Real-World effectiveness of second-line cabozantinib in metastatic renal cell carcinoma in the era of immunotherapy combinations: Results from the international metastatic renal cell carcinoma database consortium (IMDC)

Abstract

Background

Cabozantinib is approved as a subsequent therapy for patients with metastatic renal cell carcinoma (mRCC) based on the METEOR trial. However, only 5% of patients in this trial received prior immunotherapy.

Objective

Analyze the effectiveness of Cabozantinib in the second-line setting after different first-line treatments.

Methods

This retrospective study analyzed patients with mRCC who received second-line Cabozantinib between 2010 and 2023, using the International mRCC Database Consortium (IMDC). Patients were grouped by prior therapy and IMDC risk category. We assessed overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), and overall survival (OS).

Results

Among 603 patients (mean age 59 years), 31.5% had received IO-IO regimens, 24.5% IO-TKI combinations, and 34.3% TKI monotherapy as initial therapy. At Cabozantinib start, 13.8% were favorable-risk, 49.1% intermediate-risk, and 16.7% poor-risk per IMDC. The ORR for the overall cohort was 25.7%; median TTNT was 10.1 months; median TD was 8.9 months; and median OS was 19.0 months. Efficacy outcomes were consistent across first-line treatment groups.

Conclusion

This real-world analysis supports the effectiveness of Cabozantinib in the second-line setting, including among patients previously treated with immune checkpoint inhibitors. Prior treatment type did not significantly affect Cabozantinib outcomes.

Keywords

metastatic renal cell carcinoma cabozantinib immunotherapy second-line therapy real-world data IMDC

Introduction

The past decade has seen the evolution of treatment strategies for metastatic renal cell carcinoma (mRCC) because of the first-line use of immune-oncology combinations.¹ Immunotherapy combinations have emerged as the new standard in this setting, either as dual immunotherapy with nivolumab and ipilimumab (IO-IO) or with immunotherapy plus TKIs, as they have improved outcomes compared to the previous standard of care, Sunitinib. Pivotal trials like CheckMate 214² and other IO-TKI combinations^3–6 publicly declared their clinical success. These steps forward have been transformative in the care of mRCC patients, as longer-term benefits have been seen in some patients.⁷ That said, there is still a significant number of patients who will eventually progress and require reasonably effective second line options.

Due to the results of the phase III METEOR trial,⁸ cabozantinib, a strong MET, AXL, and VEGF receptor inhibitor,⁹ has emerged as one of the most important treatment options in the second-line setting. In this trial, Cabozantinib showed improved PFS and OS when compared to Everolimus in patients who progressed to a prior therapy. Of note, this trial was conducted in an era prior to the widespread use of immunotherapy combinations at first line, and ergo, this subgroup was underrepresented, with only 5% of the population treated with prior immunotherapy. As a result, the efficacy of cabozantinib following modern IO-based regimens was incompletely characterized, creating a critical gap in clinical knowledge.⁸

Two more modern phase III trials, CONTACT-03¹⁰ and CANTATA,¹¹ tried to determine the effectiveness of Cabozantinib used alone versus in combination with Atezolizumab or Telaglenastat, respectively, in the second or third line treatment of metastatic renal cell carcinoma (mRCC), mainly in patients who have been pre-treated with immune checkpoint combinations. Both studies did not achieve their primary endpoint and were not able to demonstrate improvements in the combination arm. Still, they confirmed clinical activity of Cabozantinib in the post-immunotherapy setting. Supporting these results, the multicenter, single-arm phase II BREAKPOINT study showed that Cabozantinb yielded comparable outcomes compared to the METEOR trial in 31 patients with advanced or unresectable RCC who were previously treated with immune checkpoint inhibitors.¹²

Confirming the findings requires real-world evidence, mainly because it better documents the heterogeneity of patients, treatment approaches, and clinical outcomes as seen in the everyday clinical practice, which may not be captured entirely in controlled trials.¹³ Of particular concern is the increasing use of immunotherapy (IO) in the first-line setting, which raises the critical issue of whether prior exposure to immunotherapy affects the effectiveness of later-line therapies like Cabozantinib.

To answer these questions, we undertook a multicenter, retrospective study leveraging the IMDC database to analyze the real-world effectiveness of cabozantinib in the second-line setting. Our analysis concentrated on specific clinical endpoints including overall response rate (ORR), time to next treatment (TTNT), treatment duration (TD), and overall survival (OS) and assessed whether first-line response or IMDC risk factors¹⁴ influenced the efficacy of cabozantinib. The results may enhance our understanding regarding the treatment sequence and inform optimal patient identification for second-line cabozantinib therapy in the immunotherapy era.

Methods

We performed a retrospective cohort study of patients treated at IMDC centers, including academic and community oncology practices throughout North America, Europe, and Asia. Eligible participants were ≥18 years of age, histologically confirmed mRCC patients receiving cabozantinib as second-line therapy from January 1, 2010, to December 31, 2023. Patients were stratified by their first-line systemic treatment: immune-oncology combinations (IO-IO), immune-oncology plus tyrosine kinase inhibitors (IO-TKI), and TKI monotherapy. A smaller subgroup of patients treated with “other” regimes, such as IO monotherapy, non-standard TKIs or investigational agents, were also included.

Data was collected from hospitals and pharmacies records using standardized database collection templates. Institutional review board approval was obtained from each participating center; for the coordinating center, IRB approval was granted by the Health Research Ethics Board of Alberta (HREBA), Cancer Committee (approval number HREBA.CC-17–0201). Key variables included age at diagnosis, sex, histologic subtype, presence of sarcomatoid features, IMDC risk factors (hemoglobin < lower limit of normal, corrected calcium > upper limit of normal, Karnofsky performance status <80%, diagnosis to treatment interval <1 year, neutrophil count > upper limit of normal, platelet count > upper limit of normal), sites of metastasis, and prior nephrectomy status. Treatment-related variables included dates of therapy initiation and discontinuation, best response to treatment, and reasons for treatment discontinuation.

The primary endpoint was overall response rate (ORR), defined as the proportion of patients achieving complete or partial response according to RECIST version 1.1 criteria as assessed by treating physicians. Secondary endpoints included time to next treatment (TTNT), measured from cabozantinib initiation until start of subsequent systemic therapy or death from any cause; treatment duration (TD), time from cabozantinib initiation to discontinuation for any reason; and overall survival (OS), calculated both from cabozantinib initiation and from first-line therapy initiation until death from any cause.

We also calculated descriptive statistics for baseline characteristics. Continuous variables were summarized by means with standard deviations (SDs) or medians with interquartile ranges (IQRs); categorical variables were expressed as numbers and percentages. Continuous and categorial baseline characteristics across treatment arms were compared using ANOVA and Chi-square tests, respectively.

For time-to-event analyses (TTNT, TD, OS), we constructed Kaplan-Meier curves and compared groups using the log-rank test. We performed multivariable Cox proportional hazards regression to assess the association between first-line treatment and outcomes, adjusting for potential confounders including age, IMDC risk factors, histology, and sarcomatoid features. To evaluate whether response to first-line therapy predicted cabozantinib efficacy, we conducted logistic regression analyses for ORR and Cox regression for time-to-event outcomes, with results reported as odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals.

All statistical tests were two-sided, with p < 0.05 considered statistically significant. We performed analyses using SAS version 9.4 (SAS Institute).

Results

Patient characteristics

The baseline characteristics of the 603 patients included are summarized in Table 1. The median age was 59 years (range 23–87), with 77.3% of patients being male and 82.3% of patients having clear cell histology (82.3%). On starting cabozantinib, the IMDC risk groups were favorable in 13.8% of the patients, intermediate in 49.1%, and poor in 16.7%, with 20.4% having missing information to correctly clasify them. Lung was the most frequently affected area, with 78.4% of patients showing lung metastasis, followed by bone (36.7%) and liver (17.6%). Almost 70% of cases had already undergone prior nephrectomy, with significant variation between first line treatment groups (51.1% in IO-IO vs 80.2% in TKI alone, p < 0.001).

Table 1.

Baseline characteristics. Legend: 1L: First line; IO-IO: Ipilimumab + Nivolumab; IO-TKI: immunotherapy plus Tyrosine Kinase Inhibitor; TKI: Tyrosine Kinase Inhibitor.

Variable	Overall (n = 603) %	1L IO-IO (n = 190) %	1L IO-TKI (n = 148) %	1L TKI Alone (n = 207) %	1L Other (n = 58) %	p-value
Age at diagnosis Mean (SD)	59.25 (11.19)	59.60 (11.06)	59.27 (10.60)	58.82 (11.46)	59.59 (12.24)	0.911
Male	466 (77.3)	144 (75.8)	110 (74.3)	164 (79.2)	48 (82.8)	0.491
Non clear cell histology	107 (17.7)	33 (17.4)	26 (17.6)	28 (13.5)	20 (34.5)	0.003
Sacromatoid features	69 (11.4)	21 (11.1)	22 (14.9)	19 (9.2)	7 (12.1)	0.422
Nephrectomy	416 (69.0)	97 (51.1)	110 (74.3)	166 (80.2)	43 (74.1)	<0.001
1^st line IMDC risk ^{Fav/Int/Poor (%)}	13.8/49.1/16.7	5.3/52.6/24.6	25/41.9/13.5	14/47.8/13	12.1/60.3/13.8	<0.001
2^nd line IMDC risk ^{Fav/Int/Poor (%)}	9.3/44.6/17.9	3.7/47.4/23.7	16.9/42.6/16.2	9.2/42/15.5	8.6/50/12.1	<0.001
Greater than 1 site of Metastasis	473 (78.4)	146 (76.8)	114 (77.0)	161 (77.8)	45 (77.6)	0.722
Brain Metastasis	36 (6.0)	18 (9.5)	5 (3.4)	13 (6.3)	0 (0.0)	0.022
Bone Metastasis	221 (36.7)	74 (38.9)	60 (40.5)	70 (33.8)	17 (29.3)	0.326
Liver Metastasis	106 (17.6)	32 (16.8)	26 (17.6)	39 (18.8)	9 (15.5)	0.926

Prior to cabozantinib, the first line of treatment consisted of IO-IO combinations (31.5%), IO-TKI combinations (24.5%), and TKI monotherapy (34.3%). The “other” category (9.7%) consisted of patients who received single-agent IO or investigational therapies.

Treatment outcomes

The ORR for Cabozantinib in the entire cohort was 25.7% (95% CI 22.1–29.6), with no significant differences between first-line treatment groups (IO-IO 27.2%, IO–TKI 26.4%, TKI alone 25.05.0%; p = 0.82) (Table 2). Overall, the disease control rate (complete response + partial response + stable disease) was 72.3%.

Table 2.

Overall response rate to second line cabozantinib, by first line treatment. Legend: 1L: First line; IO-IO: Ipilimumab + Nivolumab; IO-TKI: immunotherapy plus Tyrosine Kinase Inhibitor; TKI: Tyrosine Kinase Inhibitor.

	Overall	1L IO-IO	1L IO-TKI	1L TKI	1L Other
Overall Response Rate	25.7%	27.2%	26.4%	25%	22.2%

Median follow-up from Cabozantinib initiation was 19.2 months (IQR 12.4–28.7). The median OS from the start of Cabozantinib was 19.0 months (95% CI 17.5–23.4), while the OS rates were 65.3% at 12 months and 41.7% at 24 months (Figure 1A). From the start of first-line therapy, the median OS was 42.3 months (95% CI 38.1–47.8). Survival outcomes since starting 2^nd line Cabozantinib did not differ significantly by first-line treatment group (IO-IO 18.6 months, IO-TKI 17.6 months, TKI alone 21.3 months, p = 0.21).

Figure 1.

Secondary outcomes yaccording to 1^st line therapy. A. Overall Survival from Cabozantinib initiation. B. TTNT. C. TD.

The median TTNT was 10.1 months (95% CI 9.2–11.0) (Figure 1B), while median TD was 8.9 months (95% CI 7.8–10.2) (Figure 1C). Both endpoints showed no statistically significant differences across first-line treatment groups (p > 0.05 for all comparisons).

The most common non-clear cell histologies include papillary (n = 55), chromophobe (n = 13) and translocation (n = 11). The mOS for clear cell was 19.33 months (95% CI: 17.82–24.16), whereas it was 17.26 months (95% CI: 10.32–28.11) in non-clear cells and 20.75 months (95% CI: 15.88–35.57) in papillary. The ORR was 26.5% (99/373) in patients with clear cell histology, 21.3% (16/75) in non-clear cell and 16.3% (7/43) in the papillary subgroup.

Subgroup and multivariable analyses

In the multivariable analysis adjusted for IMDC risk factors (Table 3), first-line treatment group was not significantly associated with a different OS (IO-IO vs TKI alone HR 1.12, 95% CI 0.88–1.42; IO-TKI vs TKI alone HR 1.18, 95% CI 0.91–1.53). Similarly, no association was found between first-line treatment and ORR, TTNT, or TD in adjusted models.

Table 3.

Multivariable analysis of ORR to cabozantinib in 2nd line based on effectiveness of 1st line treatment.

Analysis	Overall N = 603	IO-IO n = 190	IO-TKI n = 148	TKI alone n = 207	Other n = 58
First-line ORR Crude
Disease Progression	Ref	Ref	Ref	Ref	Ref
Stable disease	1.17 (0.69–1.98)	1.14 (0.44–2.88)	1.75 (0.58–5.71)	1.44 (0.57–3.87)	0.42 (0.08–2.17)
Partial/Complete response	1.39 (0.79–2.44)	1.15 (0.38–3.30)	1.13 (0.36–3.76)	2.81 (1.07–7.89)	0.50 (0.06–3.36)
First-line ORR Multivariable
Disease Progression	Ref	Ref	Ref	Ref	Ref
Stable disease	0.99 (0.52–1.92)	1.03 (0.30–3.46)	1.90 (0.51–7.77)	0.85 (0.22–3.64)	0.51 (0.02–15.55)
Partial/complete response	1.23 (0.61–2.49)	0.91 (0.16–4.38)	1.29 (0.33–5.37)	1.81 (0.45–8.19)	0.88 (0.03–33.14)
First-line TTNT Crude
<12 months	Ref	Ref	Ref	Ref	Ref
>= 12 months	1.04 (0.67–1.60)	1.18 (0.42–3.10)	0.93 (0.39–2.21)	1.19 (0.59–2.43)	0.89 (0.20–3.68)
First-line TTNT Multivariable
<12 months	Ref	Ref	Ref	Ref	Ref
>= 12 months	1.04 (0.59–1.82)	0.95 (0.23–3.36)	1.35 (0.46–4.10)	1.33 (0.47–3.92)	0.46 (0.04–35.65)

However, an exploratory analysis showed that among patients who received first-line TKI monotherapy, those achieving a complete or partial response had significantly higher odds of responding to cabozantinib at 2L (OR 2.81, 95% CI 1.07–7.89, p = 0.03) compared to those with progressive disease as best response. This association was not evidenced in the IO containing groups.

The efficacy of Cabozantinib in each IMDC risk group is summarized in Table 4.

Table 4.

Efficacy of cabozantinib by IMDC risk.

Prior Treatment	Favorable	Intermediate	Poor
mOS
IO-IO	NR	18.87 (15.32-NR)	10.52 (7.73–26.60)
IO-TKI	18.58 (10.78-NR)	17.59 (14.30–25.18)	9.96 (5.29-NR)
TKI	34.82 (30.00-NR)	21.34 (17.26–44.75)	8.22 (5.13–16.67)
Other	NR	32.58 (19.36-NR)	6.95 (6.67-NR)
ORR
IO-IO	16.7	31.7	23.3
IO-TKI	22.2	32.1	18.8
TKI	33.3	24.4	14.8
Other	0	25.9	20.0

Discussion

Our study involving 603 patients receiving second-line cabozantinib for mRCC shows consistent efficacy across different first- line treatment backgrounds, including contemporary IO-containing regimens. Despite 56% of the participants had received priot immunotherapy, the median OS was 19.0 months and the ORR was 25.7%, which is consistent with the findings from the METEOR trial (ORR 17%; median OS 21.4 months). The evidence suggests that Cabozantinib is an effective therapy, regardless of prior treatment exposure. When looking at different histologies, the results were not significantly different between patients with clear cell and non-clear cell histologies.

The comparable outcomes with Cabozantinib across first-line treatment groups suggest that Cabozantinib activity may not be significantly affected by the mechanisms of resistance to IO and first line TKIs therapies. This is particularly relevant given the different biological pathways targeted by these agents, as IO modulates immune checkpoint pathways and TKIs mainly target VEGF signaling, while Cabozantinib's additional inhibition of MET and AXL may offer therapeutic benefits in overcoming resistance.

Notably, our finding that prior radiological response to TKI therapy predicted better outcomes with Cabozantinib (OR 2.81 for responders vs non-responders) suggests shared mechanisms of sensitivity to VEGF pathway inhibition. This observation matches preclinical findings that tumors sensitive to VEGF blockade maintain a dependence on this pathway.¹⁵ In IO-pretreated patients, the lack of this correlation may indicate that immunotherapy treatment affects other biological factors that determine response.

There are limitations associated with the retrospective design of our study, for example, the potential selection bias and heterogeneity in treatment protocols across different centers. The inclusion of patients over a 13 year period leads to temporal confusion as diagnostic and therapeutic approaches have changed over time. Moreover, the absence of centralized radiology review could have resulted in variation in response evaluations.

Real-world data complements evidence from clinical trials and provides reassurance as to whether modern first-line regimens will work well with Cabozantinib. Additional research is required to identify response biomarkers that can aid in determining optimal sequencing strategies and explore alternative combination approaches to enhance Cabozantinib's effectiveness in the post-IO setting, such as the CONTACT 3 and CANTATA trial.

Conclusion

In this large, international real-world cohort, Cabozantinib shows consistent effectiveness as second-line therapy for mRCC regardless of prior treatment with IO-based regimens. The observed response rates and survival outcomes were comparable to those reported in the pivotal METEOR trial, supporting Cabozantinib's role as a standard option in the contemporary treatment sequence. While response to prior TKI therapy predicted better outcomes with cabozantinib, no such association was observed for IO-based treatments, highlighting the need for further research into predictive biomarkers in this setting. These findings provide valuable guidance for clinicians managing mRCC in the immunotherapy era.

Footnotes

Acknowledgements

We would like to thank the investigators and data managers from the International Metastatic RCC Database Consortium (IMDC) for their continued contributions and dedication to real-world data collection.

Informed consent / patient consent

Informed consent was waived for this retrospective study. All data was de-identified prior to analysis.

Ethical statement

The study was conducted in accordance with the principles of the Declaration of Helsinki. Institutional review board (IRB) or research ethics board (REB) approval was obtained at each participating site prior to data collection. All data were anonymized.

Funding

This study received fundings from IPSEN.

Conflict of interest statement

All authors have completed the ICMJE disclosure form. Potential conflicts of interest are disclosed in the accompanying ICMJE.

Data availability statement

The data used in this study are available from the International Metastatic RCC Database Consortium (IMDC) upon reasonable request and appropriate data sharing agreements.

ORCID iDs

Martin Zarba

Aly-Khan Lalani

Haoran Li

Toni K. Choueiri

References

Powles

Albiges

Bex

, et al. Renal cell carcinoma: ESMO clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 2024; 35: 692–706.

Tannir

Albigès

McDermott

, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol 2024; 35: 1026–1038.

Plimack

Powles

Stus

, et al. Pembrolizumab plus axitinib versus sunitinib as first-line treatment of advanced renal cell carcinoma: 43-month follow-up of the phase 3 KEYNOTE-426 study [published correction appears in eur urol. 2023 nov;84(5):e123-e124. Doi: 10.1016/j.eururo.2023.08.010.] [published correction appears in eur urol. 2024 feb;85(2):e58-e59. Doi: 10.1016/j.eururo.2023.11.016.]. Eur Urol 2023; 84: 449–454.

Motzer

Porta

Eto

, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol 2024; 42: 1222–1228.

Powles

Burotto

Escudier

, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open 2024; 9: 102994.

Choueiri

Penkov

Uemura

, et al. Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN renal 101 trial. Ann Oncol 2025; 36: 387–392.

Pilié

Jonasch

. Durable complete response in renal cell carcinoma clinical trials. Lancet 2019; 393: 2362–2364.

Motzer

Escudier

Powles

, et al. Long-term follow-up of overall survival for cabozantinib versus everolimus in advanced renal cell carcinoma. Br J Cancer 2018; 118: 1176–1178.

Yakes

Chen

Tan

, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011; 10: 2298–2308.

10.

Pal

Albiges

Tomczak

, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet 2023; 402: 185–195.

11.

Tannir

Agarwal

Porta

, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial. JAMA Oncol 2022; 8: 1411–1418.

12.

Procopio

Claps

Pircher

, et al. A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: the BREAKPOINT trial (meet-uro trial 03). Tumori 2023; 109: 129–137.

13.

Dang

. Real-World evidence: a primer. Pharmaceut Med 2023; 37: 25–36.

14.

Heng

Xie

Regan

, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 2009; 27: 5794–5799.

15.

Bergers

Hanahan

. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8: 592–603.