Analysis of Factors Contributing to Adverse Events and Evaluation of Their Impact on Prognosis in Metastatic Renal Cell Carcinoma Patients—Real-World Experience in a Single-Center Retrospective Study and Narrative Review

Abstract

Background and Objectives: More than 430,000 new cases of renal cell carcinoma (RCC) were reported in 2020. Clear cell RCC, which occurs in 80% of cases, is often associated with mutations in the VHL gene, leading to dysregulation of hypoxia-induced transcription factors pathways and carcinogenesis. The purpose of this study is to examine the adverse events (AEs) of cabozantinib treatment and the relationship between individual patient factors and the frequency of their occurrence in detail. Materials and Methods: Seventy-one patients with metastatic RCC were treated with second or further lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology. Comprehensive data, including demographics, clinicopathological factors, and AEs, were collected from January 2017 to June 2021. This study evaluated the impact of various patient-related factors on the rate of adverse events and treatment tolerance using a Cox proportional hazards model. Results: Cabozantinib-induced AEs were significantly associated with body mass index (BMI), body surface area (BSA), IMDC prognostic score, and treatment line. Notably, patients receiving cabozantinib post-tyrosine kinase inhibitors reported fewer AEs. Dose reduction was unrelated to adverse event frequency, but patients requiring dose reduction were characterized with lower body mass and BSA but not BMI. Conclusions: The factors described make it possible to predict the incidence of AEs, which allows for faster detection and easier management, especially in the high-risk group. AEs should be reported in detail in real-world studies, as their occurrence has a significant impact on prognosis.

1. Introduction

In the global population, renal cell carcinoma (RCC) ranks as the 9th most common cancer in men and the 14th most common in women. In 2020 alone, there were more than 430,000 new cases of kidney cancer. The incidence of this cancer shows significant geographical variation, with a higher prevalence observed in northeastern Europe [1]. In Poland, RCC constitutes approximately 3.8% of all cancers, leading to around 6500 annual diagnoses. About 2800 people succumb to kidney cancer each year in Poland, contributing to 2.8% of all cancer-related deaths [2].

The predominant subtype is clear cell renal cell carcinoma (ccRCC), with up to 80% exhibiting a mutation in the VHL gene. The VHL protein’s role in degrading hypoxia-induced transcription factors (HIF-1α and HIF-2α) is crucial. Dysfunction in VHL leads to the accumulation of HIF1 factors, triggering the overexpression of growth factors such as vascular endothelial growth factor (VEGF) and fostering carcinogenesis [3,4].

While age is the most significant risk factor, smoking, obesity, and hypertension also significantly increase the risk of RCC. The median diagnosis age is 64 years old, varying with geographical location. Early detection through improved access to ultrasound allows for kidney-sparing treatment [5]. Nevertheless, 30% of new diagnoses are metastatic, and 20% of patients experience recurrence or metastasis after radical treatment, necessitating systemic treatment [6].

The past decade has seen a significant prolongation of overall survival in patients with metastatic clear-cell renal cell carcinoma. Advances in therapy have been made possible by improved treatment regimens and the introduction of new tyrosine kinase inhibitors and immunotherapies. Both ESMO [7] and ASCO [8] recommend the use of a combination of tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs) as the first-line treatment for patients with metastatic clear cell carcinoma, regardless of prognostic group, proving highly active and effective therapy and resulting in objective response rates as high as 55.7% [9]

Multikinase inhibitors like cabozantinib inhibiting MET, AXL, VEGFR, and other kinases and receptors are commonly used. VEGFR inhibition suppresses angiogenesis, increasing hypoxia within the tumor and limiting further growth. Research indicates that cabozantinib exhibits immunomodulatory properties by diminishing the infiltration of suppressor cells, including regulatory T cells and myeloid-derived suppressor cells (MDSCs), within the tumor [10,11]. Additionally, it directly affects tumor cells, increasing their sensitivity to the cytotoxic effects of the immune system. This might not be the sole mechanism for amplifying the efficiency of the cellular response, potentially leading to increased effectiveness of immunotherapy [12].

The second element of the aforementioned combination is ICIs. The backbone of their action is the prevention of T-cell anergy and exhaustion, resulting in their activation and effective anti-tumor response. This process involves blocking the fusion of the PD-1 receptor on T cells with PD-L1 present on tumor cells and activated T cells [13]. However, it is acknowledged that the interaction of PD-1 with PD-L1 is not the only mechanism by which T lymphocytes can be inhibited. Additionally, as T cells undergo activation, PD-L1 expression increases. Similarly, PD-L1 shows a significant rise in depleted CD4+ T cells [14], which may secondarily inhibit the anti-tumor response and lead to the depletion of activated T cells.

The purpose of this study is to examine the adverse events (AEs) and their relationship with individual patient factors and the frequency of their occurrence in detail. In the treatment of ccRCC with TKIs, AEs such as hand-foot syndrome (HFS), hypothyroidism, or diarrhea have been identified as valuable predictive factors, associated with improved overall survival (OS) and progression-free survival (PFS) [15,16,17,18]. One must bear in mind that cabozantinib was often used as a second-line drug; more geriatric patients may be in this group compared to those receiving first-line drugs, necessitating adjustments in dosing [19]. The study also aims to highlight patients particularly vulnerable to AEs, allowing clinicians to pay closer attention to facilitate more effective management.

2. Materials and Methods

2.1. Patient Collection

This retrospective analysis included seventy-one patients with biopsy-proven metastatic clear cell renal cell carcinoma (mRCC) undergoing cabozantinib treatment as a second or subsequent line at the Department of Genitourinary Oncology of the Maria Skłodowska-Curie National Research Institute of Oncology in Warsaw.

The database contained the data of patients with mRCC treated at the department between 30 January 2017 and 23 June 2021. This study was conducted following the principles of the Declaration of Helsinki. Permission to conduct this study was granted by the Maria Sklodowska-Curie National Research Institute of Oncology Bioethics Committee (permission number 38/2018).

2.2. Data Collection and Inclusion Criteria

The database contained detailed information on age, gender, clinicopathological factors, laboratory results, comorbidities, adverse events, sites of metastases, ECOG performance score, International Metastatic RCC Database Consortium (IMDC), and Memorial Sloan-Kettering Cancer Center (MSKCC) risk scores [20], along with outcome data associated with individual patients. Clinical data were extracted from medical records, and mortality data were obtained from the Polish national database. Detailed characteristics of the study group at the study’s commencement are shown in Table 1.

The study included patients aged between 42 and 80 years with biopsy-proven metastatic clear-cell renal cancer. The initial dose of cabozantinib for all patients was 60 mg per day. Dose modifications were based on the Summary of Product Characteristics [21]. Complete blood counts (CBC) were evaluated for each patient before starting the course of treatment with cabozantinib. Hematological parameters were measured using Sysmex XN-1000 (Aleje Jerozolimskie 176, Warsaw, Poland), and laboratory tests were conducted by the Diagnostic Department of the National Research Institute of Oncology. Patients were classified into three risk groups (favorable, intermediate, and poor) for both MSKCC and IMDC based on their scores, but none of these groups were excluded from the study. Adverse events were assessed following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [22]. Table 2 displays the previous lines of treatment.

This study included patients eligible for systemic treatment with biopsy-proven metastatic ccRCC. Patients with non-clear cell renal cell carcinoma were also included if they received cabozantinib through emergency access to drug technologies due to the failure of other treatment options. Moreover, cabozantinib had to be administered as a second- or subsequent-line treatment with an initial dose of 60 mg per day. Consent to treatment and participation in the study were also required.

2.3. Assessment of Treatment Response and Adverse Events

Response to treatment was assessed by examination and computed tomography (or MRI) scan every 12 weeks. All imaging data were assessed by radiologists with experience in tumor response evaluation, which was conducted according to the RECIST criteria [23]. Responses were confirmed after three months of treatment with cabozantinib. Adverse events were assessed following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [22]. Patients were duly informed of all potential AEs and were actively encouraged to provide details of any changes in their well-being or the onset of new complaints or symptoms. Subsequently, AEs were thoroughly assessed at follow-up appointments, which were scheduled every two weeks. Treatment persisted until either disease progression or the onset of significant toxicity, classified as Grade 4 (G4). Any necessary adjustments to the dosage were carefully deliberated in collaboration with the patient, following a comprehensive benefit-risk assessment. The collected data are summarized in Table 3.

2.4. Search Strategy and Selection Criteria

Publications of interest were English-language reports of real-world studies (RWEs) or randomized clinical trials (RCTs) of cabozantinib use in patients with RCC. Eligible papers for the table had to include insightful information about cabozantinib-related AEs and dosage reduction. A search of PubMed was conducted (20 December 2023) covering the period from 2012 to 2023. Search criteria were as follows: ((cabozantinib) AND (RCC or Renal cell carcinoma)) NOT (combined or nivolumab). The search yielded 222 papers, but only 51 of them were considered consistent with the topic of this paper were retrieved from PubMed. Then, we analyzed in detail and finally included information from 27 [15,18,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] publications that were considered useful for this manuscript, while the remaining references came from the personal knowledge of the authors [49,50]. In the end, we qualified 13 [15,26,27,28,29,31,33,34,35,42,44,51,52] works to formulate a table describing AEs; in the remaining 14 papers, information about AEs was insufficient. The search and preliminary selection of papers was performed by two of the authors (P.D. and W.F.). Subsequently, all authors reviewed and checked the inclusion and exclusion criteria and the data of the resulting manuscripts, which all authors agreed to include in this paper.

2.5. Statistical Analysis

Categorical variables were summarized with the number and percentage of the respective group. Quantitative variables were summarized with mean and standard deviation (SD; normally distributed) or median and first and third quartile (Q1; Q3; non-normally distributed) as specified in Results. The subgroups were compared with Pearson chi-squared test, Fisher exact test (2 × 2 tables, expected frequency < 5), t-test, or Mann-Whitney test, respectively. Spearman rank correlation coefficients were used to evaluate the associations between the number of reported adverse events during cabozantinib treatment and patients’ characteristics. All the statistical tests were two-tailed, and the results were interpreted as significant at p < 0.05. Statistica software (version 13; Tibco, Tulsa, OK, USA) was used for computations.

3. Results

The number of adverse events related to cabozantinib significantly correlated with BMI, BSA, IMDC prognostic score, and the cabozantinib treatment line, as illustrated in Figure 1. Moreover, a correlation was observed with body mass (R = −0.28; p = 0.020). Age, sex, or median time from diagnosis were not associated with the number of adverse events. Patients who received cabozantinib directly after tyrosine kinase inhibitors (TKI), regardless of the treatment line, reported a lower number of distinct adverse events: median (Q1; Q3) equaled 1 (1; 3) versus 3 (2; 4); p = 0.032. Furthermore, among patients treated with cabozantinib in third or further line, those who received TKI in second-line treatment (n = 20) experienced a lower number of adverse events: 2 (1; 3) than those who received everolimus or temsirolimus in second line (n = 18): 4 (3; 5); p < 0.001. These associations were held when comparing patients with 0–1 adverse events to those with more than 1 adverse event.

There was no association between the number of reported adverse events and the need for cabozantinib dose reduction (p = 0.2). Among the adverse events, only hypertension was more prevalent in patients requiring dose reduction (64% vs. 36%; p = 0.041). Moreover, patients requiring dose reduction were characterized with lower body mass [mean (SD): 77.1 (19.1) versus 87.1 (18.4) kg; p = 0.028] and BSA [1.85 (0.25) vs. 2.01 (0.21) m²; p = 0.010], but not BMI. Dose reduction was significantly more common in women (80% vs. 33%; p < 0.001). There was no association between dose reduction and age, treatment line, time from diagnosis, or other baseline characteristics of patients, or with previous treatment.

The number of cabozantinib adverse events was associated with BMI, BSA, IMDC prognostic score, and cabozantinib treatment line (Figure 1); it also correlated with body mass (R = −0.28; p = 0.020). Age, sex, or median time from diagnosis were not associated with the number of adverse events. Patients who received cabozantinib directly after tyrosine kinase inhibitors (TKI), irrespective of treatment line, reported a lower number of distinct adverse events: median (Q1; Q3) equaled 1 (1; 3) versus 3 (2; 4); p = 0.032. Moreover, among patients treated with cabozantinib in third or further line, those who received TKI in second-line treatment (n = 20) had a lower number of adverse events: 2 (1; 3) than those who received everolimus or temsirolimus in second line (n = 18): 4 (3; 5); p < 0.001. All the above associations were confirmed when we compared patients with 0–1 and more than 1 adverse event.

There was no association between the number of reported adverse events and the need for cabozantinib dose reduction (p = 0.2). Among the adverse events, only hypertension was more prevalent in patients requiring dose reduction (64% vs. 36%; p = 0.041). Moreover, patients who needed dose reduction were characterized with lower body mass [mean (SD): 77.1 (19.1) vs. 87.1 (18.4) kg; p = 0.028] and BSA [1.85 (0.25) vs. 2.01 (0.21) m²; p = 0.010], but not BMI. Dose reduction was much more common in women (80% vs. 33%; p < 0.001). There was no association between dose reduction and age, treatment line, time from diagnosis, or other baseline characteristics of patients, or with previous treatment.

4. Discussion

4.1. Interpretation of Results Based on Analysis of Existing Literature

The study showed that lower scores according to IMDC criteria correlate with a higher incidence of AEs. Furthermore, the findings illustrated in Figure 1D emphasize a consistent pattern: the more advanced the line of cabozantinib treatment, the higher the incidence of AEs. This phenomenon could potentially be attributed to the robust therapeutic activity of cabozantinib in the further stages of RCC treatment [53]. Alternatively, it might be associated with the likelihood that patients undergoing subsequent lines of treatment are more susceptible to frailty syndrome, thereby elevating the risk of AEs. Recent investigations into RCC have indicated no correlation or have even suggested that obese cancer patients may have a lower risk of mortality compared to their normal-weight counterparts [54]. This is known as the obesity paradox. Nishihara et al. found that the inverse links between BMI and mortality among some disease subgroups may be due to the high heterogeneity of the disease [55]. The longer survival among obese patients could be due to a less aggressive disease subtype [56,57] and also the fact, that obesity is associated with a higher incidence of clear cell histology than other histological types [58,59]. We observed a noteworthy correlation between higher BMI and BSA and a reduced incidence of AEs.

4.2. Mini Review of Cabozantinib-Related AEs in Randomized Clinical Trials and Real-World Experiences

After a comprehensive literature review, we have opted to prepare a Table 4 showing cabozantinib-related AEs. We emphasize the noteworthy distinctions observed between the reporting of AEs in RCTs and RWEs. We are aware of all the difficulties associated with accurate data collection in day-to-day work. However, this indicates good communication with patients and the ability to collect much-needed information. The identified studies unanimously confirm that hypothyroidism, HFS, diarrhea, and hypertension are the most prevalent cabozantinib-related AEs. This aspect holds crucial implications for the overall treatment landscape, as many of these AEs may serve as predictive factors [16,17,18,60,61]. Effective management of a substantial number of AEs poses challenges for both clinicians and patients. The increased occurrence of AEs can hinder patient compliance, and it is crucial to recognize that each AE carries the potential for severe, even life-threatening complications. However, it is important to acknowledge that AEs also serve as indicators of the therapy’s efficacy, with some being anticipated outcomes in the treatment process.

The correlation between AEs and prognosis has been observed in many systemic therapies—starting with chemotherapy, followed by TKIs and ending with immunotherapy [16,17,18,62,63]. In studies involving RCC patients, AEs occurred as potential predictive factors across various ongoing treatments [60,61,63,64]. Notably, early onset of hypertension or its worsening during ongoing sunitinib therapy has been identified as a favorable factor in advanced stages of the RCC and can be considered as a predictive factor for PFS and ORR [61]. Additionally, the manifestation of HFS during sunitinib treatment was noticed to improve OS and PFS [60]. Verzoni et al. observed a prolonged OS in patients receiving nivolumab after experiencing any type of AEs [64]. This underscores their potential role as valuable indicators in guiding therapeutic strategies for enhanced efficacy of treatment, especially in RCC.

Similar associations have been observed across various cancer types. Chen et al. and Zhou et al. reported that immune-related adverse events (irAEs) served as a positive predictive factor for PFS in non-small cell cancer lung patients undergoing treatment with anti-PD1 inhibitors as a subsequent line of therapy [62,63]. Additionally, similar potential in this prognosis has also been found by blood markers like PLR, NLR, SII [65], and CRP levels [66]. Nevertheless, more studies need to be done in this field to understand the correlation between onset of AEs and prediction of prognosis as an underlying mechanism of above mentioned interplay; despite some hypothesis, this still remains unknown [63,64,67].

4.3. Efficacy of Cabozantinib and the Search for Synergistic Combines

Many studies have confirmed the efficacy of cabozantinib in RCC. To begin with, the METEOR trial compared the efficacy of cabozantinib versus everolimus in second-line treatment aRCC and showed that cabozantinib achieves better results in terms of median OS and PFS (21.4 months vs. 16.5 months and 7.4 months vs. 3.8 months, respectively) [33]. These results were consistent with many real-world retrospective studies such as CERES, in which the ranges of OS and PFS were 6.01 and 10.84 months, respectively. Nevertheless, the median PFS in the CERES study was shorter, which can be explained by the fact that 99% of patients were treated at stage IV [47]. Median PFS for patients treated with cabozantinib in the Polish Managed Access Program (MAP) and Italian MAP were 12.5 months and 8 months, respectively [15,30]. The CABOSUN compared the efficacy of sunitinib verus cabozantinib as first-line treatment in the poor risk group and proved cabozantinib to improve outcomes in terms of PFS and OS (8.2 months [95% CI, 6.2 to 8.8 months] versus 5.6 months [95% CI, 3.4 to 8.1 months] and 30.3 months [95% CI, 14.6 to 35.0 months] versus 21.8 months [95% CI, 16.3 to 27.0 months], respectively [31]. Chun Loo Gan et al. conducted a retrospective study examining the effectiveness of cabozantinib therapy from first to subsequent lines of treatment. The ORR, time to treatment failure (TTF), and OS of patients treated with cabozantinib in the first to fourth lines of therapy were comparable; that was also reported in our previous study [53]. It is noteworthy that across all lines of therapy, the TTF and mOS were significantly longer for patients who required dose reduction versus. patients who did not, with an adjusted HR of 0.37 (95% CI 0.202–0.672, p < 0.01) and 0.46 (95% CI 0.215–0.980, p = 0.04), respectively. There was no difference in the ORR in patients with or without dose reduction (23% vs. 26%, p = 0.69) [32].

Cabozantinib emerged as an effective therapy for treating bone metastases in patients with prostate cancer, prompting researchers to conduct a subgroup analysis within the METEOR trial, which included patients with or without bone metastases. PFS for patients with bone metastases was 7.4 months (95% CI, 5.5 to 10.4 months) for patients treated with cabozantinib versus 2.7 (HR, 0.33 [95% CI, 0.21 to 0.51]) for patients treated with everolimus. Among patients with bone metastases, ORR evaluated by the Independent Radiology Committee was 17%, whereas no ORR was observed with everolimus. Additionally, the median OS for patients treated with cabozantinib was 20.1 months, compared to 12.1 months for those treated with everolimus. However, it is worth mentioning that the METEOR study was not powered for statistical testing of subgroup analysis [68].

The combination of ICIs with VEGFR inhibitiors (VEGFRi) has emerged as a significant step forward in cancer treatment. A synergistic effect has been observed between these two classes of drugs, contributing to improved outcomes across various studies, with a continually expanding number of registered clinical trials. The combination of cabozantinib with nivolumab in aRCC therapy was compared with sunitinib in the CheckMate 9ER trial—this novel approach achieved better results in terms of PFS and probability of OS at 12 months (16.6 months [95% CI 12.5 to 24.9] versus 8.3 months [95% CI, 7.0 to 9.7] and 85.7% [95% CI, 81.3 to 89.1] versus 75.6% [95% CI, 70.5 to 80.0], respectively [9]. A systemic review by Niewada et al. compared the combination of cabozantinib with nivolumab to other ICI-VEGFRi or ICI-ICI combinations. This review revealed no statistically significant differences in terms of OS in cabozantinib + nivolumab and any other combination [69].

The CANTATA trial, which compared a glutaminase inhibitor telaglenastat + cabozantinib versus placebo + cabozantinib, confirmed the effectiveness of cabozantinib in the population that was previously treated with IPI-NIVO. There was no improvement in the antitumor activity of cabozantinib in the telaglenastat + cabozantinib group [70].

4.4. The Synergism Phenomenon of Combining VEGFR Inhibitors with Immune Checkpoint Inhibitors

Through VEGFR inhibition, cabozantinib not only provides an antiangiogenic effect [71], limiting a tumor’s growth potential [72], but also demonstrates notable immunomodulatory properties. The accumulation of VEGF within the tumor inhibits ICAM-1 and VCAM-1 expression on endothelial cells, potentially impeding immune cell infiltration [73]. Simultaneously, it promotes lymphocytes CD8+ apoptosis while increasing Treg infiltration [74]. Moreover, it contributes to the myeloid-derived suppressor cells (MDSCs) maturation [75] and inhibits the maturation of dendritic cells (DCs) [76,77]. TKIs have the potential to counteract these effects: they alter the relationship between effector and regulatory cells [12], thus creating an immunostimulatory environment [78,79] and enhancing tumor infiltration through normalization of vascularization [80]. Additionally, they restore DC maturation [81] and reduce the number of MDSCs [12]

In mouse models, cabozantinib significantly decreased the expression of PD-L1 on renal cancer cells via c-Met signaling inhibition [82]; a similar effect is hypothesized to occur through AXL inhibition [53].

Taken together, these effects indicate that cabozantinib not only influences the tumor microenvironment but also directly modifies the tumor cells, making them more vulnerable to immune-mediated destruction [12], thus supporting the use of TKI plus immunotherapy combinations in oncology.

4.5. Difficult Treatment Choice after Progression

The latest treatment guidelines form ESMO [7] and ASCO [8] recommend highly active VEGFRi-ICIs treatment as the first-line choice in eligible patients. Despite its tremendous activity, there is a group of patients who will not respond or will progress during treatment with VEGFRi-ICIs. This raises the question of second-line treatment following VEGFRi-ICIs failure. While some prospective and retrospective studies have explored the outcomes of using VEGFR TKIs, such as pazopanib, sunitinib, or cabozantinib, in post-immunotherapy regimens, it is important to note that these studies often involve small and heterogeneous patient cohorts. Powles T.B. et al. reported a mPFS of 7.4 months in a group of patients receiving pazopanib after the failure of the ICI-based treatment regimens [83]. The INMUNOSUN-SOGUG trial by E. Grande et al. aimed to assess the activity of sunitinib as a second-line treatment in patients pre-treated with ICI-based regimens. The study failed to reach the pre-specified endpoint (i.e., a 30% ORR). The relatively short mPFS of 5.6 months may suggest that possibly a different choice of VEGFRi-TKI should be considered [84]. McGregor et al. explored the activity of cabozantinib in the same setting. The study included 86 patients, out of which 29% were pre-treated with VEGFRi-ICIs combination. The median TTF was 6.5 months and the mOS was 13.1 months [52]. The possibility of further usage of ICIs in the second line of treatment after the failure of VEGFRi-ICIs is still a subject of research lacking sufficient evidence and is not included in the ESMO guidelines [7]. Moreover, a combined therapy with cabozantinib and belzutifan, an HIF-2α inhibitor, is also currently being researched. Choueiri et al. examined the efficacy of belzutifan + cabozantinib as a subsequent line after previous immunotherapy. In the intervention arm, 16 of 52 (31%) patients had a confirmed objective response: one (2%) complete response and 15 (29%) partial responses, showing promise as a subsequent line of therapy for this patient group, though further investigation is needed [85].

4.6. Limitations

Limitations of this study include the small size of the subgroups and the retrospective nature of the research. Additionally, the paper is a narrative review. A detailed systematic review with meta-analysis would provide results with a lower risk of bias. A single-center study allows for uniform and well-defined criteria, but we are aware that a multicenter study would significantly increase the number of patients included in the study and the reliability of the study. Further studies should be conducted to assess the other correlations between individual factors such as BMI, BSA, IMDC prognostic score, or treatment line and adverse events. Uncovering and reporting these correlations can contribute to providing more informed and personalized patient care. Our findings, therefore, serve as a valuable reference point for future real-world studies focusing on metastatic renal cell carcinoma (mRCC).

5. Conclusions

Factors like IMDC score, BMI, and BSA may be useful tools in the day-to-day prediction of AEs risk in mRCC patients. That, in turn, will allow for faster detection and easier management, especially in the high-risk group. Profile and intensity of AEs may be equivalent of treatment response, and their careful interpretation can contribute to achieving better therapeutic outcomes. Further improvement in knowledge of AEs and more frequent reporting of them in RWEs studies is needed. This study showed that reporting accuracy in RWEs is comparable to RCTs, yet the vast majority of papers omit this clinically relevant aspect.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by P.D. (Piotr Domański), M.P., B.K., S.S., A.K., P.B., A.M., T.D., W.F., B.S.-K. and P.D. (Paulina Dumnicka)—statistical analysis and J.K.—senior supervisor. The first draft of the manuscript was written by P.D. (Piotr Domański) and M.P. All authors commented on previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Ethics Committee the Maria Sklodowska-Curie National Research Institute of Oncology (permission number 38/2018).

Informed Consent Statement

Informed consent was obtained from all individual participants included in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author (accurately indicate status).

Conflicts of Interest

Honoraria: Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, Pfizer, Research Funding: Novartis. All unrelated to the present paper.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Figure and Tables

Figure 1. Statistically significant associations between the patients’ characteristics and the number of cabozantinib adverse events. Data are shown as median (middle bar), interquartile range (box), non-outlier range (whiskers); points represent raw data. Spearman rank correlation coefficients and the respective p-values are shown on the graphs. (A)—Correlation of BMI and number of adverse events. (B)—Correlation of BSA and number of adverse events. (C)—Correlation of IMDC score and number of adverse events. (D)—Correlation of treatment line and number of adverse events.

Table 1

Characteristics of studied group at the start of the study (=start of cabozantinib treatment).

Characteristic	Values Observed in mRCC Patients(n = 71)
Male sex, n (%)	46 (65)
Mean age (SD), years	63 (9)
Median time from RCC diagnosis (Q1; Q3), years	4.3 (2.0; 8.2)
Mean body weight (SD), kg	82.1 (19.3)
Mean BMI (SD), kg/m2	28.1 (5.9)
Mean body surface area (BSA) (SD), m2	1.93 (0.24)
Morphology
Clear cell, n (%)	69 (97)
Non-clear cell, n (%)	6 (8)
Sarcomatoid differentiation, n (%)	11 (14)
Nephrectomy, n (%)	69 (97)
Fuhrman grade
1, n (%)	6 (8)
2, n (%)	33 (46)
3, n (%)	21 (30)
4, n (%)	11 (15)
MSKCC score
0, n (%)	19 (27)
1, n (%)	36 (51)
2, n (%)	15 (21)
3, n (%)	1 (1)
IMDC prognostic score
0, n (%)	16 (23)
1, n (%)	30 (42)
2, n (%)	15 (21)
3, n (%)	7 (10)
4, n (%)	3 (4)
Metastases
Lungs, n (%)	53 (75)
Bone, n (%)	24 (34)
Liver, n (%)	12 (17)
Pancreas, n (%)	6 (8)
Other sites, n (%)	31 (44)
Median number of sites (Q1; Q3)	2 (2; 3)
ECOG performance score
0, n (%)	19 (27)
1, n (%)	42 (59)
2, n (%)	9 (13)
3, n (%)	1 (1)
Karnofsky performance scale
100, n (%)	10 (14)
90, n (%)	21 (30)
80, n (%)	37 (52)
<80, n (%)	3 (4)
Cabozantinib as second-line treatment, n (%)	30 (42)
Cabozantinib as third-line treatment, n (%)	36 (50)
Cabozantinib as fourth- or fifth-line treatment, n (%)	5 (7)

Table 2

Previous treatment (before the initiation of cabozantinib).

	n (%)
First-line treatment
TKI (sunitinib, pazopanib, sorafenib), n (%)	65 (92)
Other (immunotherapy), n (%)	6 (8)
Second-line treatment
TKI (axitinib, sunitinib, pazopanib, sorafenib), n (%)	20 (28)
Everolimus, temsirolimus, n (%)	18 (25)
Nivolumab, n (%)	3 (4)
Third-line treatment
TKI (sorafenib, pazopanib), n (%)	4 (6)
Nivolumab, n (%)	1 (1)
Fourth-line treatment (nivolumab), n (%)	1 (1)

Table 3

Adverse events observed in patients and the need for dose reduction.

Variable	Values Observed in mRCC Patients (n = 71)
Any adverse event, n (%)	65 (92)
Hypothyroidism, n (%)	35 (49)
Hand-foot syndrome, n (%)	33 (46)
Hypertension, n (%)	28 (39)
Diarrhea, n (%)	28 (39)
Asthenia, n (%)	24 (34)
Liver toxicity, n (%)	11 (15)
>1 reported adverse event, n (%)	39 (55)
Median number of adverse events (Q1, Q3)	2 (1–4)
Dose reduction	35 (49)

Table 4

Cabozantinib-related adverse events in previous studies.

Author (Year)	Patients, nMale n (%)Female n (%)	Mean Age (SD),Years	ECOG Performance Score, n (%)	IMDC Score,n (%)	CTAE All Stages, n (%)	CTAE ≥ 3, n (%)	Dose Reduction, n (%)
Domański et al.(2024) [59]	71	63 (9)	0, n = 19 (27)1, n = 42 (59)2, n = 9 (13)3, n = 1 (1)	0, n = 16 (23)1, n = 30 (42)2, n = 15 (21)3, n = 7 (10)4, n = 3 (4)	Hypothyroidism, n = 35 (49)Diarrhea, n = 28 (39)HFS, n = 33 (46)Hypertension, n = 28 (39)Any AEs: n = 65 (92)	N/D	35 (49)
Patients treated in clinical trials
METEOR Choueiri et al. (2016) [33]	330,male,n = 253 (77)female,n = 77 (23)	63	0, n = 226 (68)1, n = 104 (32)	Favorable, n = 66 (20) Intermediate, n = 210 (64) Poor, n = 54 (16)	Hypothyroidism, n = 76 (23)Diarrhea, n = 249 (75)HFS, n = 142 (43)Hypertension, n = 122 (37)Any AEs: n = 331 (100)	Hypothyroidism, n = 0Diarrhea, n = 43 (13)HFS, n = 27 (8)Hypertension, n = 49 (15)Any AEs: n = 235 (71)	206 (62)
CABOSUN Choueiri et al. (2017) [31]	79,male,n = 66 (84) female,n = 13 (16)	63	0, n = 36 (46)1, n = 33 (42)2, n = 10 (13)	Intermediate, n = 64 (81) Poor,n = 15 (19)	Hypothyroidism, n = 18 (23)Diarrhea, n = 57 (73)HFS, n = 33 (43)Hypertension, n = 52 (67)Any AEs: n = 75 (96)	Hypothyroidism, n = 0Diarrhea, n = 8 (10)HFS, n = 6 (8)Hypertension, n = 22 (28)Any AEs: n = 53 (68)	36 (46)
Retrospective cohort and real-world experience studies
Prisciandaro et al. (2019) [29]	17male,n = 11 (65) female,n = 6 (35)	66	0, n = 3 (18)1, n = 12 (70)2, n = 2 (12)	Favorable,n = 9 (53)Intermediate,n = 8 (47)Poor,n = 0	Hypothyroidism, n = 4 (24)Diarrhea, n = 6 (35)HFS, n = 4 (24)Hypertension, n = 3 (18)Any AEs: n = 16 (94)	Hypothyroidism, n = 1 (6)Diarrhea, n = 2 (11)HFS, n = 0Hypertension, n = 3 (18)Any AEs: n = 7 (41)	8 (47)
Lemke et al. (2019) [44]	38male,n = 25 (66)female,n = 13 (34)	58	0, n = 2 (5)1, n = 21 (55)2, n = 15 (40)	Favorable,n = 7 (18)Intermediate,n = 20 (56)Poor,n = 9 (26)	Hypothyroidism, n = 13 (34)Diarrhea, n = 11 (29)HFS, n = 13 (34)Hypertension, n = 9 (24)Any AEs: N/D	Hypothyroidism, n = 4 (24)Diarrhea, n = 0HFS, n = 1 (3)Hypertension, n = 0Any AEs: N/D	22 (58)
McElwee et al. (2019) [26]	35male,n = 30 (86) female,n = 5 (14)	64	0, n = 8 (23)1, n = 20 (57)2, n = 7 (20)	N/D	Hypothyroidism, no dataDiarrhea, N/DHFS, n = 9 (26)Hypertension, n = 8 (23)Any AEs: N/D	N/D	8 (23)
Gomez de Liano Lista et al. (2018) [51]	128male,n = 87 (68)female,n = 41 (32)	62	0, n = 20 (16)1, n = 85 (66)2, n = 23 (18)	Favorable, n = 35 (27) Intermediate, n = 62 (49) Poor, n = 27 (21) Unknown, n = 4 (3)	N/D	Hypothyroidism, N/DDiarrhea, n = 12 (9)HFS, n = 6 (5)Hypertension, N/DAny AEs: 48 (37)	N/D
Bodnar et al. (2019) [15]	115malen = 84 (73)female,n = 31 (27)	64	0, n = 19 (16)1, n = 79 (69)2, n = 17 (15)	Favorable,n = 14 (12)Intermediate,n = 79 (69)Poor,n = 22 (19)	Hypothyroidism, n = 77 (67)Diarrhea, n = 70 (61)HFS, n = 52 (45)Hypertension, n = 51 (44)Any AEs: n = 115 (100)	Hypothyroidism, n = 0Diarrhea, n = 11 (10)HFS, n = 14 (12)Hypertension, n = 6 (5)Any AEs: n = 56 (49)	79 (69)
McGregor et al. (2020) [52]	86malen = 61 (71)female,n = 25 (29)	63	N/D	Favorable,n = 4 (5)Intermediate,n = 57 (66)Poor,n = 24 (28)	Hypothyroidism, N/DDiarrhea, n = 9 (10)HFS, n = 14 (16)Hypertension, n = 3 (3)Any AEs: n = 81 (94)	Hypothyroidism, N/DDiarrhea, n = 1 (1)HFS, n = 2 (2)Hypertension, n = 2 (2)Any AEs: n = 20 (23)	39 (45)
Sumanta K. Pal et al. (2021) [42]	44malen = 36 (82)femalen = 8 (18)	65	N/D	Favorable,n = 10 (23)Intermediate,n = 28 (64)Poor,n = 6 (14)	Hypothyroidism, N/DDiarrhea, n = 24 (55)HFS, n = 21 (48)Hypertension, n = 28 (65)Any AEs: n = 42 (97)	Hypothyroidism, N/DDiarrhea, n = 2 (4)HFS, n = 9 (20)Hypertension, n = 14 (32)Any AEs: n = 32 (74)	10 (23) *
Matthew T. Campbell et al. (2018) [28]	30malen = 26 (87)femalen = 4 (13)	58	N/D	Favorable,n = 2 (7)Intermediate,n = 23 (77)Poor,n = 5 (17)	Hypothyroidism, N/DDiarrhea, n = 17 (57)HFS, n = 11 (37)Hypertension, N/DAny AEs: N/D	Hypothyroidism, N/DDiarrhea, n = 0HFS, n = 2 (7)Hypertension, N/DAny AEs: N/D	17 (57)
Nieves Martínez Chanzá et al. (2019) [27]	112malen = 85 (76)femalen = 27 (24)	60	0, n = 23 (20)1, n = 59 (53)2–3, n = 11 (10)	Favorable,n = 9 (8)Intermediate,n = 71 (63)Poor,n = 29 (26)unknown,n = 3 (3)	Hypothyroidism, n = 17 (15)Diarrhea, n = 38 (34)HFS, n = 35 (31)Hypertension, n = 31 (28)Any AEs: N/D	Hypothyroidism **, n = 0Diarrhea **, n = 3 (3)HFS **, n = 5 (4)Hypertension **, n = 4 (4)Any AEs **: N/D	51 (46)
Noboru Nakaigawa et al. (2023) [34]	35male, N/Dfemale,N/D	63	N/D	Favorable,n = 6 (17)Intermediate,n = 22 (63)Poor,n = 7 (20)	Hypothyroidism, n = 6 (17)Diarrhea, n = 24 (67)HFS, n = 23 (66)Hypertension, n = 15 (43)Any AEs: 35 (100)	Hypothyroidism, n = 0Diarrhea, n = 3 (9)HFS, n = 3 (9)Hypertension, n = 5 (14)Any AEs: 29 (83)	33 (94)
Koji Iinuma et al. (2022) [35]	53malen = 44 (83)femalen = 9 (17)	72	0, n = 18 (34)1, n = 17 (32)2, n = 9 (17)3, n = 8 (15)4, n = 1 (2)	Favorable,n = 12 (23)Intermediate,n = 17 (51)Poor,n = 14 (26)	Hypothyroidism, n = 9 (17))Diarrhea, n = 14 (26)HFS, n = 9 (17)Hypertension, n = 11 (21)Any AEs: 42 (79)	Hypothyroidism, n = 0Diarrhea, n = 2 (4)HFS, n = 3 (6)Hypertension, n = 1 (2)Any AEs: 10 (19)	4 (8) *

N/D—no data; * discontinuation of treatment; ** includes only AEs CTAE 3.

References

1. World Cancer Research Fund. Kidney Cancer Statistics. Available online: https://www.wcrf.org/cancer-trends/kidney-cancer-statistics/ (accessed on 20 December 2023).

2. Didkowska, J.; Wojciechowska, U.; Michalek, I.M.; Caetano dos Santos, F.L. Cancer Incidence and Mortality in Poland in 2019. Sci. Rep.; 2022; 12, 10875. [DOI: https://dx.doi.org/10.1038/s41598-022-14779-6]

3. Klatte, T.; Pantuck, A.J. Molecular Biology of Renal Cortical Tumors. Urol. Clin. N. Am.; 2008; 35, pp. 573-580. [DOI: https://dx.doi.org/10.1016/j.ucl.2008.07.006]

4. Zbar, B.; Brauch, H.; Talmadge, C.; Linehan, M. Loss of Alleles of Loci on the Short Arm of Chromosome 3 in Renal Cell Carcinoma. Nature; 1987; 327, pp. 721-724. [DOI: https://dx.doi.org/10.1038/327721a0]

5. Aron, M.; Nguyen, M.M.; Stein, R.J.; Gill, I.S. Impact of Gender in Renal Cell Carcinoma: An Analysis of the SEER Database. Eur. Urol.; 2008; 54, pp. 133-140. [DOI: https://dx.doi.org/10.1016/j.eururo.2007.12.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18160207]

6. Berger, A.P.; Hobisch, A. Treatment Options in Localised and Metastatic Renal Cell Carcinoma. Memo—Mag. Eur. Med. Oncol.; 2008; 1, pp. 167-170. [DOI: https://dx.doi.org/10.1007/s12254-008-0055-9]

7. Bedke, J.; Albiges, L.; Capitanio, U.; Giles, R.H.; Hora, M.; Lam, T.B.; Ljungberg, B.; Marconi, L.; Klatte, T.; Volpe, A. et al. Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Nivolumab plus Cabozantinib Joins Immune Checkpoint Inhibition Combination Therapies for Treatment-naïve Metastatic Clear-Cell Renal Cell Carcinoma. Eur. Urol.; 2021; 79, pp. 339-342. [DOI: https://dx.doi.org/10.1016/j.eururo.2020.12.005]

8. Rathmell, W.K.; Rumble, R.B.; Van Veldhuizen, P.J.; Al-Ahmadie, H.; Emamekhoo, H.; Hauke, R.J.; Louie, A.V.; Milowsky, M.I.; Molina, A.M.; Rose, T.L. et al. Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline. J. Clin. Oncol.; 2022; 40, pp. 2957-2995. [DOI: https://dx.doi.org/10.1200/JCO.22.00868] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35728020]

9. Choueiri, T.K.; Powles, T.; Burotto, M.; Escudier, B.; Bourlon, M.T.; Zurawski, B.; Oyervides Juárez, V.M.; Hsieh, J.J.; Basso, U.; Shah, A.Y. et al. Nivolumab Plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N. Engl. J. Med.; 2021; 384, pp. 829-841. [DOI: https://dx.doi.org/10.1056/NEJMoa2026982] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33657295]

10. Apolo, A.B.; Nadal, R.; Tomita, Y.; Davarpanah, N.N.; Cordes, L.M.; Steinberg, S.M.; Cao, L.; Parnes, H.L.; Costello, R.; Merino, M.J. et al. Cabozantinib in Patients with Platinum-Refractory Metastatic Urothelial Carcinoma: An Open-Label, Single-Centre, Phase 2 Trial. Lancet Oncol.; 2020; 21, pp. 1099-1109. [DOI: https://dx.doi.org/10.1016/S1470-2045(20)30202-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32645282]

11. Ott, P.A.; Hodi, F.S.; Buchbinder, E.I. Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data. Front. Oncol.; 2015; 5, 202. [DOI: https://dx.doi.org/10.3389/fonc.2015.00202]

12. Kwilas, A.R.; Ardiani, A.; Donahue, R.N.; Aftab, D.T.; Hodge, J.W. Dual Effects of a Targeted Small-Molecule Inhibitor (Cabozantinib) on Immune-Mediated Killing of Tumor Cells and Immune Tumor Microenvironment Permissiveness When Combined with a Cancer Vaccine. J. Transl. Med.; 2014; 12, 294. [DOI: https://dx.doi.org/10.1186/s12967-014-0294-y]

13. Bagchi, S.; Yuan, R.; Engleman, E.G. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu. Rev. Pathol.; 2021; 16, pp. 223-249. [DOI: https://dx.doi.org/10.1146/annurev-pathol-042020-042741]

14. Jancewicz, I.; Szarkowska, J.; Konopinski, R.; Stachowiak, M.; Swiatek, M.; Blachnio, K.; Kubala, S.; Oksinska, P.; Cwiek, P.; Rusetska, N. et al. PD-L1 Overexpression, SWI/SNF Complex Deregulation, and Profound Transcriptomic Changes Characterize Cancer-Dependent Exhaustion of Persistently Activated CD4(+) T Cells. Cancers; 2021; 13, 4148. [DOI: https://dx.doi.org/10.3390/cancers13164148]

15. Bodnar, L.; Kopczyńska, A.; Żołnierek, J.; Wieczorek-Rutkowska, M.; Chrom, P.; Tomczak, P. Real-world Experience of Cabozantinib as Second- or Subsequent Line Treatment in Patients With Metastatic Renal Cell Carcinoma: Data From the Polish Managed Access Program. Clin. Genitourin. Cancer; 2019; 17, pp. e556-e564. [DOI: https://dx.doi.org/10.1016/j.clgc.2019.02.002]

16. Buda-Nowak, A.; Kucharz, J.; Dumnicka, P.; Kuzniewski, M.; Herman, R.M.; Zygulska, A.L.; Kusnierz-Cabala, B. Sunitinib-Induced Hypothyroidism Predicts Progression-Free Survival in Metastatic Renal Cell Carcinoma Patients. Med. Oncol.; 2017; 34, 68. [DOI: https://dx.doi.org/10.1007/s12032-017-0928-z]

17. Kucharz, J.; Budnik, M.; Dumnicka, P.; Pastuszczak, M.; Kuśnierz-Cabala, B.; Demkow, T.; Popko, K.; Wiechno, P. Hand-Foot Syndrome and Progression-Free Survival in Patients Treated with Sunitinib for Metastatic Clear Cell Renal Cell Carcinoma. Adv. Exp. Med. Biol.; 2019; 1133, pp. 35-40. [DOI: https://dx.doi.org/10.1007/5584_2018_328]

18. Kucharz, J.; Dumnicka, P.; Kusnierz-Cabala, B.; Demkow, T.; Wiechno, P. The Correlation between the Incidence of Adverse Events and Progression-Free Survival in Patients Treated with Cabozantinib for Metastatic Renal Cell Carcinoma (mRCC). Med. Oncol.; 2019; 36, 19. [DOI: https://dx.doi.org/10.1007/s12032-018-1239-8] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30666498]

19. Anderson, S.; Brenner, B.M. The Aging Kidney: Structure, Function, Mechanisms, and Therapeutic Implications. J. Am. Geriatr. Soc.; 1987; 35, pp. 590-593. [DOI: https://dx.doi.org/10.1111/j.1532-5415.1987.tb01407.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/3553292]

20. Heng, D.Y.; Xie, W.; Regan, M.M.; Warren, M.A.; Golshayan, A.R.; Sahi, C.; Eigl, B.J.; Ruether, J.D.; Cheng, T.; North, S. 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, pp. 5794-5799. [DOI: https://dx.doi.org/10.1200/JCO.2008.21.4809] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19826129]

21. Agency, European Medicines. Summmary of Product Characteristics Cabozantinib. 2021; Available online: https://www.ema.europa.eu/en/documents/product-information/cabometyx-epar-product-information_en.pdf (accessed on 21 February 2024).

22. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (Ctcae) Version 5.0. 2017; Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf (accessed on 21 February 2024).

23. Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M. et al. New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). Eur. J. Cancer; 2009; 45, pp. 228-247. [DOI: https://dx.doi.org/10.1016/j.ejca.2008.10.026] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19097774]

24. Hirsch, L.; Martinez Chanza, N.; Farah, S.; Xie, W.; Flippot, R.; Braun, D.A.; Rathi, N.; Thouvenin, J.; Collier, K.A.; Seront, E. et al. Clinical Activity and Safety of Cabozantinib for Brain Metastases in Patients With Renal Cell Carcinoma. JAMA Oncol.; 2021; 7, pp. 1815-1823. [DOI: https://dx.doi.org/10.1001/jamaoncol.2021.4544]

25. Richter, I.; Poprach, A.; Zemankova, A.; Buchler, T.; Bartos, J.; Samal, V.; Studentova, H.; Rozsypalova, A.; Dvorak, J.; Brom, O. et al. Patients with Metastatic Renal Cell Carcinoma Treated with Cabozantinib in the Czech Republic: Analysis of Four Cancer Centers. Biomed. Pap. Med. Fac. Palacky Univ. Olomouc; 2022; 166, pp. 97-104. [DOI: https://dx.doi.org/10.5507/bp.2020.055]

26. McElwee, J.H.; Gourdin, T.S.; Mikoll, J.; Weeda, E.; Sion, A.M. Cabozantinib Use in Metastatic Renal Cell Carcinoma Patients in Clinical Practice: Evaluation of Dosing Patterns, Tolerability, and Outcomes Compared to Clinical Trials. J. Oncol. Pharm. Pract.; 2020; 26, pp. 861-865. [DOI: https://dx.doi.org/10.1177/1078155219875509] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31566113]

27. Martínez Chanzá, N.; Xie, W.; Asim Bilen, M.; Dzimitrowicz, H.; Burkart, J.; Geynisman, D.M.; Balakrishnan, A.; Bowman, I.A.; Jain, R.; Stadler, W. et al. Cabozantinib in Advanced Non-Clear-Cell Renal Cell Carcinoma: A Multicentre, Retrospective, Cohort Study. Lancet Oncol.; 2019; 20, pp. 581-590. [DOI: https://dx.doi.org/10.1016/S1470-2045(18)30907-0] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30827746]

28. Campbell, M.T.; Bilen, M.A.; Shah, A.Y.; Lemke, E.; Jonasch, E.; Venkatesan, A.M.; Altinmakas, E.; Duran, C.; Msaouel, P.; Tannir, N.M. Cabozantinib for the Treatment of Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma: A Retrospective Analysis. Eur. J. Cancer; 2018; 104, pp. 188-194. [DOI: https://dx.doi.org/10.1016/j.ejca.2018.08.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30380460]

29. Prisciandaro, M.; Ratta, R.; Massari, F.; Fornarini, G.; Caponnetto, S.; Iacovelli, R.; De Giorgi, U.; Facchini, G.; Scagliarini, S.; Sabbatini, R. et al. Safety and Efficacy of Cabozantinib for Metastatic Nonclear Renal Cell Carcinoma: Real-world Data From an Italian Managed Access Program. Am. J. Clin. Oncol.; 2019; 42, pp. 42-45. [DOI: https://dx.doi.org/10.1097/COC.0000000000000478] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30204614]

30. Procopio, G.; Prisciandaro, M.; Iacovelli, R.; Cortesi, E.; Fornarini, G.; Facchini, G.; Cartenì, G.; Sabbatini, R.; Del Bene, G.; Galli, L. et al. Safety and Efficacy of Cabozantinib in Metastatic Renal-Cell Carcinoma: Real-World Data From an Italian Managed Access Program. Clin. Genitourin. Cancer; 2018; 16, pp. e945-e951. [DOI: https://dx.doi.org/10.1016/j.clgc.2018.03.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29753637]

31. Choueiri, T.K.; Halabi, S.; Sanford, B.L.; Hahn, O.; Michaelson, M.D.; Walsh, M.K.; Feldman, D.R.; Olencki, T.; Picus, J.; Small, E.J. et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J. Clin. Oncol.; 2017; 35, pp. 591-597. [DOI: https://dx.doi.org/10.1200/JCO.2016.70.7398] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28199818]

32. Gan, C.L.; Dudani, S.; Wells, J.C.; Donskov, F.; Pal, S.K.; Dizman, N.; Rathi, N.; Beuselinck, B.; Yan, F.; Lalani, A.A. et al. Cabozantinib Real-World Effectiveness in the First-Through Fourth-Line Settings for the Treatment of Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Cancer Med.; 2021; 10, pp. 1212-1221. [DOI: https://dx.doi.org/10.1002/cam4.3717]

33. Choueiri, T.K.; Escudier, B.; Powles, T.; Tannir, N.M.; Mainwaring, P.N.; Rini, B.I.; Hammers, H.J.; Donskov, F.; Roth, B.J.; Peltola, K. et al. Cabozantinib versus Everolimus in Advanced Renal Cell Carcinoma (METEOR): Final Results from a Randomised, Open-Label, Phase 3 Trial. Lancet Oncol.; 2016; 17, pp. 917-927. [DOI: https://dx.doi.org/10.1016/S1470-2045(16)30107-3]

34. Nakaigawa, N.; Tomita, Y.; Tamada, S.; Tatsugami, K.; Osawa, T.; Oya, M.; Kanayama, H.; Miura, Y.; Sassa, N.; Nishimura, K. et al. Final Efficacy and Safety Results and Biomarker Analysis of a Phase 2 Study of Cabozantinib in Japanese Patients with Advanced Renal Cell Carcinoma. Int. J. Clin. Oncol.; 2023; 28, pp. 416-426. [DOI: https://dx.doi.org/10.1007/s10147-022-02283-w]

35. Iinuma, K.; Tomioka-Inagawa, R.; Kameyama, K.; Taniguchi, T.; Kawada, K.; Ishida, T.; Nagai, S.; Enomoto, T.; Ueda, S.; Kawase, M. et al. Efficacy and Safety of Cabozantinib in Patients with Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study. Biomedicines; 2022; 10, 3172. [DOI: https://dx.doi.org/10.3390/biomedicines10123172]

36. Thouvenin, J.; Alhalabi, O.; Carlo, M.; Carril-Ajuria, L.; Hirsch, L.; Martinez-Chanza, N.; Négrier, S.; Campedel, L.; Martini, D.; Borchiellini, D. et al. Efficacy of Cabozantinib in Metastatic Mit Family Translocation Renal Cell Carcinomas. Oncologist; 2022; 27, pp. 1041-1047. [DOI: https://dx.doi.org/10.1093/oncolo/oyac158]

37. Procopio, G.; Sepe, P.; Claps, M.; Buti, S.; Colecchia, M.; Giannatempo, P.; Guadalupi, V.; Mariani, L.; Lalli, L.; Fucà, G. et al. Cabozantinib as First-line Treatment in Patients With Metastatic Collecting Duct Renal Cell Carcinoma: Results of the Bonsai Trial for the Italian Network for Research in Urologic-Oncology (Meet-URO 2 Study). JAMA Oncol.; 2022; 8, pp. 910-913. [DOI: https://dx.doi.org/10.1001/jamaoncol.2022.0238]

38. Hahn, A.W.; Surasi, D.S.; Viscuse, P.V.; Bathala, T.K.; Wiele, A.J.; Campbell, M.T.; Zurita, A.J.; Shah, A.Y.; Jonasch, E.; Gao, J. et al. Treatment Outcomes in Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid and/or Rhabdoid Dedifferentiation After Progression on Immune Checkpoint Therapy. Oncologist; 2023; oyad302. [DOI: https://dx.doi.org/10.1093/oncolo/oyad302]

39. Baudry, E.; Naoun, N.; Auclin, E.; Saldana, C.; Barthelemy, P.; Geoffrois, L.; Thibault, C.; de Vries-Brilland, M.; Borchiellini, D.; Maillet, D. et al. Efficacy and Safety of Cabozantinib Rechallenge in Metastatic Renal Cell Carcinoma: A Retrospective Multicentric Study. Eur. J. Cancer; 2023; 193, 113292. [DOI: https://dx.doi.org/10.1016/j.ejca.2023.113292]

40. Maráz, A.; Nagyiványi, K.; Balogh, I.; Bodoky, G.; Mangel, L.; Küronya, Z.; Géczi, L.; Torday, L.; Dudás, S.; Szűcs, M. et al. Multicentric Hungarian Results of Cabozantinib Therapy in Patients with Metastatic Kidney Cancer Based on Real-World Data. Magy Onkol.; 2023; 67, pp. 73-83.

41. Santoni, M.; Massari, F.; Grande, E.; Procopio, G.; Matrana, M.R.; Rizzo, M.; De Giorgi, U.; Basso, U.; Milella, M.; Iacovelli, R. et al. Cabozantinib in Pretreated Patients with Metastatic Renal Cell Carcinoma with Sarcomatoid Differentiation: A Real-World Study. Target. Oncol.; 2021; 16, pp. 625-632. [DOI: https://dx.doi.org/10.1007/s11523-021-00828-z] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34338966]

42. Pal, S.K.; Tangen, C.; Thompson, I.M., Jr.; Balzer-Haas, N.; George, D.J.; Heng, D.Y.C.; Shuch, B.; Stein, M.; Tretiakova, M.; Humphrey, P. et al. A Comparison of Sunitinib with Cabozantinib, Crizotinib, and Savolitinib for Treatment of Advanced Papillary Renal Cell Carcinoma: A Randomised, Open-Label, Phase 2 Trial. Lancet; 2021; 397, pp. 695-703. [DOI: https://dx.doi.org/10.1016/S0140-6736(21)00152-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33592176]

43. Fogli, S.; Porta, C.; Del Re, M.; Crucitta, S.; Gianfilippo, G.; Danesi, R.; Rini, B.I.; Schmidinger, M. Optimizing Treatment of Renal Cell Carcinoma with VEGFR-TKIs: A Comparison of Clinical Pharmacology and Drug-Drug Interactions of Anti-Angiogenic Drugs. Cancer Treat. Rev.; 2020; 84, 101966. [DOI: https://dx.doi.org/10.1016/j.ctrv.2020.101966] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32044644]

44. Lemke, E.A.; Shah, A.Y.; Campbell, M.; Tannir, N.M. Real-World Experience With Cabozantinib in Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis. J. Adv. Pract. Oncol.; 2019; 10, pp. 333-339. [DOI: https://dx.doi.org/10.6004/jadpro.2019.10.4.2]

45. Proskorovsky, I.; Benedict, A.; Negrier, S.; Bargo, D.; Sandin, R.; Ramaswamy, K.; Desai, J.; Cappelleri, J.C.; Larkin, J. Axitinib, Cabozantinib, or Everolimus in the Treatment of Prior Sunitinib-Treated Patients with Metastatic Renal Cell Carcinoma: Results of Matching-Adjusted Indirect Comparison Analyses. BMC Cancer; 2018; 18, 1271. [DOI: https://dx.doi.org/10.1186/s12885-018-5157-0]

46. Mennitto, A.; Zattarin, E.; Di Maio, M.; Bimbatti, D.; De Giorgi, U.; Buti, S.; Santini, D.; Casadei, C.; Sorarù, M.; Messina, C. et al. Cabozantinib beyond Progression Improves Survival in Advanced Renal Cell Carcinoma Patients: The CABEYOND Study (Meet-URO 21). Expert Rev. Anticancer Ther.; 2022; 22, pp. 115-121. [DOI: https://dx.doi.org/10.1080/14737140.2022.2002688]

47. Venugopal, B.; Pillai, M.; Powles, T.; Savage, P.; Michael, A.; Fife, K.; Klair, B.; Perrot, V.; Szabados, B. Early Clinical Experience with Cabozantinib for Advanced Renal Cell Carcinoma in the UK: Real-World Treatment Pathways and Clinical Outcomes. Clin. Genitourin. Cancer; 2022; 20, pp. 94-94.e10. [DOI: https://dx.doi.org/10.1016/j.clgc.2021.09.005]

48. Martini, D.J.; Evans, S.T.; Liu, Y.; Shabto, J.M.; Uner, O.E.; Olsen, T.A.; Brown, J.T.; Russler, G.A.; Yantorni, L.; Caulfield, S. et al. Analysis of Toxicity and Clinical Outcomes in Full Versus Reduced Starting Dose Cabozantinib in Metastatic Renal Cell Carcinoma Patients. Clin. Genitourin. Cancer; 2022; 20, pp. 53-59. [DOI: https://dx.doi.org/10.1016/j.clgc.2021.11.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34922840]

49. Procopio, G.; Claps, M.; Pircher, C.; Porcu, L.; Sepe, P.; Guadalupi, V.; De Giorgi, U.; Bimbatti, D.; Nolè, F.; Carrozza, F. 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, pp. 129-137. [DOI: https://dx.doi.org/10.1177/03008916221138881] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36447337]

50. Pal, S.; Albiges, L.; Rodriguez, C.; Liu, B.; Doss, J.; Khurana, S.; Scheffold, C.; Voss, M.; Choueiri, T. CONTACT-03: Randomized, Open-Label Phase III Study of Atezolizumab Plus Cabozantinib versus Cabozantinib Monotherapy Following Progression on/after Immune Checkpoint Inhibitor (ICI) Treatment in Patients with Advanced/Metastatic Renal Cell Carcinoma. J. Clin. Oncol.; 2021; 39, TPS370. [DOI: https://dx.doi.org/10.1200/JCO.2021.39.6_suppl.TPS370]

51. Gomez de Liaño Lista, A.; Venugopal, B.; Fife, K.; Symeonides, S.; Vasudev, N.; Rudman, S.; Vohra, S.; Khasati, L.; Pettinger, C.; Szabados, B. et al. 893PCabozantinib in Metastatic Renal Cell Carcinoma (mRCC): Data from UK Expanded Access Program (EAP). Ann. Oncol.; 2018; 29, viii317. [DOI: https://dx.doi.org/10.1093/annonc/mdy283.102]

52. McGregor, B.A.; Lalani, A.K.A.; Xie, W.; Steinharter, J.A.; Bakouny, Z.E.; Martini, D.J.; Fleischer, J.H.; Abou-Alaiwi, S.; Nassar, A.; Nuzzo, P.V. et al. Activity of Cabozantinib after Immune Checkpoint Blockade in Metastatic Clear-Cell Renal Cell Carcinoma. Eur. J. Cancer; 2020; 135, pp. 203-210. [DOI: https://dx.doi.org/10.1016/j.ejca.2020.05.009] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32599410]

53. Domański, P.; Jarosińska, J.; Kruczyk, B.; Piętak, M.; Mydlak, A.; Demkow, T.; Kuncman, Ł.; Darewicz, M.; Sikora-Kupis, B.; Dumnicka, P. et al. Activity of Cabozantinib in Further Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma. Real-World Experience in a Single-Center Retrospective Study. Contemp. Oncol./Współczesna Onkol.; 2023; 27, pp. 190-197. [DOI: https://dx.doi.org/10.5114/wo.2023.133545] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38239858]

54. Choi, Y.; Park, B.; Jeong, B.C.; Seo, S.I.; Jeon, S.S.; Choi, H.Y.; Adami, H.O.; Lee, J.E.; Lee, H.M. Body Mass Index and Survival in Patients with Renal Cell Carcinoma: A Clinical-Based Cohort and Meta-Analysis. Int. J. Cancer; 2013; 132, pp. 625-634. [DOI: https://dx.doi.org/10.1002/ijc.27639]

55. Nishihara, R.; VanderWeele, T.J.; Shibuya, K.; Mittleman, M.A.; Wang, M.; Field, A.E.; Giovannucci, E.; Lochhead, P.; Ogino, S. Molecular Pathological Epidemiology Gives Clues to Paradoxical Findings. Eur. J. Epidemiol.; 2015; 30, pp. 1129-1135. [DOI: https://dx.doi.org/10.1007/s10654-015-0088-4]

56. Renfro, L.A.; Loupakis, F.; Adams, R.A.; Seymour, M.T.; Heinemann, V.; Schmoll, H.J.; Douillard, J.Y.; Hurwitz, H.; Fuchs, C.S.; Diaz-Rubio, E. et al. Body Mass Index Is Prognostic in Metastatic Colorectal Cancer: Pooled Analysis of Patients From First-Line Clinical Trials in the ARCAD Database. J. Clin. Oncol.; 2016; 34, pp. 144-150. [DOI: https://dx.doi.org/10.1200/JCO.2015.61.6441]

57. Waalkes, S.; Merseburger, A.S.; Kramer, M.W.; Herrmann, T.R.; Wegener, G.; Rustemeier, J.; Hofmann, R.; Schrader, M.; Kuczyk, M.A.; Schrader, A.J. Obesity Is Associated with Improved Survival in Patients with Organ-Confined Clear-Cell Kidney Cancer. Cancer Causes Control.; 2010; 21, pp. 1905-1910. [DOI: https://dx.doi.org/10.1007/s10552-010-9618-2]

58. Lowrance, W.T.; Thompson, R.H.; Yee, D.S.; Kaag, M.; Donat, S.M.; Russo, P. Obesity Is Associated with a Higher Risk of Clear-Cell Renal Cell Carcinoma Than with Other Histologies. BJU Int.; 2010; 105, pp. 16-20. [DOI: https://dx.doi.org/10.1111/j.1464-410X.2009.08706.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19583732]

59. Domański, P.; Jarosińska, J.; Kruczyk, B.; Piętak, M.; Mydlak, A.; Demkow, T.; Kuncman, Ł.; Darewicz, M.; Sikora-Kupis, B.; Michalski, W. et al. Prognostic Value of Pan-Immune-Inflammation Value and Body Mass Index in Geriatric Patients with Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors as First Line Treatment. A Single-Center Retrospective Study. Contemp. Oncol./Współczesna Onkol.; 2024; 27, [DOI: https://dx.doi.org/10.5114/wo.2023.134786]

60. Poprach, A.; Pavlik, T.; Melichar, B.; Puzanov, I.; Dusek, L.; Bortlicek, Z.; Vyzula, R.; Abrahamova, J.; Buchler, T. Skin Toxicity and Efficacy of Sunitinib and Sorafenib in Metastatic Renal Cell Carcinoma: A National Registry-Based Study. Ann. Oncol.; 2012; 23, pp. 3137-3143. [DOI: https://dx.doi.org/10.1093/annonc/mds145] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22700990]

61. Bono, P.; Rautiola, J.; Utriainen, T.; Joensuu, H. Hypertension as Predictor of Sunitinib Treatment Outcome in Metastatic Renal Cell Carcinoma. Acta Oncol.; 2011; 50, pp. 569-573. [DOI: https://dx.doi.org/10.3109/0284186X.2010.543696] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21208033]

62. Chen, M.; Li, Q.; Xu, Y.; Zhao, J.; Zhang, L.; Wei, L.; Zhong, W.; Wang, M. Immunotherapy as Second-Line Treatment and beyond for Non-Small Cell Lung Cancer in a Single Center of China: Outcomes, Toxicities, and Clinical Predictive Factors from a Real-World Retrospective Analysis. Thorac. Cancer; 2020; 11, pp. 1955-1962. [DOI: https://dx.doi.org/10.1111/1759-7714.13488] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32468726]

63. Zhou, X.; Yao, Z.; Yang, H.; Liang, N.; Zhang, X.; Zhang, F. Are Immune-Related Adverse Events Associated with the Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer? A Systematic Review and Meta-Analysis. BMC Med.; 2020; 18, 87. [DOI: https://dx.doi.org/10.1186/s12916-020-01549-2] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32306958]

64. Verzoni, E.; Cartenì, G.; Cortesi, E.; Giannarelli, D.; De Giglio, A.; Sabbatini, R.; Buti, S.; Rossetti, S.; Cognetti, F.; Rastelli, F. et al. Real-World Efficacy and Safety of Nivolumab in Previously-Treated Metastatic Renal Cell Carcinoma, and Association between Immune-Related Adverse Events and Survival: The Italian expanded access program. J. Immunother. Cancer; 2019; 7, 99. [DOI: https://dx.doi.org/10.1186/s40425-019-0579-z]

65. Iinuma, K.; Enomoto, T.; Kawada, K.; Fujimoto, S.; Ishida, T.; Takagi, K.; Nagai, S.; Ito, H.; Kawase, M.; Nakai, C. et al. Utility of Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Systemic Immune Inflammation Index as Prognostic, Predictive Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab and Ipilimumab. J. Clin. Med.; 2021; 10, 5325. [DOI: https://dx.doi.org/10.3390/jcm10225325]

66. Yano, Y.; Ohno, T.; Komura, K.; Fukuokaya, W.; Uchimoto, T.; Adachi, T.; Hirasawa, Y.; Hashimoto, T.; Yoshizawa, A.; Yamazaki, S. et al. Serum C-reactive Protein Level Predicts Overall Survival for Clear Cell and Non-Clear Cell Renal Cell Carcinoma Treated with Ipilimumab plus Nivolumab. Cancers; 2022; 14, 5659. [DOI: https://dx.doi.org/10.3390/cancers14225659]

67. Wang, Y.; Zou, J.; Li, Y.; Jiao, X.; Wang, Y.; Zhuo, N.; Gao, M.; Gong, J.; Li, J.; Zhang, X. et al. Serological Biomarkers Predict Immune-Related Adverse Events and Clinical Benefit in Patients with Advanced Gastrointestinal Cancers. Front. Immunol.; 2022; 13, 987568. [DOI: https://dx.doi.org/10.3389/fimmu.2022.987568]

68. Escudier, B.; Powles, T.; Motzer, R.J.; Olencki, T.; Arén Frontera, O.; Oudard, S.; Rolland, F.; Tomczak, P.; Castellano, D.; Appleman, L.J. et al. Cabozantinib, a New Standard of Care for Patients with Advanced Renal Cell Carcinoma and Bone Metastases? Subgroup Analysis of the METEOR Trial. J. Clin. Oncol.; 2018; 36, pp. 765-772. [DOI: https://dx.doi.org/10.1200/JCO.2017.74.7352] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29309249]

69. Niewada, M.; Macioch, T.; Konarska, M.; Mela, A.; Goszczynski, A.; Przekopinska, B.; Rajkiewicz, K.; Wysocki, P.; Krzakowski, M. Immune Checkpoint Inhibitors Combined with Tyrosine Kinase Inhibitors or Immunotherapy for Treatment-Naive Metastatic Clear-Cell Renal Cell Carcinoma-A Network Meta-Analysis. Focus on Cabozantinib Combined with Nivolumab. Front. Pharmacol.; 2022; 13, 1063178. [DOI: https://dx.doi.org/10.3389/fphar.2022.1063178]

70. Tannir, N.M.; Agarwal, N.; Porta, C.; Lawrence, N.J.; Motzer, R.; McGregor, B.; Lee, R.J.; Jain, R.K.; Davis, N.; Appleman, L.J. 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, pp. 1411-1418. [DOI: https://dx.doi.org/10.1001/jamaoncol.2022.3511] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36048457]

71. Choueiri, T.K.; Escudier, B.; Powles, T.; Mainwaring, P.N.; Rini, B.I.; Donskov, F.; Hammers, H.; Hutson, T.E.; Lee, J.L.; Peltola, K. et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med.; 2015; 373, pp. 1814-1823. [DOI: https://dx.doi.org/10.1056/NEJMoa1510016] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26406150]

72. Libertino, J.; Gee, J. Renal Cancer Contemporary Management: Contemporary Management; Springer: Berlin/Heidelberg, Germany, 2020.

73. Dirkx, A.E.; Oude Egbrink, M.G.; Kuijpers, M.J.; van der Niet, S.T.; Heijnen, V.V.; Bouma-ter Steege, J.C.; Wagstaff, J.; Griffioen, A.W. Tumor Angiogenesis Modulates Leukocyte-Vessel Wall Interactions In Vivo by Reducing Endothelial Adhesion Molecule Expression. Cancer Res.; 2003; 63, pp. 2322-2329. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12727857]

74. Motz, G.T.; Santoro, S.P.; Wang, L.P.; Garrabrant, T.; Lastra, R.R.; Hagemann, I.S.; Lal, P.; Feldman, M.D.; Benencia, F.; Coukos, G. Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors. Nat. Med.; 2014; 20, pp. 607-615. [DOI: https://dx.doi.org/10.1038/nm.3541] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24793239]

75. Nakamura, I.; Shibata, M.; Gonda, K.; Yazawa, T.; Shimura, T.; Anazawa, T.; Suzuki, S.; Sakurai, K.; Koyama, Y.; Ohto, H. et al. Serum Levels of Vascular Endothelial Growth Factor Are Increased and Correlate with Malnutrition, Immunosuppression Involving MDSCs and Systemic Inflammation in Patients with Cancer of the Digestive System. Oncol. Lett.; 2013; 5, pp. 1682-1686. [DOI: https://dx.doi.org/10.3892/ol.2013.1231]

76. Gabrilovich, D.; Ishida, T.; Oyama, T.; Ran, S.; Kravtsov, V.; Nadaf, S.; Carbone, D.P. Vascular Endothelial Growth Factor Inhibits the Development of Dendritic Cells and Dramatically Affects the Differentiation of Multiple Hematopoietic Lineages In Vivo. Blood; 1998; 92, pp. 4150-4166. [DOI: https://dx.doi.org/10.1182/blood.V92.11.4150] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9834220]

77. Dikov, M.M.; Ohm, J.E.; Ray, N.; Tchekneva, E.E.; Burlison, J.; Moghanaki, D.; Nadaf, S.; Carbone, D.P. Differential Roles of Vascular Endothelial Growth Factor Receptors 1 and 2 in Dendritic Cell Differentiation. J. Immunol.; 2005; 174, pp. 215-222. [DOI: https://dx.doi.org/10.4049/jimmunol.174.1.215] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15611243]

78. Overwijk, W.W. Breaking Tolerance in Cancer Immunotherapy: Time to ACT. Curr. Opin. Immunol.; 2005; 17, pp. 187-194. [DOI: https://dx.doi.org/10.1016/j.coi.2005.01.011] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15766680]

79. Sato, E.; Olson, S.H.; Ahn, J.; Bundy, B.; Nishikawa, H.; Qian, F.; Jungbluth, A.A.; Frosina, D.; Gnjatic, S.; Ambrosone, C. et al. Intraepithelial CD8+ Tumor-Infiltrating Lymphocytes and a High CD8+/Regulatory T Cell Ratio Are Associated with Favorable Prognosis in Ovarian Cancer. Proc. Natl. Acad. Sci. USA; 2005; 102, pp. 18538-18543. [DOI: https://dx.doi.org/10.1073/pnas.0509182102] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16344461]

80. Jain, R.K. Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy. Science; 2005; 307, pp. 58-62. [DOI: https://dx.doi.org/10.1126/science.1104819] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15637262]

81. Alfaro, C.; Suarez, N.; Gonzalez, A.; Solano, S.; Erro, L.; Dubrot, J.; Palazon, A.; Hervas-Stubbs, S.; Gurpide, A.; Lopez-Picazo, J.M. et al. Influence of Bevacizumab, Sunitinib and Sorafenib as Single Agents or in Combination on the Inhibitory Effects of VEGF on Human Dendritic Cell Differentiation from Monocytes. Br. J. Cancer; 2009; 100, pp. 1111-1119. [DOI: https://dx.doi.org/10.1038/sj.bjc.6604965] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19277038]

82. Balan, M.; Mier y Teran, E.; Waaga-Gasser, A.M.; Gasser, M.; Choueiri, T.K.; Freeman, G.; Pal, S. Novel Roles of c-Met in the Survival of Renal Cancer Cells through the Regulation of HO-1 and PD-L1 Expression. J. Biol. Chem.; 2015; 290, pp. 8110-8120. [DOI: https://dx.doi.org/10.1074/jbc.M114.612689] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25645920]

83. Powles, T.; Oudard, S.; Grünwald, V.; Calvo, E.; Michaelson, M.D.; Burotto, M.; Melichar, B.; Tyagi, R.; Hilmi, F.; Gaur, A. 718P A Phase II Study of Patients with Advanced or Metastatic Renal Cell Carcinoma (mRCC) Receiving Pazopanib after Previous Checkpoint Inhibitor Treatment. Ann. Oncol.; 2020; 31, S564. [DOI: https://dx.doi.org/10.1016/j.annonc.2020.08.790]

84. Grande, E.; Gordoa, T.A.; Torras, O.R.; Esteban, E.; Castellano, D.; Muro, X.G.d.; Vidal, M.J.M.; García-Donas, J.; Arranz, J.A.; Rodriguez, C.S. INMUNOSUN-SOGUG Trial: A Prospective Phase II Study to Assess the Efficacy and Safety of Sunitinib as Second-Line (2L) Treatment in Patients (pts) with Metastatic Renal Cell Cancer (RCC) Who Received Immunotherapy-Based Combination Upfront. J. Clin. Oncol.; 2020; 38, 5060. [DOI: https://dx.doi.org/10.1200/JCO.2020.38.15_suppl.5060]

85. Choueiri, T.K.; McDermott, D.F.; Merchan, J.; Bauer, T.M.; Figlin, R.; Heath, E.I.; Michaelson, M.D.; Arrowsmith, E.; D’Souza, A.; Zhao, S. et al. Belzutifan plus Cabozantinib for Patients with Advanced Clear Cell Renal Cell Carcinoma Previously Treated with Immunotherapy: An Open-Label, Single-Arm, Phase 2 Study. Lancet Oncol.; 2023; 24, pp. 553-562. [DOI: https://dx.doi.org/10.1016/S1470-2045(23)00097-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37011650]