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Immune-Based Combinations in Intermediate-/Poor-Risk Patients with Non-Clear Cell Renal Cell Carcinoma: Results from the ARON-1 Study - Beyond the Abstract

Renal cell carcinoma (RCC) accounts for 2–3% of adult cancers and is classified into clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). While ccRCC comprises 80% of cases, nccRCC is more diverse and includes papillary (pRCC), chromophobe (chRCC), collecting duct carcinoma, translocation RCC (tRCC), renal medullary carcinoma, and unclassified RCC (uRCC). The 2022 WHO classification highlighted the importance of molecular diagnostics in addition to histology.

Management of metastatic ccRCC has evolved with the approval of immune checkpoint inhibitors (ICIs), often combined with tyrosine kinase inhibitors (TKIs). However, nccRCC treatments still rely primarily on VEGF-targeting TKIs, due to limited high-level evidence supporting ICIs in this setting. Some phase II trials (e.g., KEYNOTE-427, CheckMate 374, and SUNNIFORECAST) and retrospective studies have suggested promising outcomes using ICI-based therapies for nccRCC. These findings have yet to be fully validated in real-world, multicenter data, hence the rationale for the ARON-1 study.

The ARON-1 study is a large international, retrospective analysis of real-world data from patients with metastatic nccRCC treated with first-line immune-based combination therapies between January 2021 and December 2024. The data were collected from 56 centers in 17 countries, with a focus on intermediate- and poor-risk patients according to the IMDC risk model.


Figure 1. Map of participating Countries in the ARON-1 study.

Eligible patients had histologically confirmed nccRCC, measurable metastatic disease, and had received at least one cycle of an ICI-based first-line therapy. Patients were excluded if they lacked tumor response data or follow-up. The primary endpoints were overall survival (OS) and progression-free survival (PFS), evaluated using RECIST 1.1 criteria. Secondary outcomes included objective response rate (ORR) and safety.

Statistical analyses included Kaplan-Meier survival curves, Cox regression models, and comparisons among different ICI-based combinations (e.g., nivolumab/ipilimumab, pembrolizumab/axitinib, pembrolizumab/lenvatinib, and nivolumab/cabozantinib).

Out of 2,401 patients in the ARON-1 dataset treated with immune combinations, 323 had nccRCC and were included in this analysis. The median age was 63 years; 75% were male.

Histologic subtypes included:
  • Papillary RCC (46%)
  • Chromophobe RCC (11%)
  • Other/rare nccRCC (43%)
About 17% had sarcomatoid features, and 59% had undergone nephrectomy. All patients were either intermediate (71%) or poor risk (29%) per IMDC.

First-line immune-based combinations included:
  • Pembrolizumab/axitinib (34%)
  • Nivolumab/ipilimumab (31%)
  • Nivolumab/cabozantinib (23%)
  • Pembrolizumab/lenvatinib (12%)
Overall Survival (OS)

  • Median OS (mOS) in the overall population was 31.1 months with a 2-year OS rate of 58%.
  • Patients who had undergone nephrectomy had significantly longer OS (40.4 vs. 19.9 months).
  • Intermediate-risk patients had mOS of 36.1 months compared to 11.9 months for poor-risk patients.
  • OS was significantly worse for patients with bone or liver metastases.
By treatment:
  • Pembrolizumab/lenvatinib: mOS 31.9 months; 2-year OS: 69%
  • Pembrolizumab/axitinib: mOS 31.2 months; 2-year OS: 61%
  • Nivolumab/cabozantinib: mOS 27.8 months; 2-year OS: 54%
  • Nivolumab/ipilimumab: mOS 24.6 months; 2-year OS: 51%
In subgroup analyses by histology:
  • pRCC patients benefited most from pembrolizumab/lenvatinib (2-year OS 77%)
  • chRCC patients showed best OS with pembrolizumab/axitinib (mOS 40.5 months)
  • uRCC patients had variable results, with nivolumab-based therapies showing potential benefit
Overall_Survival_in_metastatic_nccRCC_patients_receiving_first-line_immune-base_combinations_stratified_by_clinical_features.jpeg
Figure 2. Overall Survival in metastatic nccRCC patients receiving first-line immune-base combinations, stratified by clinical features.

Progression-Free Survival (PFS)

Median PFS across the entire cohort was 13.0 months, with a 1-year PFS rate of 52%.

PFS by treatment:
  • Pembrolizumab/lenvatinib: 24.5 months, 1-year PFS: 66%
  • Nivolumab/cabozantinib: 18.4 months, 1-year PFS: 63%
  • Pembrolizumab/axitinib: 13.4 months, 1-year PFS: 57%
  • Nivolumab/ipilimumab: 6.8 months (shortest), 1-year PFS: 35%
Statistical comparison confirmed significantly poorer PFS with nivolumab/ipilimumab compared to the ICI/TKI combinations.

Among patients with pRCC, pembrolizumab/lenvatinib showed the highest 1-year PFS (73%).

Overall_Survival_and_Progression-Free_Survival_in_metastatic_nccRCC_patients_stratified_by_type_of_first-line_immune-based_combination.jpeg
Figure 3. Overall Survival and Progression-Free Survival in metastatic nccRCC patients stratified by type of first-line immune-based combination.

Objective Response Rate (ORR)

The overall ORR was 38%, with 2% achieving complete response (CR) and 36% partial response (PR).

ORRs by treatment:
  • Pembrolizumab/lenvatinib: 59% (highest), with 5% CR
  • Nivolumab/cabozantinib: 40%
  • Pembrolizumab/axitinib: 35%
  • Nivolumab/ipilimumab: 32%
These differences were statistically significant (p = 0.005).

In the poor-risk subgroup, pembrolizumab/lenvatinib also achieved the highest ORR (49%) but sample size was small.

Response_to_first-line_immune-based_combinations_in_patients_with_advanced_nccRCC.jpeg
Figure 4. Response to first-line immune-based combinations in patients with advanced nccRCC.

This study represents the largest real-world multicenter dataset assessing ICI-based therapies in intermediate-/poor-risk nccRCC patients. Results confirm that ICI/TKI combinations are more effective than ICI-doublets, supporting their role as preferred first-line options.

Among all regimens:

  • Pembrolizumab/lenvatinib was associated with the highest ORR (59%), longest PFS (24.5 months), and best 2-year OS (69%), aligning well with findings from the KEYNOTE-B61 trial.
  • Pembrolizumab/axitinib was widely used and showed favorable outcomes, especially in pRCC and chRCC, although prospective data for this combination in nccRCC are lacking.
  • Nivolumab/cabozantinib performed well in chRCC and uRCC, despite the chRCC cohort being discontinued early in a previous trial due to lack of benefit.
  • Nivolumab/ipilimumab, although included in standard care for ccRCC, had relatively lower effectiveness in nccRCC, especially in terms of PFS and ORR.
These findings reinforce the view that ICI-based combinations should be prioritized over TKI monotherapy for first-line treatment in intermediate-/poor-risk nccRCC, especially for pRCC and chRCC histologies.

Written by: Veronica Mollica,1 Francesco Massari,1,2 Matteo Santoni3

  1. Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy;
  2. Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy;
  3. Medical Oncology Unit, Macerata Hospital, Macerata, Italy.
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