First Interim Analysis of the CABONEXT Study: A Retrospective Evaluation of Treatment Patterns Following Cabozantinib Treatment for Advanced Renal Cancer ^†

Abstract

The CABONEXT study is the first multicenter retrospective analysis evaluating subsequent systemic therapies after cabozantinib-based treatment in metastatic renal cell carcinoma (mRCC). This interim analysis includes 77 patients receiving subsequent treatments across two cohorts: after cabozantinib–nivolumab first-line treatment (Group A) and after ICI-based first-line treatment followed by cabozantinib (Group B). Time to subsequent treatment failure (TTF) and disease control rate (DCR) remain higher in Group A with a median TTF of 5 months (vs. 3.4 months in Group B) and a DCR of 86% (vs. 48%). Second-generation TKIs, mostly axitinib or lenvatinib, seemed to be the best option in Group B compared to other treatments including everolimus or first-generation TKIs (HR = 3.82, 95%CI [1.64; 8.93], p = 0.1). These findings already emphasize the need for innovative therapies targeting resistance mechanisms and optimal treatment sequences. Along with ongoing accrual, further analyses are expected.

1. Introduction

Immune checkpoint inhibitor (ICI) and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) improved dramatically the patient outcome for metastatic renal cell carcinoma (RCC) [1]. First-line treatment is now well defined, based on the International Metastatic RCC Database Consortium (IMDC) score. A cornerstone of first-line therapy involves an ICI-based combination with either another ICI or a TKI [2]. Four large phase 3 trials showed that these combinations improve overall survival (OS) compared to sunitinib alone, with a similar relative reduction in the risk of death by 40% [3,4,5,6]. Cabozantinib, axitinib, and nivolumab have also shown survival benefits over everolimus or sorafenib in second-line treatment and more in the pre-ICI area [7,8,9]. However, the question of optimal therapeutic sequences remains unanswered, especially after ICI-based first-line treatment.

Current guidelines for second and later lines of treatment recommend the use of sequential monotherapies, either with ICI, if not used before, or VEGFR-TKIs such as cabozantinib, lenvatinib, axitinib, or tivozanib if not used in previous lines [2]. Prospective and retrospective studies have already shown the effectiveness of TKIs like axitinib and cabozantinib after ICI treatment, but data on the optimal sequence of these TKIs remain limited [8,10]. The effectiveness of TKIs may vary depending on overlapping tumor resistance mechanisms acquired from prior TKI treatments [11]. For example, the activation of c-MET or mTOR pathways are well-known acquired resistance to first-generation TKIs. These may explain why cabozantinib, which inhibits c-Met and AXL, significantly improves OS by more than 4 months compared to everolimus following a first-generation TKI such as sunitinib or pazopanib [7,11]. After ICI-based therapy, cabozantinib has also shown major efficacy in achieving an overall response rate (ORR) of 52% and a median progression-free survival (PFS) of over 10 months [12]. The retrospective CABOSEQ study confirms the activity of cabozantinib in second-line treatment in 346 patients, including 78 patients (23%) who previously received nivolumab + ipilimumab and 46 patients (13%) who received ICI + TKI combinations [10]. This significant clinical activity has been observed across various treatment sequences, positioning cabozantinib as one of the best-characterized TKIs currently available for metastatic RCC.

To date, no recent study has reported data on subsequent therapies following cabozantinib failure. CABONEXT is a retrospective, multicenter study collecting data from patients who received treatment after a cabozantinib-based regimen for advanced RCC. Here, we present the first interim analysis, based on data from sixteen European centers.

2. Materials and Methods

2.1. Design

Patients’ data were retrospectively collected from 16 cancer centers in France and Cyprus through the Oncodistinct network. Eligible patients were diagnosed with metastatic RCC and received at least one systemic therapy following either a first-line cabozantinib + nivolumab or a first-line ICI-based regimen followed by second-line cabozantinib monotherapy. Patients must have received at least three months of cabozantinib-based therapy. Patients who did not receive ICI or for whom their clinical chart had critical missing data, such as systemic treatment characteristics, were excluded. For this first interim analysis, data were collected from February 2024 to May 2025 through an electronic case report form on CleanWeb©.

To guide statistical analysis, patients were divided into two groups: Group A was for patients that received first-line cabozantinib–nivolumab and Group B was for patients treated by ICI-based therapy followed by second-line cabozantinib monotherapy. Group B was divided into two sub-groups with patients who received the ICI associated with TKI followed by cabozantinib (Group B1) and patients who received dual ICI followed by cabozantinib (Group B2).

2.2. Outcomes

The primary endpoint was time to treatment failure (TTF) of first systemic therapy used after cabozantinib. TTF was defined as the interval between initiation and discontinuation of the therapy for any reason, including disease progression, toxicity, or death. TTF was analyzed separately in Groups A and B. In Group B, TTF was also reported according to the type of treatment following cabozantinib (second-generation TKIs including axitinib, lenvatinib, and tivozanib versus other option). Descriptive analysis was also reported in this first data analysis.

A multivariable analysis of the TTF in Group B was conducted, incorporating the following covariates: age, IMDC score, ICI-based therapy before cabozantinib, duration of cabozantinib, dose reduction in cabozantinib, and type of treatment after cabozantinib (second-generation TKIs or other treatment). Variables were included if they were deemed clinically relevant or demonstrated statistically significant associations in univariate analyses (p-value < 0.05). Sub-group and multivariable analysis were not performed in Group A due to the small sample size.

Secondary endpoints reported here were ORR and DCR in each group, according to RECIST 1.1 criteria and assessed by a local investigator; median OS was defined as the time from the start of any systemic line for advanced disease and the death of the patient, and safety data was assessed by the frequency of grade 3 to 5 treatment-related side effects according to the Qualitative Toxicity Scale, NCI-CTCAE 5.0.

2.3. Statistical Analysis

Qualitative data are described by their frequency, percentage, and 95% confidence interval. Quantitative data are described by their mean and standard deviation or median and interquartile range. For quantitative variables, means and standard deviations are presented, as is the number of missing data.

In each pre-specified group, TTF and OS are calculated and analyzed using the Kaplan–Meier method, logrank test and Cox’s proportional hazards model. We used R version 2023.06.1 for the different analysis.

3. Results

3.1. Patients’ Characteristics

Between February 2024 and May 2025, 77 patients were enrolled. In the overall population, 62 patients (81%) were male with a median age of 67 years. Most patients (n = 67; 87%) had clear cell RCC, and sarcomatoïd features were reported for 9 patients (13%). Thirty-four patients (44%) had synchronous metastatic disease at diagnosis. The IMDC prognostic score classified 15 (31%), 26 (53%), and 8 (16%) patients in the favorable, intermediate, and poor risk groups, respectively. At the time of cabozantinib initiation, 58 patients (75%) had lung metastases, 34 (44%) had bone metastases, and 10 (13%) had brain metastases. Seventeen patients received first-line cabozantinib and nivolumab (Group A) and sixty patients received the sequence ICI-based therapy followed by cabozantinib monotherapy (Group B). Baseline characteristics for the entire cohort and in each group are reported in

Table 1. Patients’ characteristics across the entire cohort and in each main group. Group A includes patients who received cabozantinib with nivolumab as the first systemic line. Group B includes patients who received cabozantinib in second-line therapy after first-line ICI-based therapy. Abbreviation: ICI: immune checkpoint inhibitor, IQR: interquartile range, TKI: tyrosine kinase inhibitor. * TKIs used in the ICI + TKI combination were axitinib for 31 patients and lenvatinib for 3 patients. °: 1 missing data; °°: 5 missing data; °°°: 28 missing data.

		All Patients	Group A	Group B
	Number of patients, N	77	17	60
	Male N (%)	62 (81)	11 (65)	51 (85)
	Median age [IQR] (years)	67 [59; 76]	67 [42; 83]	68 [41; 86]
Histology	Clear Cell, N (%) °	67 (87)	14 (82)	53 (88)
	Papillary, N (%)	5 (6)	1 (6)	4 (7)
	Chromophobe, N (%)	4 (5)	2 (12)	2 (3)
	Sarcomatoïd feature °°, N (%)	9 (13)	2 (12)	7 (12)
IMDC °°°, N (%)	Favorable	15 (31)	1 (6)	14 (23)
	Intermediate	26 (53)	4 (24)	22 (37)
	Poor	8 (16)	1 (6)	7 (12)
	Median time between diagnosis and systemic treatment (months)	5.5	4.6	6.4
	De Novo metastatic disease, N (%)	34 (44)	8 (47)	26 (43)
	Nephrectomy, N (%)	50 (65)	8 (47)	42 (70)
Metastatic site at Cabozantinib start, N (%)	Lung	58 (75)	11 (65)	47 (78)
	Bone	34 (44)	6 (35)	28 (47)
	Lymph nodes	45 (58)	7 (41)	38 (63)
	Brain	10 (13)	2 (12)	8 (13)
1st systemic line, N (%)	Cabozantinib + Nivolumab	17 (22)	17 (100)	-
	ICI + TKI *	36 (47)	-	36 (60)
	ICI + ICI	24 (31)	-	24 (40)

.

The efficacy of the cabozantinib-based therapy was similar in both groups. In Group A, cabozantinib–nivolumab lead to an ORR of 35%, a DCR of 86%, and a median PFS of 11.3 months. In Group B, ORR, DCR, and median PFS of cabozantinib monotherapy were 35%, 88%, and 9.9 months, respectively. In Group A, only one patient started treatment at a lower dose than the standard 40 mg/day. Eight patients (47%) experienced grade ≥ 3 adverse events related to the combination therapy, and dose reductions were required in ten patients (59%). In Group B, 20 patients (33%) began treatment with a reduced dose of cabozantinib (20 mg/day for 1 patient and 40 mg/day for the others). Adverse events of similar severity were reported in 38 patients (63%), with 25 patients (63%) requiring dose reductions. In both groups, the primary reason for cabozantinib discontinuation was disease progression, accounting for 91% of cases (

Table 2. Efficacy and safety data related to the cabozantinib treatment in each group. Abbreviation: Cabo: cabozantinib, DCR: disease control rate, Nivo: nivolumab, PFS: progression-free survival, ORR: Overall response rate. * Expected full doses of cabozantinib were 40 mg/d for the combination with nivolumab and 60 mg/d on monotherapy.

	Group A (1 L Cabo-Nivo)	Group B (2 L Cabo)
N	17	60
Median PFS (months)	11.3	9.9
ORR (%)	35	35
DCR (%)	88	85
Start of cabozantinib at full dose, N (%) *	16 (94)	45 (75)
Dose reduction (%)	59	63

).

3.2. Outcomes from Group A

A total of 17 patients received first-line treatment with cabozantinib and nivolumab (

Table 3. Description and efficacy of the therapeutic line following cabozantinib, in Groups A and B. Group B was divided into two sub-groups according to the treatment received before cabozantinib: TKI and ICI (B1) or dual ICI (B2). Abbreviation: Cabo: cabozantinib; DCR: disease control rate, ICI: immune checkpoint inhibitor, Nivo: nivolumab; PD: progressive disease, PFS: progression-free survival, ORR: overall response rate, TTF: time to treatment failure, TKI: tyrosine kinase inhibitor. * One patient received axitinib in combination with pembrolizumab.

	Group A (1 L Cabo-Nivo)	Group B	Group B1 (ICI-TKI, 2 L Cabo)	Group B2 (dual ICI, 2 L Cabo)
N	17	60	36	24
Axitinib	12 *	16	4	12
Lenvatinib	1	16 °	11	5
Everolimus alone	1	16	13	3
ICI	0	3	2	1
Tivozanib	0	3	2	1
Other	3	6	4	2
Median TTF (months)	5	3.4	3.1	3.9
ORR (%)	29 **	12 °°	13	10
DCR (%)	86 **	48 °°	41	60
PD (%)	14 **	52 °°	59	40

** Tumoral assessment was not realized for 3 patients (1 died and 2 stopped because of side effects before new imaging). ° Lenvatinib was associated with everolimus for 8 patients, pembrolizumab for 3 patients, and was in monotherapy for 5 patients. °° Tumoral assessment was not realized for 8 patients (3 died and 5 stopped because of side effects before new imaging).

). Among them, twelve patients (71%) received subsequent axitinib-based therapy (including one in combination with pembrolizumab), one received lenvatinib, and three received first-generation TKIs such as pazopanib or sunitinib. The median TTF was 5.0 months, with an ORR of 29% and a DCR of 86%. The median OS was 26.8 months, with five patients who were dead at the time of the analyses. Due to the small sample size, sub-group analyses were not performed.

Nine patients (53%) received another systemic line following failure of the post-cabozantinib line, seven patients were still under treatment, and one died before starting a new line. In terms of safety, 3 patients (19%) reported a grade 3 or higher adverse event related to the treatment (2 patients reported grade 3 diarrhea and 1 patient reported grade 3 arterial hypertension).

3.3. Outcomes from Group B

First-line ICI-based therapy consisted of dual ICI for 36 patients (47%) and ICI combined with a TKI for 24 patients (31%). The TKI used in combination with ICI were axitinib (31 patients), lenvatinib (3 patients), and tivozanib (2 patients) (Table 3). Following cabozantinib, subsequent therapies included axitinib in 16 patients (27%), lenvatinib in 16 patients (27%), including 8 in combination with everolimus and 3 with pembrolizumab, everolimus alone in 16 patients (27%), ICI monotherapy and tivozanib in 3 patients each, and other treatments in 6 patients, including 4 with first-generation TKIs and 2 with belzutifan.

In the overall cohort, the median TTF was 3.4 months, with an ORR of 12.0% and a DCR of 48.0%. Based on the therapeutic sequence, Group B1 showed a median TTF of 3.1 months, an ORR of 13%, and a DCR of 41%. In Group B2, which received dual ICI followed by cabozantinib, the median TTF was 3.9 months, with an ORR of 10% and a DCR of 60% (Figure 1). Median OS was comparable between the two groups, at 34.9 months for Group B1 and 35.8 months for Group B2.

In the univariate analysis, only the use of a second-generation TKI (lenvatinib, axitinib, or tivozanib) versus other treatments (e.g., everolimus or first-generation TKIs) was significantly associated with longer TTF in univariate analysis (HR = 1.9, 95% CI [1.11–3.36]), favoring the second-generation TKI group (Figure 2).

The multivariable analysis in Group B included clinically relevant variables, such as patient age, IMDC score, and the type of treatment combined with ICI. Given the potential impact of TKI exposure on the frequency of acquired resistance, cabozantinib dose reduction was also incorporated into the analysis. The type of therapy administered after cabozantinib was added to the analysis based on the significant results from the univariate analysis. Both patient age (HR = 1.04, 95% CI [1.01; 1.08], p = 0.05) and use of second-generation TKIs (HR = 3.82, 95%CI [1.64; 8.93], p = 0.01) were significantly associated with TTF (

Table 4. Multivariable analysis of the time to treatment failure (TTF) in Group B.

Variables	HR (95% CI)
Age	1.04 (1.01; 1.08), p = 0.05
IMDC score	1.15 (0.72; 1.85), NS (p = 0.57)
Previous 1st line therapy (ICI-TKI vs. dual ICI)	1.64 (0.78; 3.45), NS (p = 0.19)
Duration of cabozantinib	0.95 (0.90; 1.00), NS (p = 0.08)
Dose reduction in cabozantinib	2.33 (1.09; 4.98), p = 0.05
Post cabozantinib treatment (2nd generation TKI vs. others)	3.82 (1.64; 8.93), p = 0.01

). Dose reduction in cabozantinib, which indicates lower exposure to the drug, was also significantly associated with TTF in this model (HR = 2.33, 95% CI [1.09; 4.98], p = 0.05). This result is in favor of better efficacy for subsequent therapy in the case of reduced exposure to cabozantinib.

At the time of this analysis, 13 patients continued the same therapy (22%), 28 started a new one (47%), and 23 patients died without another systemic line (38%). Treatment-related grade 3 or higher adverse events occurred for 16 patients (27%) with 7 gastro-intestinal events, 3 respiratory events, and 2 vascular events.

4. Discussion

CABONEXT is one of the first studies to report efficacy data from a modern therapeutic sequence of post-cabozantinib and ICI for advanced RCC. This interim analysis provides an initial insight into treatment efficacy across the predefined patient groups. As reported, the efficacy of modern TKIs, mostly axitinib, following first-line cabozantinib and nivolumab remained notable with significant ORR and DCR. However, this efficacy appears more limited in the setting of third-line TKI therapy, with an ORR of only 12% and a median TTF of 3.4 months. Notably, in patients who had already received two prior TKIs, including cabozantinib, outcomes were particularly poor, with a median TTF of 3 months. Exposure to TKIs is correlated to the risk of acquired resistance. It does explain the reduced effect of sequential TKIs but also the remaining efficacy of second-generation TKIs in the case of sub-optimal exposure to cabozantinib administered previously. Our multivariable analysis reported a significant impact of cabozantinib dose reduction on the subsequent TTF. In the case of reduced exposure to cabozantinib, less resistance is acquired and another VEGF-TKI may remain efficient. However, all these findings underscore the urgent need for innovative treatment strategies that target novel tumor pathways or mechanisms of acquired resistance to currently available TKIs.

Since current-generation TKIs, such as cabozantinib, were developed concurrently with evolving treatment standards, only a small number of patients in pivotal trials received what is now considered the standard of care, e.g., ICI combination. In the METEOR and AXIS trials, no patients that were treated, respectively, by cabozantinib or axitinib received previous ICI therapy [7,8]. Despite this irremediable situation, cabozantinib remains one of the most reviewed TKIs with an important multicentric retrospective trial that aimed to assess its efficacy in the modern era of RCC treatment.

Two retrospective trials have already evaluated the efficacy of cabozantinib in the modern therapeutic landscape. In the CABOSEQ trial, 114 of 346 patients received second-line cabozantinib after ICI-based therapy [10]. The median OS reported in this study was higher in patients with previous dual ICI and TKI-naïve (21 months) treatment compared to patients that had received modern TKI in combination with ICI (15 months). This decrease in efficacy along with the use of modern TKI is similar to the one that we reported here and was also reported in the CABOPOINT study. In this study, it was reported that there was a decrease in ORR and PFS for patients treated by the sequence ICI + TKI and cabozantinib compared to the dual ICI followed by cabozantinib group [13]. In each group, ORR was 28% vs. 41% and PFS was 8.3 vs. 10.9 months. Including our actual results, these three studies emphasized the high probability of overlapping acquired resistance to second-generation TKIs.

Thus, the therapeutic sequencing among TKIs remains crucial for optimizing patient outcomes, as well as between TKI and ICI. In the CABIR study, two second- and third-line treatment strategies were evaluated: one arm received cabozantinib followed by nivolumab monotherapy upon progression (CN), while the other received the reverse sequence (NC) [14]. PFS, measured from the start of second-line therapy to progression after third-line therapy, was improved by 10 months in the NC group compared to the CN group. Early use of ICI appears to be more beneficial, likely because acquired resistance following TKI therapy may also impact the efficacy of other treatment modalities. Based on these findings, the selection of the most effective subsequent therapy has to be carefully considered. However, only limited data exist within the modern therapeutic landscape and CABONEXT is conducted to give more insight through an actual therapeutic sequence option.

A recently published study, LENVA-LAT, assessed the efficacy of lenvatinib beyond first-line therapy between 2020 and 2024 [15]. It reported efficacy data from 133 patients of whom 90% were previously treated by cabozantinib, not necessarily in the immediate previous line. This study is one of the few that report TKI efficacy after cabozantinib use. In the overall population, patients had a median of three previous lines of treatment; ORR and median TTF were, respectively, 29% and 6.2 months. In our study, patients from Group B who received two previous systemic lines had an ORR (12%) and a median TTF (3.4 months) that were less favorable. However, as only 16% of the patients from Group B received lenvatinib-based therapy, results from the LENV-LAT study may propose lenvatinib as an interesting option following cabozantinib. Further investigation in our cohort may help to confirm this assumption as we have already reported that second-generation TKIs still remain the best choice compared to other actual therapeutic classes.

To overcome acquired resistance and propose more efficient therapeutic options, several trials are actually ongoing. On one hand, they evaluate strategy to promote the efficacy of immunotherapy with new ICI, CAR-T cell therapy, or multi-specific antibodies. On the other hand, they aim to report the efficacy of targeting the current VEGF axis with HIF2a inhibitors, or other pathways with a cyclin-dependent kinase inhibitor or drug-conjugated antibodies. Some radiopharmaceuticals therapies are also under investigation and may represent some alternative and promising options for patients following VEGF-TKI failure [16].

Actual data from CABONEXT remain frail and have to be considered with caution due to the small sample size. In particular, the exploratory multivariable analysis required adjustment for several potential confounders, and its findings will need confirmation in the overall cohort. However, as enrollment continues, more detailed analysis is planned and will be available notably in the specific setting of post-cabozantinib and nivolumab combination.

5. Conclusions

CABONEXT is the first multicenter retrospective trial to assess the efficacy of current therapy after ICI and cabozantinib in patients treated for advanced RCC. This interim analysis confirms the efficacy of TKIs, mostly axitinib and lenvatinib, after first-line cabozantinib and nivolumab or after dual ICI followed by cabozantinib. However, it also highlights the need for therapies that target acquired resistance or novel antitumor pathways regarding the overall modest activity of available treatment after ICI + TKI and cabozantinib. With the ongoing recruitment, further exploratory analyses will be performed to determine the most optimal therapeutic sequence for our patients with current available therapy.