# Real-World Outcomes of First-Line Immune-Based Combination Therapies in Bone-Metastatic Clear Cell Renal Cell Carcinoma

Alia Harba, Fabien Moinard-Butot, Edouard Auclin, Philippe Barthélémy, Johanna Noel, Clément Dumont, Hélène Gauthier, Olivier Huillard, Loïc Jaffrelot, Thomas Seisen, et al.

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## ► To cite this version:

Alia Harba, Fabien Moinard-Butot, Edouard Auclin, Philippe Barthélémy, Johanna Noel, et al. Real-World Outcomes of First-Line Immune-Based Combination Therapies in Bone-Metastatic Clear Cell Renal Cell Carcinoma. Clinical Genitourinary Cancer, 2026, pp.102506. 10.1016/j.clgc.2026.102506. hal-05500432

HAL Id: hal-05500432

https://hal.sorbonne-universite.fr/hal-05500432v1

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Original Study

# Real-World Outcomes of First-Line Immune-Based Combination Therapies in Bone-Metastatic Clear Cell Renal Cell Carcinoma

Alia Harba,<fnref n="1" /> Fabien Moinard-Butot,<fnref n="2" /> Edouard Auclin,<fnref n="3" /> Philippe Barthélémy,<fnref n="2" />
Johanna Noel,<fnref n="4" /> Clément Dumont,<fnref n="5" /> Hélène Gauthier,<fnref n="5" /> Olivier Huillard,<fnref n="4" />
Loïc Jaffrelot,<fnref n="6" /> Thomas Seisen,<fnref n="7" /> Charlotte Joly,<fnref n="8" /> Christophe Tournigand,<fnref n="8" />
Mostefa Bennamoun,<fnref n="9" /> Matthieu Roulleaux-Dugage,<fnref n="10" /> Mathilde Cancel,<fnref n="11" />
Victor Heurtier,<fnref n="12" /> Hamid Lardjani,<fnref n="12" /> Stéphane Oudard,<fnref n="12" /> Constance Thibault<fnref n="12" />

## Abstract

Bone metastases affect one-third of patients with metastatic clear cell renal cell carcinoma and remain a major cause of morbidity. In this multicenter real-world study of 124 patients treated with first-line ICI-ICI or ICI-TKI combinations, both strategies showed comparable outcomes. Bone progression and skeletal events remained frequent, with bone-targeting agents independently associated with improved bone progression-free survival.

**Background:** Bone metastases occur in one third of patients with metastatic clear cell renal cell carcinoma (mccRCC) and are associated with poor prognosis. Optimal first-line treatment for this subgroup of patients remains undefined.

**Methods:** We conducted a multicenter retrospective study of patients with bone-metastatic (BM+) mccRCC treated with first-line immune checkpoint inhibitor (ICI)-based combinations between January 2015 and February 2024 across 8 French centers. The primary endpoint was time to next treatment (TTNT). Secondary endpoints included overall survival (OS), bone progression-free survival (bPFS), incidence of skeletal-related events (SREs) and changes in bone pain.

**Results:** A total of 124 patients were included; 55% received ICI-ICI and 45% an ICI plus a tyrosine kinase inhibitor (TKI). Median follow-up was 36.8 months. Median TTNT was 11.7 months (95% CI, 8.38-20.0), OS 28.8 months (95% CI, 23.7-40.2) and bPFS 11.7 months (95% CI, 7.69-21.7). Median TTNT was numerically longer with ICI-TKI compared to ICI-ICI (17.9 vs. 8.5 months; *P* = .40), with no significant difference in OS or bPFS between treatment groups. SREs occurred in 32% of patients. Bone progression was observed in 48%, with a concomitant SRE in 54% mostly involving preexisting lesions (78%). Bone pain improved in 45% of evaluable patients. No significant differences were observed between treatment groups for SRE incidence or bone pain improvement. Hypercalcemia was associated with shorter OS and bPFS, while bone-only disease correlated with improved OS. Use of bone-targeting agents (BTAs) was independently associated with longer bPFS. **Conclusion:** ICI-ICI and ICI-TKI combinations showed comparable outcomes in BM+ mccRCC. Bone progression and SREs remained frequent and often involved preexisting bone lesions. These findings support early integration of local treatments as well as BTAs, which were independently associated with longer bPFS.

Clinical Genitourinary Cancer, Vol. 000, No. xxx, 102506 © 2026 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

**Keywords:** Bone metastases, Bone-targeting agents, Clear Cell renal Cell Carcinoma, First-line treatment combinations, Skeletal-related events

<footnote n="1">¹Department of Medical Oncology, Hôpital Européen Georges Pompidou, AP-HP, Sorbonne Université, Paris, France</footnote>

<footnote n="2">²Department of Medical Oncology, ICANS, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</footnote>

<footnote n="3">³Department of Medical Oncology, Institut Bergonié, Bordeaux, France</footnote>

<footnote n="4">⁴Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France</footnote>

<footnote n="5">⁵Department of Medical Oncology, Hôpital Saint Louis, AP-HP, Paris, France</footnote>

<footnote n="6">⁶Department of Medical Oncology, Pitié-Salpêtrière Hospital, AP-HP, Institut Universitaire de Cancérologie, Sorbonne Université, Paris, France</footnote>

<footnote n="7">⁷Department of Urology, GRC 5 Predictive Onco-Urology, AP-HP, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France</footnote>

<footnote n="8">⁸Department of Medical Oncology, University Medicine Department of Cancer, AP-HP, GH Henri Mondor, University Paris-Est Creteil, Créteil, France</footnote>

<footnote n="9">⁹Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France</footnote>

<footnote n="10">¹⁰Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France</footnote>

<footnote n="11">¹¹Department of Medical Oncology, Bretonneau Hospital, Tours, France</footnote>

<footnote n="12">¹²Department of Medical Oncology, Hôpital Européen Georges Pompidou, Institut du Cancer Paris CARPEM, AP-HP centre, Paris, France</footnote>

<footnote>Submitted: Oct 9, 2025; Revised: Dec 23, 2025; Accepted: Jan 7, 2026; Epub: xxx</footnote>

<footnote>Address for correspondence: Alia Harba, MD, Department of Medical Oncology, Hôpital Européen Georges Pompidou, AP-HP, Sorbonne Université, 105 boulevard de l'Hôpital, Paris 75013, France.</footnote>

<footnote>E-mail contact: aliaharba@gmail.com, alia.harba@etu.sorbonne-universite.fr</footnote>
# Real-World Outcomes of First-Line Immune-Based

## Introduction

Bone metastases (BM) occur in approximately 30% of patients with metastatic clear cell renal cell carcinoma (mccRCC).¹,² They are associated with a high risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, and the need for radiotherapy or surgery, all of which contribute significantly to the overall disease burden.³,⁴ Beyond that, BM have been associated with poor prognosis and reduced overall survival (OS) in patients treated with vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs).⁵⁻⁹ Limited benefit has also been observed with immune checkpoint inhibitor (ICI) monotherapy, as demonstrated in the real-world NIVOREN cohort, which reported lower response rates and shorter progression-free survival (PFS) in patients with BM.¹⁰

In recent years, ICI-based combinations, including dual ICI (nivolumab plus ipilimumab (NivoIpi)) and ICI-TKI regimens (nivolumab plus cabozantinib (NivoCabo), pembrolizumab plus Lenvatinib (PembroLenva) or axitinib (PembroAxi)), have become the standard of care for the first-line treatment of mccRCC, based on improved outcomes in phase III trials.¹¹⁻¹⁴ Subgroup analyses from CheckMate 214, CheckMate 9ER and CLEAR showed that ICI-based combinations improved survival outcomes versus sunitinib in both patients with (BM+) and without baseline bone metastases (BM-), with a numerically smaller OS benefit for NivoIpi in BM+ patients¹¹,¹⁵ and maintained or even greater benefit for NivoCabo and PembroLenva in this subgroup.¹²,¹⁶,¹⁷

Despite their inclusion in pivotal trials, BM+ patients represented small subgroups and none of these trials were designed to assess bone-specific outcomes. The role of bone-targeting agents (BTAs) such as bisphosphonates and denosumab in mccRCC remains also poorly defined. Most studies suggesting a reduction in SREs predate the ICI era.¹⁸⁻²¹ In NIVOREN, use of BTAs were associated with fewer SREs under nivolumab monotherapy,¹⁰ but no data exist with combination therapies and their use is not routinely recommended in current guidelines.²²

Thus, clinical guidance for the management of BM in mccRCC remains scarce, and the role of local therapies is not clearly defined.²²⁻²⁶ To address these gaps, we conducted a multicenter retrospective analysis of BM+ patients treated with first-line ICI-ICI or ICI-TKI combinations for mccRCC, focusing on treatment outcomes and bone-specific endpoints in a real-world setting.

## Materials and Methods

### Patients

This was a retrospective observational multicenter study including all consecutive BM+ patients who initiated first-line treatment with either a dual ICI combination or an ICI-TKI combination for mccRCC across 8 French academic centers between January 1, 2015, and February 1, 2024. Patients were included if they had histologically confirmed ccRCC and at least 1 radiologically confirmed BM at the time of first-line treatment initiation. Patients with non-clear-cell histology or any prior systemic therapy were excluded. Treatment allocation reflected real-world clinical practice. The choice between ICI-ICI and ICI-TKI combinations was made at the discretion of the treating physician, based on contemporary clinical guidelines, IMDC risk stratification, patient comorbidities

and anticipated toxicity profiles at the time of treatment initiation. Patients were monitored through routine clinical assessments at each participating center, without centralized radiological review.

### Data Collection

Patients' clinical characteristics, bone disease features, treatments, and outcome data were retrospectively collected from medical records at each participating center. Baseline variables were recorded at the time of first-line treatment initiation. Bone disease features at baseline included the number and location of BM, presence of bone pain, presence of hypercalcemia, any use of BTAs, number and type of SREs prior to treatment. Data on the introduction of any subsequent systemic treatment or bone-directed intervention during or after first-line therapy were also recorded.

### Endpoints

The primary endpoint was time to next treatment (TTNT), defined as the interval from initiation of first-line therapy to the start of any subsequent systemic treatment or death from any cause, whichever occurred first. TTNT was selected as the primary endpoint as it represents a pragmatic and clinically meaningful outcome in real-world retrospective studies without centralized radiological review. Secondary endpoints included:

- Overall survival (OS), defined as the time from first-line treatment initiation to death from any cause.

- Bone progression-free survival (bPFS), defined as the time from treatment initiation to radiologically confirmed progression of bone disease or death. Bone progression was defined as the appearance of a new BM, a significant increase in the size or tissular component of a pre-existing lesion or increased metabolic uptake on PET scans.

- Incidence of SREs, including pathologic fracture, spinal cord compression, bone surgery, radiotherapy to bone, or image-guided interventional procedures.

- Changes in bone pain, evaluated during follow-up among patients with bone pain at baseline and categorized as improved, stable, or worsened based on patient-reported symptoms documented in clinical notes.

Importantly, hypercalcemia was not considered as a SRE but was collected separately.

### Regulatory and Ethical Approvals

This study followed the STROBE recommendations for reporting cohort studies and was conducted in accordance with the Declaration of Helsinki and applicable French regulations. It was approved by the Research Ethics Committee (Comité d'Éthique de la Recherche) of AP-HP (reference number: 2024-05-04). Due to the retrospective nature of the study, formal informed consent was not required. However, all patients were informed of the use of their anonymized data for research purposes, and a letter of nonopposition was provided as per institutional policy. The database was registered with the French Data Protection Authority (CNIL-Commission Nationale de l'Informatique et des Libertés) under registration number 2230683v0.
## Statistical Analysis

Patient characteristics were described using frequencies with percentages for categorical variables, and median with interquartile range (IQR) for continuous variables. Comparisons between groups were performed using Chi-square test or Fisher's exact test for categorical variables, depending on sample size. For continuous variables, independent samples t-tests were used. Median follow-up was estimated using reverse Kaplan-Meier method. Time-to-event outcomes were estimated using Kaplan-Meier method. Patients were censored at the time of last follow-up if they had not experienced the event of interest. For bPFS, patients who switched treatment due to extra skeletal progression without experiencing bone progression were censored at the date of treatment change. Survival distributions were compared between subgroups using Log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify baseline factors associated with TTNT, OS, and bPFS. Univariate and multivariate logistic regression models were also performed to identify factors associated with the occurrence of a SRE. Variables with a P-value < .10 in univariate analysis were considered for inclusion in multivariate models. IMDC risk group was initially included as a covariate in multivariate analyses, however, given the consistent prognostic impact of hypercalcemia in univariate analyses and its potential collinearity with IMDC, only a final model excluding IMDC and including hypercalcemia was retained. Analyses were conducted using a complete-case approach for variables with missing data. All statistical tests were 2-sided, with an alpha threshold of 0.05 for significance. Analyses were performed RStudio (version 2022.02.1).

## Results

### Patients' Characteristics

Overall, 124 BM+ patients treated with first-line ICI-ICI (n = 68; 55%) or ICI-TKI (n = 56; 45%) combinations for mccRCC were included in the present study. Patient distribution by center is provided in Supplementary Table 1. Table 1 summarizes baseline characteristics in the overall population and by treatment group. There were no statistically significant differences in baseline characteristics between the 2 treatment groups, except for IMDC risk group distribution: ICI-TKI group included a higher proportion of favorable-risk patients (21% vs. 4.4%) and a lower proportion of intermediate-risk patients (41% vs. 60%), while the proportion of poor-risk patients was similar between groups.

### Bone Disease Characteristics

Bone involvement at baseline is summarized in Table 2. The spine was the most commonly involved bone metastatic site (64%) (Figure 1). No statistically significant differences in baseline bone disease characteristics were found between treatment groups, except for pelvic bone involvement, which was more frequent in patients treated with ICI-ICI (54% vs. 36%, P = .04). A numerically higher proportion of patients in the ICI-TKI group had a SRE at baseline (55% vs. 38%, P = .05). Patients with bone-only disease had local therapies at baseline in 44% of cases, compared to 40% among those with concomitant metastatic sites.

Additional baseline characteristics and bone involvement features stratified by ICI-TKI regimens (NivoCabo and PembroAxi) are provided in Supplemental Tables 2 and 3.

## Efficacy

**Time to Next Treatment and Overall Survival.** Median time to follow-up was 36.8 months (95% CI, 27.8-50.5). During this period, 58 patients (47%) initiated a subsequent line of systemic therapy (Supplemental Table 4). Reasons for first line treatment discontinuation were disease progression (40%, n = 50/124) and treatment-related toxicity (6%, n = 8/124). Median TTNT was 11.7 months (95% CI, 8.38-20.0; Figure 2A). A nonsignificant trend favoring ICI-TKI was observed, with a median TTNT of 17.9 months (95% CI, 12.8-38.6) versus 8.5 months (95% CI, 5.4-19.8) in the ICI-ICI group (P = 0.40; Figure 2B). Subgroup analysis by ICI-TKI regimen showed a median TTNT of 20.0 months (95% CI, 13.2-NE) with NivoCabo and 14.6 months (95% CI, 7.4-38.6) with PembroAxi. In multivariate analysis, long bone metastases showed a trend toward worse outcomes (HR: 1.54; 95% CI, 0.95-2.50; P = .082). No variable, including treatment strategy (ICI-ICI vs. ICI-TKI), was independently associated with TTNT (Supplemental Table 5). The median OS in the overall cohort was 28.8 months (95% CI, 23.7-40.2; Figure 2C) with no statistical difference between treatment groups (ICI-ICI: 27.5 months (95% CI, 21.3-66.3) and ICI-TKI: 28.8 months (95% CI, 23.7-40.8), P = .80; Figure 2D). Subgroup analysis by ICI-TKI regimen showed a median OS of 34.1 months (95% CI, 23.7-NE) with PembroAxi and 28.8 months (95% CI, 20.0-NE) with NivoCabo. In multivariate analysis, male sex, ECOG-PS 2-3, hypercalcemia, and long bone metastases were independently associated with shorter OS, while having bone-only metastases was independently associated with improved OS (HR: 0.42; 95% CI, 0.20-0.88; P = .022). No significant association was found with first-line treatment regimen (Supplemental Table 6).

**Bone Specific Endpoints.** Bone disease progression occurred in 48% of patients and was numerically more frequent in the ICI-TKI group (54% vs. ICI-ICI: 43%; Table 3). Subgroup analysis further revealed a higher incidence in the PembroAxi subgroup (63%) compared to NivoCabo (44%; Supplemental Table 7). Median bPFS was 11.7 months (95% CI, 7.69-21.7; Figure 2E) with no difference between treatment groups (ICI-ICI: 10.9 months (95% CI, 7.23-NE) and ICI-TKI: 12.9 months (95% CI, 7.36-30.8); P = .50, Figure 2F). Subgroup analysis by ICI-TKI regimen showed a median bPFS of 13.9 months (95% CI, 4.2-NE) with NivoCabo and 9.3 months (95% CI, 4.3-37.1) with PembroAxi. In multivariate analysis, male sex and hypercalcemia were independently associated with shorter bPFS, while the use of BTAs at baseline was independently associated with improved bPFS (HR: 0.19; 95% CI, 0.04-0.80; P = .023; Supplemental Table 8). No significant association was found with the first-line treatment regimen. Among patients with bone progression, new bone lesions were reported in 45% and increase in the size of pre-existing lesions in 71%. Bone progression was concomitant with a SRE in 54% of cases, most of which (78%) affected a pre-existing bone lesion at baseline (Supplemental Table 9). SREs occurred in 32% of patients and
Real-World Outcomes of First-Line Immune-Based

<table><caption>**Table 1** Baseline Characteristics of the Patients</caption><thead><tr><th>Variable</th><th>Overall,<br>N = 124</th><th>ICI-ICI,<br>N = 68</th><th>ICI-TKI,<br>N = 56</th><th>P-Value<sup>a</sup></th></tr></thead><tbody><tr><td>Age, median (range)</td><td>64 (37-91)</td><td>64 (42-87)</td><td>64 (37-91)</td><td>.4</td></tr><tr><td>Age, N (%)</td><td></td><td></td><td></td><td>> .9</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;≤ 65</td><td>66 (53%)</td><td>36 (53%)</td><td>30 (54%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;&gt; 65</td><td>58 (47%)</td><td>32 (47%)</td><td>26 (46%)</td><td></td></tr><tr><td>Gender, N (%)</td><td></td><td></td><td></td><td>.3</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Female</td><td>34 (27%)</td><td>16 (24%)</td><td>18 (32%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Male</td><td>90 (73%)</td><td>52 (76%)</td><td>38 (68%)</td><td></td></tr><tr><td>ECOG-PS at baseline, N (%)</td><td></td><td></td><td></td><td>> .9</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;0</td><td>25 (20%)</td><td>14 (21%)</td><td>11 (20%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;1</td><td>61 (49%)</td><td>32 (47%)</td><td>29 (52%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;2</td><td>33 (27%)</td><td>19 (28%)</td><td>14 (25%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;3</td><td>5 (4.0%)</td><td>3 (4.4%)</td><td>2 (3.6%)</td><td></td></tr><tr><td>Metastatic disease at initial diagnosis</td><td>70 (56%)</td><td>35 (51%)</td><td>35 (63%)</td><td>.2</td></tr><tr><td>IMDC score, N (%)</td><td></td><td></td><td></td><td>.008</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Favorable</td><td>15 (12%)</td><td>3 (4.4%)</td><td>12 (21%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Intermediate</td><td>64 (52%)</td><td>41 (60%)</td><td>23 (41%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Poor</td><td>45 (36%)</td><td>24 (35%)</td><td>21 (38%)</td><td></td></tr><tr><td>Extra skeletal metastatic sites</td><td></td><td></td><td></td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Lung</td><td>75 (60%)</td><td>41 (60%)</td><td>34 (61%)</td><td>> .9</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Lymph nodes</td><td>60 (48%)</td><td>35 (51%)</td><td>25 (45%)</td><td>> .9</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Liver</td><td>20 (16%)</td><td>11 (16%)</td><td>9 (16%)</td><td>.7</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Adrenal Gland</td><td>15 (12%)</td><td>4 (6.0%)</td><td>11 (20%)</td><td>.06</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Brain</td><td>7 (5.6%)</td><td>4 (6.0%)</td><td>3 (5.0%)</td><td>> .9</td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Other</td><td>29 (23%)</td><td>16 (24%)</td><td>13 (23%)</td><td>> .9</td></tr><tr><td>Bone only metastases</td><td>27 (22%)</td><td>14 (21%)</td><td>13 (23%)</td><td>.8</td></tr><tr><td>History of nephrectomy</td><td>61 (49%)</td><td>37 (54%)</td><td>24 (43%)</td><td>.2</td></tr><tr><td>First line of therapy, N (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Nivolumab-axitinib</td><td>1 (0.8%)</td><td>—</td><td>1 (1.8%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Nivolumab-cabozantinib</td><td>23 (19%)</td><td>—</td><td>23 (41%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Nivolumab-ipilimumab</td><td>68 (55%)</td><td>68 (100%)</td><td>—</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Nivolumab-tivozanib</td><td>1 (0.8%)</td><td>—</td><td>1 (1.8%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Pembrolizumab-axitinib</td><td>30 (24%)</td><td>—</td><td>30 (54%)</td><td></td></tr><tr><td>&nbsp;&nbsp;&nbsp;&nbsp;Pembrolizumab-lenvatinib</td><td>1 (0.8%)</td><td>—</td><td>1 (1.8%)</td><td></td></tr></tbody></table>

Abbreviations: ECOG-PS = Eastern Cooperative Oncology Group-Performance Status; ICI = immune checkpoint inhibitor; IMDC = International Metastatic Renal Cell Carcinoma Database; TKI = tyrosine kinase inhibitor.

was numerically more frequent in the ICI-TKI group (38% vs. ICI-ICI: 28%; $P = .3$). Most patients experienced only 1 on-treatment SRE (70%), while 30% had 2. The most frequent SREs were radiotherapy (65%), interventional procedures (25%), and surgery (20%), with similar distributions across treatment groups (Supplemental Table 10). No significant predictors of SREs were identified (Supplemental Tables 11 and 12). Bone pain improved during treatment in 45% of evaluable patients, with comparable rates between treatment groups (ICI-ICI: 44%, ICI-TKI: 46%; $P = .8$; Table 3). Hypercalcemia was observed in 6.5% of patients.

Discussion

To our knowledge, this is the largest retrospective study addressing bone-specific endpoints in patients with BM+ mccRCC treated with first line ICI-based combinations. In our cohort of 124

patients, the median OS was 28.8 months, and the median TTNT was 11.7 months. Data specific to BM+ patients receiving first-line ICI-based combinations remain scarce. Among pivotal trials, only CLEAR and CheckMate 9ER specifically reported survival outcomes for this subgroup, with a median OS of 36.9 months with PembroLenva and 34.8 months (95% CI, 21.4-58.9) with NivoCabo.16,17 In our study, patients treated with NivoCabo had a median OS of 28.8 months, which may reflect the higher proportion (38%) of poor-risk IMDC patients compared to 19% in CheckMate 9ER. Only 1 patient in our cohort received PembroLenva, precluding any meaningful comparison with the CLEAR trial. This limited representation likely reflects the timing of its approval, as PembroLenva was the most recently authorized ICI-TKI combination. Desai et al.27 reported a median OS of 25.6 months with NivoIpi in a multi-institutional retrospective analysis

<footnote>a Independent samples t-test; Fisher's exact test; Pearson's Chi-squared test.</footnote>
<table><caption>**Table 2** Baseline Bone Disease Characteristics</caption><thead><tr><th>Variable</th><th>Overall,<br>N = 124</th><th>ICI-ICI,<br>N = 68</th><th>ICI-TKI,<br>N = 56</th><th>P-Value<sup>b</sup></th></tr></thead><tbody><tr><td>Number of bone lesions, N (%)</td><td></td><td></td><td></td><td>.8</td></tr><tr><td>1</td><td>47 (38%)</td><td>27 (40%)</td><td>20 (36%)</td><td></td></tr><tr><td>2-3</td><td>47 (38%)</td><td>24 (35%)</td><td>23 (41%)</td><td></td></tr><tr><td>&gt; 3</td><td>30 (24%)</td><td>17 (25%)</td><td>13 (23%)</td><td></td></tr><tr><td>Bone metastases sites, N (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Spine</td><td>79 (64%)</td><td>39 (57%)</td><td>40 (71%)</td><td>.1</td></tr><tr><td>Pelvic bone</td><td>57 (46%)</td><td>37 (54%)</td><td>20 (36%)</td><td>.04</td></tr><tr><td>Rib/sternum</td><td>36 (29%)</td><td>19 (28%)</td><td>17 (30%)</td><td>.9</td></tr><tr><td>Long bone</td><td>34 (27%)</td><td>21 (31%)</td><td>13 (23%)</td><td>.3</td></tr><tr><td>Other</td><td>12 (9.7%)</td><td>5 (7.4%)</td><td>7 (13%)</td><td>.3</td></tr><tr><td>Bone pain at baseline</td><td>92 (74%)</td><td>49 (72%)</td><td>43 (77%)</td><td>.5</td></tr><tr><td>Hypercalcemia at baseline</td><td>16 (13%)</td><td>8 (12%)</td><td>8 (14%)</td><td>.7</td></tr><tr><td>Use of a BTA at baseline</td><td>9 (7.3%)</td><td>5 (7.4%)</td><td>4 (7.1%)</td><td>&gt; .9</td></tr><tr><td>History of SRE at baseline</td><td>57 (46%)</td><td>26 (38%)</td><td>31 (55%)</td><td>.05</td></tr><tr><td>Number of SRE, N (%)<sup>a</sup></td><td></td><td></td><td></td><td>&gt; .9</td></tr><tr><td>1</td><td>45 (79%)</td><td>20 (77%)</td><td>25 (81%)</td><td></td></tr><tr><td>2</td><td>8 (14%)</td><td>4 (15%)</td><td>4 (13%)</td><td></td></tr><tr><td>3</td><td>4 (7.0%)</td><td>2 (7.7%)</td><td>2 (6.5%)</td><td></td></tr><tr><td>Type of SRE, N (%)<sup>a</sup></td><td></td><td></td><td></td><td>.3</td></tr><tr><td>Surgery to bone</td><td>19 (33%)</td><td>9 (35%)</td><td>10 (32%)</td><td></td></tr><tr><td>Interventional radiology procedure on bone</td><td>12 (21%)</td><td>6 (23%)</td><td>6 (19%)</td><td></td></tr><tr><td>Spinal cord compression</td><td>5 (8.8%)</td><td>4 (15%)</td><td>1 (3%)</td><td></td></tr><tr><td>Pathological fractures</td><td>4 (7.0%)</td><td>3 (12%)</td><td>1 (3%)</td><td></td></tr><tr><td>Radiotherapy to bone</td><td>29 (51%)</td><td>10 (38%)</td><td>19 (61%)</td><td></td></tr></tbody></table>

Abbreviations: BTA = bone-targeting agent; ICI = immune checkpoint inhibitor; SRE = skeletal-related event; TKI = tyrosine kinase inhibitor.

<table><caption>**Table 3** Bone-Specific Outcomes in the Overall Population and by Treatment Group</caption><thead><tr><th>Variable</th><th>Overall,<br>N = 124</th><th>ICI-ICI,<br>N = 68</th><th>ICI-TKI,<br>N = 56</th><th>P-Value<sup>a</sup></th></tr></thead><tbody><tr><td>Efficacy on bone pain, N (%)</td><td></td><td></td><td></td><td>.8</td></tr><tr><td>Improvement</td><td>41 (45%)</td><td>22 (44%)</td><td>19 (46%)</td><td></td></tr><tr><td>Stability</td><td>21 (23%)</td><td>10 (20%)</td><td>11 (27%)</td><td></td></tr><tr><td>Worsening</td><td>29 (32%)</td><td>18 (36%)</td><td>11 (27%)</td><td></td></tr><tr><td>No bone pain at baseline</td><td>27</td><td>14</td><td>13</td><td></td></tr><tr><td>Missing Data</td><td>6</td><td>4</td><td>2</td><td></td></tr><tr><td>Hypercalcemia during treatment, N (%)</td><td>8 (6.5%)</td><td>5 (7.4%)</td><td>3 (5.4%)</td><td>.7</td></tr><tr><td>Bone disease progression, N (%)</td><td>59 (48%)</td><td>29 (43%)</td><td>30 (54%)</td><td>.2</td></tr><tr><td>SRE during treatment, N (%)</td><td>40 (32%)</td><td>19 (28%)</td><td>21 (38%)</td><td>.3</td></tr></tbody></table>

Abbreviations: ICI = immune checkpoint inhibitor; SRE = skeletal-related events; TKI = tyrosine kinase inhibitor.

of 80 BM+ patients, closely aligning with the 27.5 months observed in our cohort. When comparing our results to the Canadian CKCis cohort of 893 BM+ patients, our median OS was lower (35.8 vs. 28.8 months).<sup>28</sup> However, fewer patients in the CKCis cohort had poor-risk disease (17% vs. 36%) and only a third received ICI-based combinations (20% ICI-ICI, 13% ICI-TKI), limiting direct comparisons.

In our cohort, bone-only metastatic disease was associated with a favorable prognosis, being independently associated with longer OS.

This aligns with findings from Ruatta et al.<sup>24</sup> who conducted a retrospective analysis of 300 patients with BM+ mccRCC. Their study demonstrated that the absence of concomitant visceral metastases was significantly associated with longer OS, particularly in patients presenting with a single bone lesion. One hypothesis is that patients with bone-confined disease may benefit from aggressive local treatment strategies aimed at oligometastatic control. However, in our cohort, the proportion of patients who received local therapies at baseline was comparable between those with bone-only disease

<footnote><sup>a</sup> Percentages for the number and type of SREs were calculated among patients who experienced at least 1 SRE (n = 57; ICI-ICI group: n = 26, ICI-TKI group: n = 31).</footnote>

<footnote><sup>b</sup> Fisher's exact test; Pearson's Chi-squared test.</footnote>

<footnote><sup>a</sup> Pearson's Chi-squared test.</footnote>
Real-World Outcomes of First-Line Immune-Based

<figure><img src="image_3.png" /><figcaption>**Figure 1** Bone metastases sites.</figcaption></figure>

(44%) and those with additional metastatic sites (40%), suggest-
ing that other factors may contribute to the favorable prognosis
observed. It is also plausible that bone-only disease represents a
biologically more indolent subset of mccRCC, which remains to be
confirmed in molecularly annotated cohorts.

Baseline hypercalcemia was as an independent prognostic factor for both OS and bPFS in our study. This observation is consistent with the prognostic role historically attributed to hypercalcemia in mccRCC. In the original Memorial Sloan-Kettering Cancer Center (MSKCC) model, Motzer et al.²⁹ identified elevated corrected serum calcium as one of the 5 independent predictors of poor survival. This finding was subsequently validated in the targeted therapy era, notably in the large multicenter cohort reported by Heng et al.³⁰ where baseline hypercalcemia remained independently associated with inferior overall survival. Hypercalcemia was later retained as a core adverse prognostic factor in the IMDC risk model,³¹ confirming its robustness across treatment eras. Our results extend these observations by demonstrating its prognostic relevance for bone-specific outcomes in bone-metastatic disease.

Bone-specific endpoints were a central focus of our study. Nearly
half of patients experienced bone progression, with a median bPFS
of 11.7 months. These findings provide novel insight, as bone
progression has not been reported in pivotal trials or most retro-
spective series. Importantly bPFS was independently improved in
patients receiving BTAs such as bisphosphonates or denosumab, at
baseline. This observation supports the potential role of adjunctive
BTAs in delaying skeletal progression. While Velev et al.¹⁰ reported

a lower incidence of SREs with BTA use in patients treated with
nivolumab monotherapy in the NIVOREN cohort, our logistic
regression analysis could not reliably estimate this effect because
only 7% of patients in our cohort received BTAs. Despite modern
therapy, on-treatment SREs still occurred in about one-third of
patients. Among patients who experienced bone progression, over
half developed an SRE concomitantly, most often involving pre-
existing bone lesions. These findings highlight the clinical burden
of bone disease despite systemic treatment and support the use of
early local interventions to mitigate skeletal complications.

A key aim of our study was to assess whether first-line treat-
ment choice impacts outcomes in patients with BM. In our cohort,
patients treated with ICI-TKI experienced a numerically longer
TTNT than those treated with ICI-ICI, although this difference did
not reach statistical significance and did not translate into an overall
survival advantage. This trend may partially reflect treatment-related
factors, including TKI dose escalation for some patients and a high
proportion of favorable-risk disease in the ICI-TKI group. The
absence of an OS difference may also be explained by subsequent
therapies, as most patients initially treated with ICI-ICI received
a VEGFR-TKI at progression. Higher rates of bone progression
and SREs were observed in the ICI-TKI group, which may be
attributed to more aggressive bone disease at baseline, as indicated
by a greater proportion of patients with pretreatment SREs. In
exploratory analyses comparing ICI-TKI regimens, patients treated
with NivoCabo had numerically longer TTNT (20.0 vs. 14.6
months) and bPFS (13.9 vs. 9.31 months) than those treated with
<figure><img src="image_4.png" /><figcaption>**Figure 2** Kaplan-Meier curves for time to next treatment (A and B), overall survival (C and D) and bone progression-free survival (E and F) in the overall population and by treatment group, respectively.</figcaption></figure>
# Real-World Outcomes of First-Line Immune-Based

PembroAxi. These findings are descriptive and should be interpreted with caution given the limited sample size. However, they may reflect pharmacodynamic differences between regimens, particularly as cabozantinib uniquely targets the mesenchymal-epithelial transition (MET) receptor, a tyrosine kinase involved in the HGF/MET pathway.³² MET is frequently overexpressed in BM+ mccRCC, and preclinical data suggest that cabozantinib can modulate the bone microenvironment, with effects such as inhibition of osteoclast production.³³⁻³⁵ In an ancillary analysis of the METEOR trial, Escudier et al.³⁶ reported more pronounced changes in bone biomarkers with cabozantinib compared to everolimus. Prospective validation remains warranted.

There are several limitations to our study. Owing to the retrospective design, treatment allocation was not randomized, and the choice between ICI-ICI and ICI-TKI may have introduced potential selection bias. This design may also have resulted in reporting biases, missing data, and heterogeneity in imaging follow-up. Bone progression was assessed based on local radiology reports without central review, potentially introducing inter-institutional variability. Changes in bone pain were not assessed using standardized scales, and analgesic use was inconsistently reported during follow-up, limiting pain evaluation to qualitative information based on patient-reported symptoms described in clinical records. In addition, variability in supportive care practices across centers may have influenced outcome assessment. Despite the multicenter nature of the study, the overall sample size (n = 124) remained relatively small, limiting statistical power of subgroup analyses. Furthermore, while median follow-up exceeded 3 years, some patients were censored early for bPFS due to treatment discontinuation related to toxicity or progression at extra skeletal sites. Finally, the study focused exclusively on patients with clear-cell histology treated in the first-line setting; thus, findings may not be generalizable to non-clear-cell RCC or subsequent lines of therapy.

## Conclusion

Our findings provide new insights into bone-specific outcomes in patients with BM+mccRCC treated with contemporary first-line ICI-based therapies. Although TTNT was numerically longer with ICI-TKI combinations, neither a survival advantage nor improvements in bone-specific outcomes were observed between the treatment strategies. Nearly half of patients experienced bone progression, and SREs remained frequent, underscoring the continued importance of local management strategies. Incorporating bone-specific endpoints in future trials, may better guide treatment decisions and identify subgroups most likely to benefit from tailored systemic approaches or adjunctive local and bone-targeted therapies.

## Clinical Practice Points

* What is already known about this subject?

Bone metastases occur in approximately one-third of patients with metastatic clear cell renal cell carcinoma (mccRCC) and are associated with poor prognosis and frequent skeletal-related events (SREs). Although immune checkpoint inhibitor (ICI)-based combinations have improved overall outcomes in mccRCC, the optimal first-line strategy and the bone-specific impact of

these regimens in patients with bone metastases remain poorly defined.

* What are the new findings?

This large multicenter real-world study specifically evaluated bone-specific outcomes in patients with bone-metastatic mccRCC treated with first-line ICI-ICI or ICI-TKI combinations. Both strategies yielded comparable overall survival and bone progression-free survival (bPFS). Nearly half of patients developed bone progression, and SREs occurred in about one-third, most often involving preexisting bone lesions. Use of bone-targeting agents (BTAs) such as bisphosphonates or denosumab was independently associated with prolonged bPFS.

* How might it impact on clinical practice in the foreseeable future?

These findings emphasize that despite modern systemic therapies, bone disease remains a major source of morbidity in mccRCC. The results support early integration of local treatments and BTAs to delay bone progression. The absence of a clearly superior first-line strategy underscores the need for prospective comparative studies specifically designed for patients with bone metastases.

## Disclosure

Fabien Moinard-Butot: Advisory Board – Bristol Myers Squibb; Hospitality – Merck, Gilead. Edouard Auclin: Invited Speaker – MSD; Advisory Board – Amgen, Sanofi; Funding – Ipsen (Inst); Travel – Amgen. Philippe Barthélémy: Advisory Board, Invited Speaker, Travel – Bristol Myers Squibb, MSD, Merck, Pfizer, Ipsen, Eisai, Bayer, Johnson & Johnson, Astellas, Novartis, Gilead, AstraZeneca, Accord Healthcare; Coordinating PI – Ipsen (Inst). Johanna Noël: Invited Speaker – Ipsen (Inst). Clément Dumont: Consulting or Advisory Role – Pfizer, Bristol Myers Squibb, Astellas Pharma, Bayer, Merck Serono, Ipsen, MSD; Travel/Accommodation/Expenses – Ipsen, Pfizer, MSD, Janssen, Bayer. Hélène Gauthier: Advisory Board – Adacap, Bristol Myers Squibb, Pfizer, Merck; Invited Speaker – Novartis. Olivier Huillard: Advisory Board – Janssen, Bristol Myers Squibb, AstraZeneca, Pfizer, Eisai, Bayer, AAA, Merck, MSD; Invited Speaker – Sanofi, Ipsen, Novartis. Loïc Jaffrelot: Advisory Board – Bayer, Merck; Invited Speaker – Bristol Myers Squibb. Thomas Seisen: Consulting or Advisory Role – Adacap, Bristol Myers Squibb, Janssen, Pfizer, Astellas, Bayer, VitaDX; Honoraria – Adacap, Bristol Myers Squibb, Janssen, Pfizer, Astellas, Bayer, VitaDX; Travel/Accommodation/Expenses – Ipsen, Bayer, Janssen. Charlotte Joly: Consulting – Eisai; Educational Session – Ipsen, Bayer; Travel – Bayer. Christophe Tournigand: Advisory Board – Pfizer; Invited Speaker – MSD; Leadership Role – GERCOR; Advisory Role – Fondation AP-HP; Travel – AstraZeneca. Mostefa Bennamoun: Invited Speaker – Astellas; Advisory Board – Janssen, Novartis; Principal Investigator – Janssen. Mathilde Cancel: Invited Speaker – Sanofi, Bristol Myers Squibb; Research Grant – Ipsen (Inst). Stéphane Oudard: Advisory Board – Sanofi, AstraZeneca, MSD, Merck, Astellas, Ipsen, Pfizer, Roche, Bristol Myers Squibb, Bayer, Novartis; Invited Speaker – Janssen, Astellas, Ipsen, Bayer; Funding – AstraZeneca (Inst), Sanofi (Inst), Bristol Myers Squibb (Inst), Bayer (Inst); Research Grant – Janssen (Inst), Ipsen (Inst). Constance Thibault: Advisory Board – Janssen, Astellas, Ipsen,
Pfizer, Merck, MSD, Bristol Myers Squibb, AstraZeneca, AAA, Seagen, Gilead; Invited Speaker – Amgen, Bayer; Funding – AstraZeneca (Inst), Sanofi (Inst), Bristol Myers Squibb (Inst); Research Grant – Janssen (Inst). Other authors have declared that they have no conflict of interest.

CRediT authorship contribution statement

**Alia Harba:** Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
**Fabien Moinard-Butot:** Writing – review & editing, Data curation.
**Edouard Auclin:** Writing – review & editing, Methodology, Formal analysis.
**Philippe Barthélémy:** Writing – review & editing.
**Johanna Noel:** Writing – review & editing.
**Clément Dumont:** Writing – review & editing.
**Hélène Gauthier:** Writing – review & editing.
**Olivier Huillard:** Writing – review & editing.
**Loïc Jaffrelot:** Writing – review & editing.
**Thomas Seisen:** Writing – review & editing.
**Charlotte Joly:** Writing – review & editing.
**Christophe Tournigand:** Writing – review & editing.
**Mostefa Bennamoun:** Writing – review & editing.
**Matthieu Roulleaux-Dugage:** Writing – review & editing.
**Mathilde Cancel:** Writing – review & editing, Data curation.
**Victor Heurtier:** Writing – review & editing, Data curation.
**Hamid Lardjani:** Data curation.
**Stéphane Oudard:** Writing – review & editing.
**Constance Thibault:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Investigation, Formal analysis.

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Real-World Outcomes of First-Line Immune-Based

Supplementary material

<table><caption>**Supplemental Table 1** Number of Patients Included per Center</caption><thead><tr><td>Center</td><td>Number of Patients</td></tr></thead><tbody><tr><td>ICANS</td><td>38</td></tr><tr><td>Hôpital Européen Georges Pompidou</td><td>22</td></tr><tr><td>Hôpital Cochin</td><td>17</td></tr><tr><td>Hôpital Pitié Salpêtrière</td><td>14</td></tr><tr><td>Hôpital Saint-Louis</td><td>14</td></tr><tr><td>Hôpital Henri Mondor</td><td>11</td></tr><tr><td>Institut Mutualiste Montsouris</td><td>6</td></tr><tr><td>CHU de Tours</td><td>2</td></tr></tbody></table>

<table><caption>**Supplemental Table 2** Baseline Characteristics by ICI-TKI Regimen (Nivolumab-Cabozantinib vs. Pembrolizumab-Axitinib)</caption><thead><tr><td>Variable</td><td>Nivolumab-Cabozantinib<br>N = 23</td><td>Pembrolizumab-Axitinib,<br>N = 30</td></tr></thead><tbody><tr><td>Age, median (range)</td><td>62 (47-91)</td><td>68 (47-86)</td></tr><tr><td>Age, N (%)</td><td></td><td></td></tr><tr><td>≤ 65</td><td>14 (61%)</td><td>14 (47%)</td></tr><tr><td>> 65</td><td>9 (39%)</td><td>16 (53%)</td></tr><tr><td>Gender, N (%)</td><td></td><td></td></tr><tr><td>Female</td><td>9 (39%)</td><td>9 (30%)</td></tr><tr><td>Male</td><td>14 (61%)</td><td>21 (70%)</td></tr><tr><td>ECOG-PS at baseline, N (%)</td><td></td><td></td></tr><tr><td>0</td><td>5 (22%)</td><td>6 (20%)</td></tr><tr><td>1</td><td>9 (39%)</td><td>18 (60%)</td></tr><tr><td>2</td><td>8 (35%)</td><td>5 (17%)</td></tr><tr><td>3</td><td>1 (4.3%)</td><td>1 (3.3%)</td></tr><tr><td>IMDC score, N (%)</td><td></td><td></td></tr><tr><td>Favorable</td><td>2 (8.7%)</td><td>9 (30%)</td></tr><tr><td>Intermediate</td><td>10 (43%)</td><td>9 (30%)</td></tr><tr><td>Poor</td><td>11 (48%)</td><td>12 (40%)</td></tr><tr><td>Metastatic disease at initial diagnosis</td><td>15 (65%)</td><td>18 (60%)</td></tr><tr><td>Extraskeletal metastatic sites</td><td></td><td></td></tr><tr><td>Lung</td><td>14 (61%)</td><td>18 (60%)</td></tr><tr><td>Lymph nodes</td><td>9 (39%)</td><td>16 (53%)</td></tr><tr><td>Liver</td><td>3 (13%)</td><td>6 (20%)</td></tr><tr><td>Adrenal Gland</td><td>3 (13%)</td><td>7 (23%)</td></tr><tr><td>Brain</td><td>2 (9%)</td><td>1 (3%)</td></tr><tr><td>Other</td><td>6 (26%)</td><td>7 (23%)</td></tr><tr><td>Bone only metastases</td><td>5 (22%)</td><td>8 (27%)</td></tr><tr><td>History of nephrectomy</td><td>8 (35%)</td><td>15 (50%)</td></tr></tbody></table>

Abbreviations: ECOG-PS = Eastern Cooperative Oncology Group-Performance Status; IMDC = International Metastatic Renal Cell Carcinoma Database.
<caption>Supplemental Table 3</caption>

Baseline Bone Disease Characteristics by ICI-TKI Regimen (Nivolumab-Cabozantinib vs. Pembrolizumab-Axitinib)

<table><thead><tr><th>Variable</th><th>Nivolumab-Cabozantinib<br>N = 23</th><th>Pembrolizumab-Axitinib,<br>N = 30</th></tr></thead><tbody><tr><td>Number of bone lesions, N (%)</td><td></td><td></td></tr><tr><td>1</td><td>10 (43%)</td><td>10 (33%)</td></tr><tr><td>2-3</td><td>10 (43%)</td><td>10 (33%)</td></tr><tr><td>&gt; 3</td><td>3 (13%)</td><td>10 (33%)</td></tr><tr><td>Bone metastases sites, N (%)</td><td></td><td></td></tr><tr><td>Rib/sternum</td><td>7 (30%)</td><td>9 (30%)</td></tr><tr><td>Spine</td><td>15 (65%)</td><td>22 (73%)</td></tr><tr><td>Pelvic bone</td><td>7 (30%)</td><td>12 (40%)</td></tr><tr><td>Long bone</td><td>5 (22%)</td><td>8 (27%)</td></tr><tr><td>Other</td><td>1 (4.3%)</td><td>6 (20%)</td></tr><tr><td>Bone pain at baseline</td><td>18 (78%)</td><td>22 (73%)</td></tr><tr><td>Hypercalcemia at baseline</td><td>5 (22%)</td><td>3 (10%)</td></tr><tr><td>Use of a BTA at baseline</td><td>3 (13%)</td><td>1 (3.3%)</td></tr><tr><td>History of SRE at baseline</td><td>14 (61%)</td><td>15 (50%)</td></tr><tr><td>Number of SRE, N (%)<sup>a</sup></td><td></td><td></td></tr><tr><td>1</td><td>10 (71%)</td><td>13 (87%)</td></tr><tr><td>2</td><td>2 (14%)</td><td>2 (13%)</td></tr><tr><td>3</td><td>2 (14%)</td><td>0 (0%)</td></tr><tr><td>Type of SRE, N (%)<sup>a</sup></td><td></td><td></td></tr><tr><td>Surgery to bone</td><td>6 (43%)</td><td>4 (27%)</td></tr><tr><td>Interventional radiology procedure on bone</td><td>2 (14%)</td><td>3 (20%)</td></tr><tr><td>Spinal cord compression</td><td>1 (7%)</td><td>0 (0%)</td></tr><tr><td>Pathological fractures</td><td>0 (0%)</td><td>1 (7%)</td></tr><tr><td>Radiotherapy to bone</td><td>9 (64%)</td><td>9 (60%)</td></tr></tbody></table>

Abbreviations: BTA = bone-targeting agent; SRE = skeletal-related event.

<caption>Supplemental Table 4</caption>

Subsequent Treatment Strategies Following First-Line ICI-ICI or ICI-TKI Combinations

<table><thead><tr><th></th><th>ICI-ICI</th><th>ICI-TKI</th></tr></thead><tbody><tr><td>TKI dose escalation</td><td>—</td><td>5/38 (13%)<sup>a</sup></td></tr><tr><td>Second-line treatment, N (%)</td><td>35 (51%)</td><td>41 (41%)</td></tr><tr><td>Cabozantinib</td><td>23</td><td>18</td></tr><tr><td>Axitinib</td><td>2</td><td>1</td></tr><tr><td>Lenvatinib</td><td>1</td><td>1</td></tr><tr><td>Sunitinib</td><td>2</td><td>0</td></tr><tr><td>Pazopanib</td><td>1</td><td>0</td></tr><tr><td>Cabozantinib-nivolumab</td><td>3</td><td>0</td></tr><tr><td>Lenvatinib-Pembrolizumab</td><td>2</td><td>1</td></tr><tr><td>Lenvatinib-belzutifan</td><td>1</td><td>0</td></tr><tr><td>Pembrolizumab-Belzutifan</td><td>0</td><td>1</td></tr><tr><td>XL092 (Zanzalintinib)</td><td>0</td><td>1</td></tr><tr><td>Third-line treatment, N (%)</td><td>18 (25%)</td><td>7 (13%)</td></tr><tr><td>Cabozantinib</td><td>6</td><td>0</td></tr><tr><td>Axitinib</td><td>4</td><td>0</td></tr><tr><td>Lenvatinib</td><td>1</td><td>3</td></tr><tr><td>Lenvatinib-everlimus</td><td>1</td><td>0</td></tr><tr><td>Pazopanib</td><td>1</td><td>0</td></tr><tr><td>Cabozantinib-nivolumab</td><td>0</td><td>1</td></tr><tr><td>Lenvatinib-Pembrolizumab</td><td>2</td><td>1</td></tr><tr><td>Axitinib-pembrolizumab</td><td>0</td><td>1</td></tr><tr><td>Nivolumab-ipilimumab</td><td>1</td><td>1</td></tr><tr><td>Nivolumab</td><td>2</td><td>0</td></tr></tbody></table>

<footnote>a Percentages for the number and type of SREs were calculated among patients who experienced at least 1 SRE (Nivolumab-Cabozantinib group: n = 14, Pembrolizumab-Axitinib group: n = 15).</footnote>

<footnote>a Only 38 of the 56 patients in the ICI-TKI group had available data regarding treatment adaptation.</footnote>
Real-World Outcomes of First-Line Immune-Based

<table><caption>Supplemental Table 5 Univariate and Multivariate Cox Proportional Hazards Analysis for Time to Next Treatment</caption><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 65</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>> 65</td><td>1.02</td><td>0.66, 1.57</td><td>.93</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Male</td><td>1.45</td><td>0.88, 2.37</td><td>.14</td><td>—</td><td>—</td><td>—</td></tr><tr><td>ECOG-PS at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>1</td><td>1.66</td><td>0.89, 3.09</td><td>.11</td><td>1.40</td><td>0.72, 2.69</td><td>.3</td></tr><tr><td>2-3</td><td>2.61</td><td>1.35, 5.02</td><td>.004</td><td>1.90</td><td>0.93, 3.90</td><td>.080</td></tr><tr><td>IMDC score</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favorable</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Intermediate</td><td>1.60</td><td>0.73, 3.49</td><td>.24</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Poor</td><td>1.82</td><td>0.86, 3.85</td><td>.12</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Metastatic disease at initial diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.15</td><td>0.74, 1.77</td><td>.54</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Bone-only metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.73</td><td>0.43, 1.24</td><td>.24</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lung metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.11</td><td>0.72, 1.72</td><td>.63</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lymph node metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.26</td><td>0.82, 1.93</td><td>.29</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Liver metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.25</td><td>0.71, 2.18</td><td>.43</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Adrenal metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.98</td><td>1.06, 3.69</td><td>.031</td><td>1.27</td><td>0.63, 2.56</td><td>.5</td></tr><tr><td>Cerebral metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.05</td><td>0.42, 2.59</td><td>.92</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Number of bone lesions</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>2-3</td><td>1.22</td><td>0.74, 2.03</td><td>.43</td><td>—</td><td>—</td><td>—</td></tr><tr><td>> 3</td><td>1.64</td><td>0.96, 2.82</td><td>.072</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Rib/sternum metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.82</td><td>0.50, 1.35</td><td>.45</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Spine metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.30</td><td>0.83, 2.04</td><td>.25</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Pelvic bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.05</td><td>0.68, 1.61</td><td>.83</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

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**Supplemental Table 5** (continued)

<table><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Long bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.75</td><td>1.11, 2.76</td><td>.016</td><td>1.54</td><td>0.95, 2.50</td><td>.082</td></tr><tr><td>Bone pain at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.95</td><td>1.14, 3.34</td><td>.015</td><td>1.38</td><td>0.73, 2.60</td><td>.3</td></tr><tr><td>Hypercalcemia at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.97</td><td>1.08, 3.59</td><td>.027</td><td>1.38</td><td>0.70, 2.70</td><td>.4</td></tr><tr><td>SRE at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.58</td><td>1.03, 2.43</td><td>.037</td><td>1.16</td><td>0.71, 1.90</td><td>.5</td></tr><tr><td>Use of a BTA at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.62</td><td>0.23, 1.69</td><td>.35</td><td>—</td><td>—</td><td>—</td></tr><tr><td>First line therapy</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ICI-ICI</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>ICI-TKI</td><td>0.81</td><td>0.53, 1.26</td><td>.35</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

Abbreviations: BTA = bone-targeting agent; ECOG-PS = Eastern Cooperative Oncology Group-Performance Status; ICI = immune checkpoint inhibitor; IMDC = International Metastatic Renal Cell Carcinoma Database; SRE = skeletal-related event; TKI = tyrosine-kinase inhibitor.

**Supplemental Table 6** Univariate and Multivariate Cox Proportional Hazards Analysis for Overall Survival

<table><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 65</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>> 65</td><td>1.43</td><td>0.89, 2.29</td><td>.13</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Male</td><td>2.03</td><td>1.13, 3.66</td><td>.018</td><td>2.46</td><td>1.31, 4.61</td><td>.005</td></tr><tr><td>ECOG-PS at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>1</td><td>2.27</td><td>1.04, 4.92</td><td>.038</td><td>2.06</td><td>0.89, 4.73</td><td>.090</td></tr><tr><td>2-3</td><td>4.63</td><td>2.11, 10.2</td><td>&lt; .001</td><td>2.70</td><td>1.09, 6.67</td><td>.031</td></tr><tr><td>IMDC score</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favorable</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Intermediate</td><td>2.56</td><td>0.99, 6.62</td><td>.053</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Poor</td><td>2.00</td><td>0.78, 5.09</td><td>.15</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Metastatic disease at initial diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.08</td><td>0.67, 1.75</td><td>.75</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Bone-only metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.48</td><td>0.25, 0.92</td><td>.026</td><td>0.42</td><td>0.20, 0.88</td><td>.022</td></tr><tr><td>Lung metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.34</td><td>0.82, 2.17</td><td>.24</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

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Real-World Outcomes of First-Line Immune-Based

<table><caption>Supplemental Table 6 (continued)</caption><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Lymph node metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.42</td><td>0.89, 2.27</td><td>.14</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Liver metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.15</td><td>0.62, 2.14</td><td>.66</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Adrenal metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>2.04</td><td>1.06, 3.93</td><td>.032</td><td>0.83</td><td>0.39, 1.78</td><td>.6</td></tr><tr><td>Cerebral metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.35</td><td>0.54, 3.36</td><td>.52</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Number of bone lesions</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>2-3</td><td>1.53</td><td>0.87, 2.69</td><td>.14</td><td>—</td><td>—</td><td>—</td></tr><tr><td>> 3</td><td>1.74</td><td>0.96, 3.18</td><td>.070</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Rib/sternum metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.91</td><td>0.53, 1.55</td><td>.73</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Spine metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.56</td><td>0.95, 2.57</td><td>.081</td><td>1.34</td><td>0.78, 2.31</td><td>.3</td></tr><tr><td>Pelvic bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.94</td><td>0.59, 1.50</td><td>.80</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Long bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.99</td><td>1.21, 3.26</td><td>.006</td><td>1.91</td><td>1.09, 3.34</td><td>.023</td></tr><tr><td>Bone pain at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.87</td><td>1.04, 3.36</td><td>.038</td><td>1.58</td><td>0.73, 3.41</td><td>.2</td></tr><tr><td>Hypercalcemia at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>3.23</td><td>1.72, 6.08</td><td>&lt; .001</td><td>3.13</td><td>1.57, 6.25</td><td>.001</td></tr><tr><td>SRE at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.53</td><td>0.96, 2.45</td><td>.076</td><td>0.97</td><td>0.55, 1.69</td><td>&gt; .9</td></tr><tr><td>Use of a BTA at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.65</td><td>0.20, 2.07</td><td>.47</td><td>—</td><td>—</td><td>—</td></tr><tr><td>First line therapy</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ICI-ICI</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>ICI-TKI</td><td>1.13</td><td>0.71, 1.82</td><td>.61</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

Abbreviations: BTA = bone-targeting agent; ECOG-PS = Eastern Cooperative Oncology Group-Performance Status; ICI = immune checkpoint inhibitor; IMDC = International Metastatic Renal Cell Carcinoma Database; SRE = skeletal-related event; TKI = tyrosine-kinase inhibitor.
<table><caption>Supplemental Table 7 Bone-Specific Outcomes by ICI-TKI Regimen (Nivolumab-Cabozantinib vs. Pembrolizumab-Axitinib)</caption><thead><tr><th>Variable</th><th>Nivolumab-Cabozantinib<br>N = 23</th><th>Pembrolizumab-Axitinib,<br>N = 30</th></tr></thead><tbody><tr><td>Efficacy on bone pain, N (%)</td><td></td><td></td></tr><tr><td>Improvement</td><td>7 (46%)</td><td>11 (46%)</td></tr><tr><td>Stability</td><td>4 (27%)</td><td>6 (25%)</td></tr><tr><td>Worsening</td><td>4 (27%)</td><td>7 (29%)</td></tr><tr><td>No bone pain at baseline</td><td>7</td><td>5</td></tr><tr><td>Missing Data</td><td>1</td><td>1</td></tr><tr><td>Hypercalcemia<br>during treatment, N (%)</td><td>1 (4.3%)</td><td>2 (6.7%)</td></tr><tr><td>Bone disease progression, N (%)</td><td>10 (44%)</td><td>19 (63%)</td></tr><tr><td>SRE during treatment, N (%)</td><td>9 (39%)</td><td>12 (40%)</td></tr></tbody></table>

<table><caption>Supplemental Table 8 Univariate and Multivariate Cox Proportional Hazards Analysis for Bone Progression-Free Survival</caption><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Age</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 65</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>> 65</td><td>1.13</td><td>0.71, 1.78</td><td>.61</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Male</td><td>1.74</td><td>1.00, 3.03</td><td>.051</td><td>1.99</td><td>1.11, 3.58</td><td>.021</td></tr><tr><td>ECOG-PS at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>1</td><td>1.92</td><td>0.95, 3.87</td><td>.068</td><td>1.40</td><td>0.66, 2.97</td><td>.4</td></tr><tr><td>2-3</td><td>3.11</td><td>1.50, 6.44</td><td>.002</td><td>2.17</td><td>0.94, 5.00</td><td>.070</td></tr><tr><td>IMDC score</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Favorable</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Intermediate</td><td>1.42</td><td>0.64, 3.15</td><td>.38</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Poor</td><td>1.73</td><td>0.81, 3.70</td><td>.16</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Metastatic disease at initial diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.12</td><td>0.70, 1.77</td><td>.64</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Bone-only metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.83</td><td>0.48, 1.45</td><td>.52</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lung metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.17</td><td>0.73, 1.87</td><td>.50</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Lymph node metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.02</td><td>0.64, 1.60</td><td>.95</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Liver metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.07</td><td>0.58, 1.99</td><td>.83</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

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Real-World Outcomes of First-Line Immune-Based

<table><caption>**Supplemental Table 8** (continued)</caption><thead><tr><th rowspan="2">Variables</th><th colspan="3">Univariate Analysis</th><th colspan="3">Multivariate Analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-Value</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Adrenal metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>2.22</td><td>1.18, 4.17</td><td>.013</td><td>1.41</td><td>0.70, 2.82</td><td>.3</td></tr><tr><td>Cerebral metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.89</td><td>0.32, 2.44</td><td>.82</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Number of bone lesions</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>2-3</td><td>1.49</td><td>0.86, 2.57</td><td>.16</td><td>0.94</td><td>0.51, 1.73</td><td>.8</td></tr><tr><td>&gt; 3</td><td>1.99</td><td>1.11, 3.56</td><td>.021</td><td>1.63</td><td>0.87, 3.05</td><td>.12</td></tr><tr><td>Rib/sternum metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.93</td><td>0.56, 1.56</td><td>.78</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Spine metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.20</td><td>0.74, 1.93</td><td>.47</td><td>1.34</td><td>0.78, 2.31</td><td>.3</td></tr><tr><td>Pelvic bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.22</td><td>0.77, 1.92</td><td>.40</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Long bone metastases</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.47</td><td>0.90, 2.40</td><td>.13</td><td>—</td><td>—</td><td>—</td></tr><tr><td>Bone pain at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>2.47</td><td>1.35, 4.53</td><td>.003</td><td>1.57</td><td>0.74, 3.30</td><td>.2</td></tr><tr><td>Hypercalcemia at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>2.29</td><td>1.22, 4.31</td><td>.010</td><td>2.24</td><td>1.07, 4.67</td><td>.031</td></tr><tr><td>SRE at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>1.53</td><td>0.97, 2.41</td><td>.070</td><td>1.31</td><td>0.78, 2.19</td><td>.3</td></tr><tr><td>Use of a BTA at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td>0.30</td><td>0.07, 1.22</td><td>.093</td><td>0.19</td><td>0.04, 0.80</td><td>.023</td></tr><tr><td>First Line Therapy</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>ICI-ICI</td><td>—</td><td>—</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>ICI-TKI</td><td>1.22</td><td>0.78, 1.93</td><td>.38</td><td>—</td><td>—</td><td>—</td></tr></tbody></table>

Abbreviations: BTA = bone-targeting agent; ICI = immune checkpoint inhibitor; ECOG-PS = Eastern Cooperative Oncology Group-Performance Status; IMDC = International Metastatic Renal Cell Carcinoma Database; SRE = skeletal-related event; TKI = tyrosine-kinase inhibitor.
<table><caption>**Supplemental Table 9** Patterns of Bone Disease Progression</caption><thead><tr><th></th><th>Overall,<br>N = 59</th><th>ICI-ICI,<br>N = 29</th><th>ICI-TKI,<br>N = 30</th></tr></thead><tbody><tr><td>Type of bone disease progression</td><td></td><td></td><td></td></tr><tr><td>New BM</td><td>25 (45%)</td><td>13 (48%)</td><td>12 (41%)</td></tr><tr><td>Increase in size of a pre-existing<br>BM</td><td>40 (71%)</td><td>20 (74%)</td><td>20 (69%)</td></tr><tr><td>Increase in the tissular<br>component of a pre-existing BM</td><td>6 (11%)</td><td>1 (3.7%)</td><td>5 (17%)</td></tr><tr><td>Increase in hypermetabolism (on<br>PETscans) of a pre-existing BM</td><td>2 (4%)</td><td>1 (4%)</td><td>1 (3%)</td></tr><tr><td>Bone disease progression<br>concomitant to SRE</td><td>32 (54%)</td><td>15 (52%)</td><td>17 (57%)</td></tr><tr><td>Affecting a pre-existing bone<br>lesion</td><td>25/32 (78%)</td><td>12/15 (80%)</td><td>13/17 (76%)</td></tr><tr><td>Affecting a new lesion</td><td>7/32 (22%)</td><td>3/15 (20%)</td><td>4/17 (24%)</td></tr></tbody></table>

<table><caption>**Supplemental Table 10** Characteristics of on-Treatment SREs</caption><thead><tr><th>SRE During<br>Treatment</th><th>Overall,<br>N = 40</th><th>ICI-ICI,<br>N = 19</th><th>ICI-TKI,<br>N = 21</th><th>P-Value</th></tr></thead><tbody><tr><td>Number of SRE, N<br>(%)</td><td></td><td></td><td></td><td>.06</td></tr><tr><td>1</td><td>28 (70%)</td><td>16 (84%)</td><td>12 (57%)</td><td></td></tr><tr><td>2</td><td>12 (30%)</td><td>3 (16%)</td><td>9 (43%)</td><td></td></tr><tr><td>Type of SRE, N (%)</td><td></td><td></td><td></td><td>.2</td></tr><tr><td>Surgery to bone</td><td>8 (20%)</td><td>4 (21%)</td><td>4 (19%)</td><td></td></tr><tr><td>Interventional<br>Radiology procedure<br>on bone</td><td>10 (25%)</td><td>2 (11%)</td><td>8 (38%)</td><td></td></tr><tr><td>Spinal cord<br>compression</td><td>2 (5.0%)</td><td>0 (0%)</td><td>2 (10%)</td><td></td></tr><tr><td>Pathological<br>fractures</td><td>1 (2.5%)</td><td>1 (5.3%)</td><td>0 (0%)</td><td></td></tr><tr><td>Radiotherapy to<br>bone</td><td>26 (65%)</td><td>13 (68%)</td><td>13 (62%)</td><td></td></tr></tbody></table>
Real-World Outcomes of First-Line Immune-Based

<table><caption>Supplemental Table 11 Univariate Logistic Regression Model of the Probability of Having a Skeletal-Related Event</caption><thead><tr><th>Variables</th><th>N = 124</th><th>OR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Age</td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 65</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>> 65</td><td></td><td>1.44</td><td>0.68, 3.10</td><td>.3</td></tr><tr><td>Gender</td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Male</td><td></td><td>1.20</td><td>0.52, 2.92</td><td>.7</td></tr><tr><td>ECOG-PS</td><td></td><td></td><td></td><td></td></tr><tr><td>0</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>1</td><td></td><td>0.68</td><td>0.26, 1.81</td><td>.4</td></tr><tr><td>2-3</td><td></td><td>0.61</td><td>0.21, 1.78</td><td>.4</td></tr><tr><td>IMDC score</td><td></td><td></td><td></td><td></td></tr><tr><td>Favorable</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Intermediate</td><td></td><td>1.37</td><td>0.43, 4.82</td><td>.6</td></tr><tr><td>Poor</td><td></td><td>0.50</td><td>0.14, 1.93</td><td>.3</td></tr><tr><td>Metastatic disease at initial diagnosis</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.98</td><td>0.91, 4.45</td><td>.089</td></tr><tr><td>Bone only metastases</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.97</td><td>0.81, 4.75</td><td>.13</td></tr><tr><td>Number of bone lesions</td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>2-3</td><td></td><td>0.91</td><td>0.37, 2.18</td><td>.8</td></tr><tr><td>> 3</td><td></td><td>1.24</td><td>0.47, 3.24</td><td>.7</td></tr><tr><td>Rib/sternum</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.52</td><td>0.67, 3.41</td><td>.3</td></tr><tr><td>Spine</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>0.79</td><td>0.36, 1.73</td><td>.6</td></tr><tr><td>Pelvic bone</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.27</td><td>0.60, 2.71</td><td>.5</td></tr><tr><td>Long bone</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>2.05</td><td>0.90, 4.67</td><td>.085</td></tr><tr><td>Bone pain at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>2.54</td><td>1.00, 7.37</td><td>.063</td></tr><tr><td>Hypercalcemia at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.77</td><td>0.59, 5.15</td><td>.3</td></tr><tr><td>Use of a bone-targeting agent at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>0.00</td><td>—</td><td>> .9</td></tr><tr><td>SRE at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.27</td><td>0.60, 2.71</td><td>.5</td></tr><tr><td>First-line treatment</td><td></td><td></td><td></td><td></td></tr><tr><td>ICI-ICI</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>ICI-TKI</td><td></td><td>1.55</td><td>0.73, 3.32</td><td>.3</td></tr></tbody></table>
<caption>**Supplemental Table 12**</caption>

<table><caption>Multivariate Logistic Regression Model of the Probability of Having a SRE</caption><thead><tr><th>Variables</th><th>N = 124</th><th>HR</th><th>95% CI</th><th>P-Value</th></tr></thead><tbody><tr><td>Metastatic disease at initial diagnosis</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.64</td><td>0.72, 3.80</td><td>.2</td></tr><tr><td>Long bone</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>2.00</td><td>0.84, 4.74</td><td>.11</td></tr><tr><td>Bone pain at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>2.01</td><td>0.75, 6.04</td><td>.2</td></tr><tr><td>Hypercalcemia at baseline</td><td></td><td></td><td></td><td></td></tr><tr><td>No</td><td></td><td>—</td><td>—</td><td></td></tr><tr><td>Yes</td><td></td><td>1.39</td><td>0.43, 4.31</td><td>.6</td></tr></tbody></table>