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. 2024 Jul;19(4):587-599.
doi: 10.1007/s11523-024-01065-w. Epub 2024 May 5.

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study)

Ondřej Fiala #  1   2 , Sebastiano Buti #  3   4 , Aristotelis Bamias  5 , Francesco Massari  6   7 , Renate Pichler  8 , Marco Maruzzo  9 , Enrique Grande  10 , Ugo De Giorgi  11 , Javier Molina-Cerrillo  12 , Emmanuel Seront  13 , Fabio Calabrò  14 , Zin W Myint  15 , Gaetano Facchini  16 , Ray Manneh Kopp  17 , Rossana Berardi  18 , Jakub Kucharz  19 , Maria Giuseppa Vitale  20 , Alvaro Pinto  21 , Luigi Formisano  22 , Thomas Büttner  23 , Carlo Messina  24 , Fernando Sabino M Monteiro  25 , Nicola Battelli  26 , Ravindran Kanesvaran  27 , Tomáš Büchler  28 , Jindřich Kopecký  29 , Daniele Santini  30 , Giulia Claire Giudice  3   4 , Camillo Porta #  31 , Matteo Santoni #  26
Affiliations

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study)

Ondřej Fiala et al. Target Oncol. 2024 Jul.

Abstract

Background: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care.

Objective: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy.

Methods: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models.

Results: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively).

Conclusions: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

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Conflict of interest statement

Ondrej Fiala received honoraria from Novartis, Janssen, Merck, BMS, MSD, Pierre Fabre, and Pfizer for consultations and lectures unrelated to this project. Sebastiano Buti has received honoraria for speaking at scientific events and advisory roles from AstraZeneca, BMS, Ipsen, Merck, Eisai, MSD, Novartis, and Pfizer and research funding from Novartis and Pfizer unrelated to this project. Francesco Massari has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Enrique Grande has received honoraria for speaker engagements, advisory roles, or funding of continuous medical education from Adacap, Amgen, Angelini, Astellas, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, Ipsen, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific and research grants from Pfizer, AstraZeneca, Astellas, and Lexicon Pharmaceuticals. All of the above are unrelated to the present paper. Ugo De Giorgi services as an advisory/board member of Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer, and Sanofi, has received research grant/funding to the institution from AstraZeneca, Roche, and Sanofi, and travel/accommodations/expenses from AstraZeneca, BMS, Ipsen, Janssen, and Pfizer. All of the above are unrelated to the present paper. Javier Molina-Cerrillo declares consultant, advisory, or speaker roles for Ipsen, Roche, Pfizer, Sanofi, Janssen, and BMS unrelated to this project. Zin W. Myint has received research support from Merck unrelated to the present paper. Ray Manneh Kopp has received research support and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, BMS, Eli Lilly, Janssen, MSD, Pfizer, Tecnofarma, and Roche unrelated to this project. Jakub Kucharz has received honoraria from Angelini, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, and Pfizer, and research funding from Novartis, all unrelated to the present paper. Maria Giuseppa Vitale has received honoraria from Astellas, BMS, MSD, and Ipsen unrelated to this project. Alvaro Pinto has received research support and/or honoraria from Pfizer, Novartis, Ipsen, BMS, Janssen, Astellas, Sanofi, Bayer, Clovis, Roche, MSD, Pierre Fabre, Merck, Bayer, Pharmacyclics, AstraZeneca, Eisai, and Aveo unrelated to this project. Thomas Büttner has received fees for speakers bureau, travel, and accommodation from Astellas, Ipsen, and MSD, all unrelated to the present paper. Carlo Messina has received fees for speakers bureau and advisory board activities from Merck, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Astellas, AstraZeneca, Baier, and GSK, all unrelated to the present paper. Fernando Sabino M. Monteiro has received research support from Janssen and Merck Sharp Dome and honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome. All unrelated to the present paper. Ravindran Kanesvaran has received fees for speakers bureau and advisory board activities from Pfizer, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Merck, Amgen, Astellas, and Bayer, all unrelated to this project. Tomáš Büchler has received research support from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis, consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis, payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer. All of the above are unrelated to the present paper. Jindřich Kopecký has received consulting fees from Bristol Myers Squibb, Novartis, Pfizer, Merck, MSD, and Ipsen and payment or honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events from Ipsen, Bristol Myers Squibb, MSD, Merck, Novartis, and Pfizer. All of the above are unrelated to the present paper. Camillo Porta has received honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, Ipsen, and MSD and acted as a Protocol Steering Committee Member for BMS, Eisai, and MSD unrelated to this project. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, A.A.A., and Bayer unrelated to the present paper. Aristotelis Bamias, Renate Pichler, Marco Maruzzo, Emmanuel Seront, Fabio Calabrò, Gaetano Facchini, Rossana Berardi, Luigi Formisano, Nicola Battelli, Daniele Santini, and Giulia Claire Giudice have no conflicts of interest that are directly relevant to the content of this article.

Figures

Fig. 1
Fig. 1
Kaplan–Meier estimates of overall survival according to the upfront cytoreductive nephrectomy for overall population (A) and stratified by International Metastatic RCC Database Consortium risk: intermediate-risk patients (B) and poor-risk patients (C)
Fig. 2
Fig. 2
Kaplan–Meier estimates of overall survival according to the upfront cytoreductive nephrectomy stratified by type: lung metastastases (A), bone metastastases (B), liver metastastases (C), and number of metastatic sites: one metastatic site (D), and two or more metastatic sites (E)
Fig. 3
Fig. 3
Kaplan–Meier estimates of progression-free survival and overall survival according to the type of first-line therapy stratified by upfront cytoreductive nephrectomy (CN). Comparison between immuno-oncology (IO) combinations containing tyrosine kinase inhibitor (TKI) plus IO (TKI+IO) vs a combination of two IO agents (IO+IO) vs TKI monotherapy (TKI) for the overall patient population (A, B), patients who underwent CN (C, D), and those without CN (E, F)
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