miller J, Johnson J, Guske C, Mannam G, Hatoum F, Nassar M Cancers (Basel). 2025; 17(2).

PMID: 39858107 PMC: 11763753. DOI: 10.3390/cancers17020326.

References

Siegel R, Miller K, Wagle N, Jemal A . Cancer statistics, 2023. CA Cancer J Clin. 2023; 73(1):17-48. DOI: 10.3322/caac.21763. View

Gulati S, Labaki C, Karachaliou G, Choueiri T, Zhang T . First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape. Oncologist. 2022; 27(2):125-134. PMC: 8895741. DOI: 10.1093/oncolo/oyab056. View

Rini B, Plimack E, Stus V, Gafanov R, Hawkins R, Nosov D . Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380(12):1116-1127. DOI: 10.1056/NEJMoa1816714. View

Motzer R, Tannir N, Mcdermott D, Frontera O, Melichar B, Choueiri T . Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018; 378(14):1277-1290. PMC: 5972549. DOI: 10.1056/NEJMoa1712126. View

Choueiri T, Powles T, Burotto M, Escudier B, Bourlon M, Zurawski B . Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021; 384(9):829-841. PMC: 8436591. DOI: 10.1056/NEJMoa2026982. View

Motzer R, Alekseev B, Rha S, Porta C, Eto M, Powles T . Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021; 384(14):1289-1300. DOI: 10.1056/NEJMoa2035716. View

Motzer R, Porta C, Alekseev B, Rha S, Choueiri T, Mendez-Vidal M . Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022; 23(6):768-780. PMC: 10284118. DOI: 10.1016/S1470-2045(22)00212-1. View

Cella D, Grunwald V, Escudier B, Hammers H, George S, Nathan P . Patient-reported outcomes of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib (CheckMate 214): a randomised, phase 3 trial. Lancet Oncol. 2019; 20(2):297-310. PMC: 6701190. DOI: 10.1016/S1470-2045(18)30778-2. View

Bedke J, Rini B, Plimack E, Stus V, Gafanov R, Waddell T . Health-related Quality of Life Analysis from KEYNOTE-426: Pembrolizumab plus Axitinib Versus Sunitinib for Advanced Renal Cell Carcinoma. Eur Urol. 2022; 82(4):427-439. DOI: 10.1016/j.eururo.2022.06.009. View

10.

Cella D, Motzer R, Suarez C, Blum S, Ejzykowicz F, Hamilton M . Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022; 23(2):292-303. PMC: 9479564. DOI: 10.1016/S1470-2045(21)00693-8. View

11.

Santoni M, Massari F, Bracarda S, Grande E, Matrana M, Rizzo M . Cabozantinib in Patients with Advanced Renal Cell Carcinoma Primary Refractory to First-line Immunocombinations or Tyrosine Kinase Inhibitors. Eur Urol Focus. 2022; 8(6):1696-1702. DOI: 10.1016/j.euf.2022.02.004. View

12.

Motzer R, Schmidinger M, Eto M, Suarez C, Figlin R, Liu Y . LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol. 2023; 19(2):113-121. DOI: 10.2217/fon-2022-0802. View

13.

Choueiri T, Mcdermott D, Merchan J, Bauer T, Figlin R, Heath E . Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023; 24(5):553-562. DOI: 10.1016/S1470-2045(23)00097-9. View

14.

Rosellini M, Marchetti A, Mollica V, Rizzo A, Santoni M, Massari F . Prognostic and predictive biomarkers for immunotherapy in advanced renal cell carcinoma. Nat Rev Urol. 2022; 20(3):133-157. DOI: 10.1038/s41585-022-00676-0. View

15.

Porta C, Bamias A, Zakopoulou R, Myint Z, Cavasin N, Iacovelli R . Geographical differences in the management of metastatic de novo renal cell carcinoma in the era of immune-combinations. Minerva Urol Nephrol. 2023; 75(4):460-470. DOI: 10.23736/S2724-6051.23.05369-7. View

16.

Santoni M, Massari F, Myint Z, Iacovelli R, Pichler M, Basso U . Clinico-Pathological Features Influencing the Prognostic Role of Body Mass Index in Patients With Advanced Renal Cell Carcinoma Treated by Immuno-Oncology Combinations (ARON-1). Clin Genitourin Cancer. 2023; 21(5):e309-e319.e1. DOI: 10.1016/j.clgc.2023.03.006. View

17.

Santoni M, Buti S, Myint Z, Maruzzo M, Iacovelli R, Pichler M . Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk.... Eur Urol Oncol. 2023; 7(1):102-111. DOI: 10.1016/j.euo.2023.07.003. View

18.

Santoni M, Massari F, Myint Z, Iacovelli R, Pichler M, Basso U . Global Real-World Outcomes of Patients Receiving Immuno-Oncology Combinations for Advanced Renal Cell Carcinoma: The ARON-1 Study. Target Oncol. 2023; 18(4):559-570. DOI: 10.1007/s11523-023-00978-2. View

19.

Marques Monteiro F, Fiala O, Massari F, Myint Z, Kopecky J, Kucharz J . Systemic Immune-Inflammation Index in Patients Treated With First-Line Immune Combinations for Metastatic Renal Cell Carcinoma: Insights From the ARON-1 Study. Clin Genitourin Cancer. 2023; 22(2):305-314.e3. DOI: 10.1016/j.clgc.2023.11.013. View

20.

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View