The efficacy of second-line nivolumab versus tyrosine kinase inhibitors for renal cell carcinoma with bone metastases: A multi-institutional retrospective study

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The efficacy of second-line nivolumab versus tyrosine kinase inhibitors for renal cell carcinoma with bone metastases: A multi-institutional retrospective study

https://doi.org/10.21203/rs.3.rs-4962940/v1

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Immune checkpoint inhibitor combination therapy has been standardized for first-line treatment for metastatic renal cell carcinoma (mRCC), leading to the changes in second-line treatment options such as nivolumab or tyrosine kinase inhibitors (TKIs). However, there have been few reports comparing the efficacy of these drugs in mRCC patients, especially with bone metastases (BM), which are associated with a poor prognosis. Therefore, we aimed to compare the efficacy of nivolumab and TKIs as second-line treatments for 87 mRCC patients with BM and the microenvironments of the primary tumor and BM lesions. Multivariate analysis revealed poor risk according to the IMDC classification (p < 0.01) and high serum ALP value (p = 0.031) as worse prognostic factors, while there was no significant difference of overall survival between patients with nivolumab and TKIs. However, the objective response rate at BM lesions was significantly higher with TKIs than with nivolumab (p = 0.014). Immunohistochemistry analysis also revealed that VEGFR2 expression was significantly higher at BM lesions compared to that in primary tumors, showing the potential benefit of TKIs over nivolumab in mRCC patients with BM. In conclusion, TKIs could be the promising second-line treatment for mRCC with metastasis limited to the bone.

Biological sciences/Cancer/Cancer microenvironment

Biological sciences/Cancer/Cancer therapy

Biological sciences/Cancer/Metastases

Biological sciences/Cancer/Urological cancer

Renal cell carcinoma

bone metastasis

second-line treatment

nivolumab

tyrosine kinase inhibitor

overall survival

Renal cell carcinoma (RCC) ranks as the fourteenth most frequently diagnosed cancer globally [1]. In 2020, an estimated 431,288 new cases of RCC and associated 179,368 deaths were reported. With the advances in imaging and inspection technology, the incidence of RCC has been increasing at an annual rate of 1–2% [2]. Immune checkpoint inhibitor (ICI) combination therapy, such as ICI plus ICI or ICI plus tyrosine kinase inhibitor (TKI), has become commonly used as the first-line systemic treatment for metastatic RCC (mRCC). After the refractoriness to ICI combination therapy, a majority of patients developed progressive disease requiring subsequent TKIs or nivolumab [3]. So far, although comparable efficacies of axitinib and nivolumab as secondary treatments for mRCC have been reported [4], There are limited real-world clinical reports on second-line treatments for RCC.

Among various types of metastases, RCC is especially susceptible to bone metastasis (BM), which occurs in approximately 30% of patients with mRCC [5]. BM may lead to severe complications, including skeletal-related events, and is a poor prognostic factor for patients with mRCC [6]. Negishi et al. reported that the effectiveness of ICI against BM site in mRCC is limited with only 5% [7]. On the other hand, the METEOR trial reported that cabozantinib, a well-known TKI, led to a better prognosis of mRCC with BM than everolimus after at least one previous TKI [8]. However, the efficacy of cabozantinib in treating bone metastatic lesion remains unclear. Therefore, this study aimed to compare the treatment efficacies of second-line TKIs and nivolumab in patients with RCC and BM. Additionally, we evaluated the expression of receptors targeted by cabozantinib, the immune microenvironment, and hypoxic conditions using immunohistochemistry to compare primary tumors and BM lesions.

Patient characteristics

The clinicopathological characteristics and outcomes of the 87 patients with mRCC and BM included in the study are summarized in Table 1. The median age of the patients in the nivolumab and TKI groups was 66 years (range, 29–87 years) and 69 years (range, 33–84 years), respectively. The most prevalent histological type was clear cell carcinoma, observed in 25 (86%) and 47 (81%) patients treated with nivolumab and TKI, respectively. The nivolumab group predominantly comprised patients with poor International Metastatic Renal Cell Carcinoma Database (IMDC) risk (52.0%), whereas 76.0% of patients treated with a TKI were classified as having favorable and intermediate risk. The most commonly prescribed TKI was axitinib (n = 35, 60%), followed by cabozantinib (n = 14, 24%).

Table 1

Patient characteristics.
	Nivolumab (n = 29)	TKI (n = 58)	P-value
Age (years)	66 (29–87)	69 (33–84)	0.76
Sex, Male: Female	24 (83%): 5 (17%)	43 (74%): 15 (26%)	0.43
Histopathology Clear cell RCC Papillary RCC Others/unknown	25 (86%) 1 (3%) 3 (10%)	47 (81%) 3 (5%) 8 (14%)	0.76 1.0 0.75
IMDC risk Favorable / Intermediate Poor	14 (48%) 15 (52%)	44 (76%) 14 (24%)	0.015
Previous partial or total nephrectomy	24 (83%)	43 (74%)	0.43
Local therapy for BM radiation therapy surgery	17 (59%) 4 (14%)	34 (59%) 4 (7%)	1.0 0.43
Patients with metastasis other than bone	26 (90%)	47 (81%)	0.37
Location of metastatic sites Bone Lung Lymph node Liver Brain Others	29 (100%) 16 (55%) 11 (38%) 6 (21%) 3 (10%) 9 (31%)	58 (100%) 39 (67%) 12 (21%) 11 (19%) 7 (12%) 13 (22%)	1.0 0.35 0.12 1.0 1.0 0.44
Number of BM Single Multiple	4 (14%) 25 (86%)	12 (21%) 46 (79%)	0.56
Prior 1st line treatment TKI ICI + TKI ICI + ICI Interferon-α Others	25 (86%) 4 (14%) 0 0 0	26 (45%) 14 (24%) 4 (7%) 8 (14%) 7 (12%)	< 0.01 0.40 0.30 0.048 0.090
Type of second-line TKI treatment Axitinib Cabozantinib Sorafenib Sunitinib	-	35 (60%) 14 (24%) 5 (9%) 4 (7%)	-
Bone modifying agents	20 (69%)	45 (76%)	0.44
ALP (U/L)	287 (153–1632)	288 (135–3406)	0.31
LDH (U/L)	218 (125–703)	213 (97–2154)	0.60
NLR	3.2 (1.4–32.5)	3.5 (1.3–16.1)	0.85
Observation period from the Second-line therapy (months)	7.0 (1–73)	11.5 (1–93)	0.81
TKI, tyrosine kinase inhibitor; RCC, renal cell carcinoma; IMDC, International Metastatic Database Consortium; BM, bone metastasis; ICI, immune checkpoint inhibitor; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio.

Clinical outcomes of patients treated with second-line nivolumab or tyrosine kinase inhibitors

Overall, the median follow-up durations of patients treated with nivolumab and TKI groups were 7.0 (range, 1–73) and 11.5 (range, 1–93) months, respectively. There were no significant differences between the cancer-specific survival (CSS) and overall survival (OS) of the patients treated with nivolumab and a TKI (p = 0.76 and p = 0.55, respectively (Fig. 1, Supplementary Table S1, Table 2). Multivariate analyses revealed that poor risk based on the IMDC classification and high serum alkaline phosphatase (ALP) concentration (≥ 288 U/L) were significantly associated with reduced OS (hazard ratio [HR] = 3.24, 95% CI; 1.84–5.71, p < 0.01; HR = 1.78, 95% CI; 1.05–3.01, p < 0.01, Table 2). Accordingly, OS was significantly shorter for patients with poor risk based on the IMDC classification and high serum ALP concentration (≥ 288 U/L) (HR = 3.58, 95% CI; 2.08–6.17, p < 0.01; HR = 2.01, 95% CI; 1.21–3.35, p < 0.01, Fig. 2).

Table 2

Univariate and multivariate analyses of OS after the introduction of second-line therapy.
	Univariate analysis			Multivariate analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age (years) < 66 ≥ 66	Reference 1.27	0.77–2.10	0.35	-	-	-
Sex Female Male	Reference 0.66	0.37–1.18	0.16	Reference 0.62	0.35–1.12	0.11
IMDC risk Favorable / Intermediate Poor	Reference 3.58	2.08–6.17	< 0.01	Reference 3.24	1.84–5.71	< 0.01
Local therapy for BM	1.25	0.73–2.14	0.42	-	-	-
Metastasis other than bone No Yes	Reference 1.29	0.64–2.63	0.48	-	-	-
Number of BM Single Multiple	Reference 1.34	0.72–2.48	0.36	-	-	-
2nd line therapy ICI TKI	Reference 1.19	0.68–2.07	0.55	-	-	-
Bone modifying agents	1.18	0.65–2.15	0.58	-	-	-
ALP (U/L) Low (< 288) High (≥ 288)	Reference 2.01	1.21–3.35	< 0.01	Reference 1.78	1.05–3.01	0.031
LDH (U/L) Low (< 215) High (≥ 215)	Reference 1.59	0.96–2.61	0.070	Reference 1.29	0.77–2.16	0.33
NLR Low (< 3.5) High (≥ 3.5)	Reference 1.31	0.79–2.16	0.29	-	-	-
OS, overall survival; HR, hazard ratio; TKI, tyrosine kinase inhibitor; IMDC, International Metastatic Database Consortium, BM, bone metastasis, ICI, immune checkpoint inhibitor; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio.

To exclude the influence of radiation therapy on BM site, we examined 72 patients with untreated BM site (Supplementary Table S2). Comparison of the outcomes of second-line treatment for BM according to the MD Anderson (MDA) criteria showed that the overall response rate (ORR) was significantly higher for the TKI group (29.2%) than for the nivolumab group (4.2%) (p = 0.014) (Table 3). This indicated that TKIs may be more effective than nivolumab for treatment-naïve BM.

Table 3

Overall response rate of second-line treatment to locally untreated BM according to the MDA criteria and RECIST 1.1.
	TKI (n = 48)	Nivolumab (n = 24)	P-value
MDA criteria
CR	0	0
PR	14	1
SD	27	16
PD	7	7
ORR	14/48 (29.2%)	1/24 (4.2%)	0.014
RECIST 1.1
CR	0	0
PR	7	1
SD	34	16
PD	7	7
ORR	7/48 (14.6%)	1/24 (4.2%)	0.25
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response rate.

Significant difference between the tumor microenvironments of primary tumors and bone metastasis

Next, we investigated the presence of tumor-infiltrated immune cells and several molecules targeted by TKIs in tumor microenvironment in primary tumors and BM sites. Representative immunohistochemistry results are shown in Figs. 3 and 4. As a result, we found a significant increase of the VEGFR2-positive cells in the BM lesions (p = 0.048). In addition, we confirmed that the CD8⁺ T-cells and CD20⁺ B-cell counts were higher in primary tumors (p = 0.075 and p = 0.10, respectively; Fig. 5). Collectively, these results indicate that primary tumors and BM have different tumor microenvironments, affecting the efficacy of TKIs and nivolumab therapies.

The guidelines of the European Association of Urology recommend ICI combination therapy as the first-line treatment for mRCC [9]. There is no established drug selection for the second-line treatment of mRCC, but several studies suggest that second-line treatment consists of nivolumab monotherapy or TKI [9]. On the other hand, the effectiveness of TKI and ICI greatly depends on the tumor microenvironment, but it varies in RCC due to several patient factors including tumor heterogeneity [10]. For RCC, the characteristics of metastatic tumor cells and the surrounding microenvironment may not always match those of primary tumors [11]. Therefore, a comparative analysis of the molecular biomarker expression profiles of primary and metastatic specimens, such as bone, should be performed [12].

The bone matrix is inherently rich in growth factors, making it a favorable and fertile environment for metastatic tumors, irrespective of the primary tumor type. BM is considered a poor prognostic factor for patients with mRCC [13]. In the microenvironment of BM lesions, regulatory T-cells and myeloid-derived suppressor cells are abundant, which suppresses tumor immunity [14, 15], which may lead to poor prognosis for mRCC patients with BM. Moreover, in RCC, inactivation of the von Hippel-Lindau tumor suppressor gene is common and leads to an increase in hypoxia-inducible factor-alpha, resulting in the overexpression of vascular endothelial growth factor (VEGF) [16]. This growth factor promotes tumor angiogenesis and plays a crucial role in the invasion and metastasis of RCC. On the other hand, tyrosine kinase is an important enzyme in intracellular signal transduction, and binding of VEGF to the VEGF receptor (VEGFR) increases receptor tyrosine kinase activity and initiates intracellular signal transduction. Considering above, we aimed to compare the efficacies of nivolumab and TKIs as second-line treatments for patients with mRCC with BM, elucidating the differences between the tumor microenvironments of primary and BM lesions.

In this study, we present two novel findings. First, we found that TKIs were more effective as second-line treatments for BM lesions in RCC than nivolumab monotherapy, as evidenced by the higher ORR at the BM sites (Table 3). Previous studies have shown a significant difference in the treatment efficacy of ICI across metastatic lesions [17]. In a large-scale tumor-agnostic study, BM lesions were associated with resistance to ICI [18]. In patients with mRCC treated with second-line nivolumab, treatment efficacy varies significantly with the metastatic site [19], with bone exhibiting a particularly low ORR of 5%, compared to 36% for lung and 50% for liver metastases [7]. In patients with mRCC treated with nivolumab as second-line therapy or beyond, BM, rather than lung or lymph node metastases, was associated with poor progression-free survival (PFS) and OS [20]. In the present study, an elevated serum ALP concentration, which reflects the overall deterioration of systemic conditions such as BM volume, was an independent poor prognostic factor for second-line treatment of mRCC with BM (Table 2). Considering above, TKIs are considered a promising option for patients with mRCC with BM and without other visceral metastases.

Second, VEGFR2 expression was higher in BM lesions than in primary tumors, and BM lesions showed a trend of decreased CD8⁺ tumor-infiltrating T-lymphocytes and tumor-infiltrating CD20⁺ B-cells (Fig. 5), which may contribute to the lower ORR of nivolumab than of TKI for BM lesions. Tao et al. reported that tumor-infiltrating B-lymphocytes in mRCC have been shown to recruit and activate CD8⁺ tumor-infiltrating T-lymphocytes, thereby enhancing anti-tumor effects [21], and this process is involved in the formation of tertiary lymphoid structures [22]. TKIs are also considered more likely to be effective for cases of RCC with high expression of VEGFR2 [23]. In this study, we described a significant increase of VEGFR2- positive cells in BM sites, demonstrating the potential benefits of TKI in patients with mRCC with BM. Especially, considering that cabozantinib displayed the strongest inhibition toward VEGFR2 among several types of TKIs, cabozantinib may likely contributes to the enhanced antitumor activity in BM [24].

This study had several limitations. First, this was a retrospective study with a few cases. While it was a multicenter study including five hospitals, the number of patients with mRCC with BM receiving second-line treatment was limited, and even fewer underwent surgery for BM lesions. Therefore, future studies with larger sample sizes and more extensive designs are warranted. Second, we used the MDA criteria and Response Evaluation Criteria in Solid Tumors to evaluate the treatment efficacy for BM lesions, but there is currently no consensus on the best response evaluation system for them [25]. Notwithstanding, several studies have used the MDA criteria to evaluate BM lesions [26].

In this study, we revealed that TKIs may have higher efficacy than nivolumab against BM lesion and poor IMDC risk classification and elevated serum ALP concentrations are associated with worse prognosis in patients with mRCC and BM receiving second-line therapy. In patients with mRCC with metastases limited to the bone, TKIs may be more effective than nivolumab.

Patient selection

We retrospectively reviewed the clinical data of 721 patients with RCC and analyzed the clinicopathological data of 87 patients with mRCC with BM who initiated second-line treatment with nivolumab (n = 29) or TKI (n = 58) at Osaka University Hospital, Osaka Police Hospital, Osaka General Medical Center, Osaka Rosai Hospital, and Osaka National Hospital between January 2008 and December 2023. BM was diagnosed using computed tomography with MRI or bone scintigraphy, which was performed as needed [27]. The TKIs included sunitinib, axitinib, cabozantinib, sorafenib, and pazopanib. The dosage and administration intervals followed standard treatment protocols.

The following patient data were collected from the hospital records of the patients: age, sex, histopathology of RCC, IMDC classification for first-line therapy, previous nephrectomy, local therapy for BM site, location of metastatic sites, number of BMs, first-line therapy regimen, type of second-line regimen, bone modifying agent, serum concentration of ALP, serum concentration of lactate dehydrogenase, neutrophil-lymphocyte ratio, best ORR for the second line therapy, second-line therapy CSS, and OS.

The therapeutic efficacy of second-line treatment was assessed every 2–3 months using computed tomography according to the Response Evaluation Criteria in Solid Tumors version 1.1 and MDA criteria [28]. The best response of each patient during treatment was determined and classified as complete response, partial response, stable disease, or progressive disease.

This study was approved by the Institutional Review Board of the Osaka University Hospital (# 018 − 0003). All procedures were conducted in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants.

Immunohistochemical staining and quantification

The primary RCC tissue resected after total nephrectomy was stored as formalin-fixed paraffin-embedded tissue blocks. The resected RCC tissue from the BM site in the same patients was subjected to tris-ethylenediaminetetraacetic acid until tissue softening was observed. This was followed by paraffin fixation. Immunohistochemical staining was performed using 4 µm-thick paraffin-embedded tissue samples of primary RCC samples and BM tissues. The tissue samples were deparaffinized using xylene and a graded series of ethanol solutions and stained with eosin. Other sections were treated with EDTA buffer (pH 9.0) and activated by warming at 125°C for 30 seconds using a Pascal pressure chamber (S2800, Dako) for antigen activation treatment. Endogenous peroxidase activity was blocked by incubating the sections with 0.3% hydrogen peroxide for 5 min, followed by overnight incubation with primary antibodies against CD8 (1:100; ab17147, Abcam) as a marker for cytotoxic T-lymphocytes, CD20 (1:800; ab9475, Abcam) as a marker for B-cells, PD-L1 (clone 28 − 8, 1:200; ab205921, Abcam), HIF2α (1:200; ab243861, Abcam), c-MET (1:100; ab51067, Abcam), VEGFR2 (1:100; ab115805, Abcam), and AXL (1:2000; ab219651, Abcam) at 4°C. The EnVision + system horseradish peroxidase-labeled polyclonal anti-rabbit and anti-mouse antibody (DAKO) was used, and staining was performed using DAB substrate (MK210, TaKaRa) according to the manufacturer’s instructions. Finally, the sections were counterstained with hematoxylin, dehydrated using a graded series of ethanol concentrations, and cleared with xylene.

The CD8⁺ and CD20⁺ cell counts within the tumor were counted separately. Three distinct random regions featuring the highest abundance of positive cells were identified using an x40 objective lens, and the average count was used for statistical analysis [28]. The membranous PD-L1 expression in the tumor cells was assessed at three random locations using an x40 objective lens, and the average count was used for statistical analysis [29, 30]. HIF2α was assessed for positivity exclusively within the nuclei of tumor cells [31]. The ratios of c-MET, VEGFR2, and AXL expressions in the membrane and cytoplasm of tumor cells were determined [32, 33]. HIF2α, c-MET, VEGFR2, and AXL were evaluated and analyzed in three random fields of view using an x40 objective lens. The number of positive cells and their levels of expression were automatically determined using a microscope (BZ-X710; KEYENCE).

Statistical analysis

Clinical characteristics were compared using the Mann-Whitney U test. Fisher's exact test was used to analyze the therapeutic effects of the ICIs and TKIs. Univariate and multivariate logistic regression analyses were performed to assess the relative contributions to CSS and OS. CSS and OS were estimated using the Kaplan-Meier method and Cox proportional hazard regression. All p-values were two-sided, and differences were considered statistically significant at p < 0.05. Data were analyzed using JMP Pro (v.17.0.0; SAS Institute, Cary, NC, USA).

Competing interests

The authors declare no competing interests.

Author Contribution

G.Y. contributed to data collection and analysis, table and figure preparation, reference collection, and manuscript writing. G.Y. and T.K. contributed to the data collection and analysis and supervised all activities. A.Y., M.T., Y.H., L.Y., S.N., Y.O., T.O., T.U., A.Y., Y.I., T.H., Y.Y., K.H., A.K., T.T., K.N., S.T., M.T., and N.N. supervised all the activities. The first draft of the manuscript was prepared by G. Y. and T. K. All authors have read and approved the published version of the manuscript.

Acknowledgment

This study was supported by JSPS KAKENHI (grant number: 21K09396).

Data Availability

The data presented in this study are available on request from the corresponding author.

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No competing interests reported.

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The efficacy of second-line nivolumab versus tyrosine kinase inhibitors for renal cell carcinoma with bone metastases: A multi-institutional retrospective study

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Abstract

Figures

Introduction

Results

Patient characteristics

Clinical outcomes of patients treated with second-line nivolumab or tyrosine kinase inhibitors

Significant difference between the tumor microenvironments of primary tumors and bone metastasis

Discussion

Methods

Patient selection

Immunohistochemical staining and quantification

Statistical analysis

Declarations

Competing interests

Author Contribution

Acknowledgment

Data Availability

References

Additional Declarations

Supplementary Files

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