Influence of immunotherapy combinations on outcomes in sarcomatoid metastatic renal cell carcinoma: results from the UK Renal Oncology Collaborative

INTRODUCTION

Renal cancers are the fourteenth most common cancer type in the world according to incidence, accounting for 2.2% of all cancers recorded worldwide according to GLOBOCAN 2022.¹ However, in the United Kingdom, renal cancers account for 4% of all cancers with 13,834 cases between 2016 to 2018.^[2] According to Cancer Research UK, the incidence of renal cancers in the United Kingdom has gone up by 88% since the 1990s, making the real-world practice regarding the management of renal cancers worth revisiting.²

Renal cancers can be histologically subdivided into various types. A large multicentre international study including more than 10,000 patients with mRCC showed that 92% of the patients had clear cell histology, followed by 7% of patients having papillary subtype and 2% having chromophobe subtype.³ Sarcomatoid change is an uncommon differentiation that can be associated with most histological subtypes and is noted in about 4-5% of renal cancers.^4,5 However, this can go up to 20% in metastatic disease.⁶ Patients with renal cancers having sarcomatoid differentiation on histology are recognised to have worse survival outcomes and the median overall survival according to various studies is generally under one year.^7-9 In fact, a higher proportion of sarcomatoid differentiation is associated with progressively worse outcomes.^5,10

Management of advanced renal cancers can be categorised according to favourable, intermediate, or poor-risk disease depending on the presence of well-characterised clinical and laboratory risk factors.¹¹ These categories of risk stratification use a validated model to assess prognosis that was developed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).^12,13 Renal cancer management relies heavily on this risk stratification model with survival outcomes being worse in poor risk group compared to favourable risk.^12,13

The recommended first-line treatment for metastatic clear cell renal cancers according to the ESMO guidelines published in 2024 includes the following: pembrolizumab/axitinib, nivolumab/cabozantinib and pembrolizumab/lenvatinib, irrespective of risk stratification.¹⁴ Ipilimumab–nivolumab is recommended as first-line treatment for IMDC intermediate- and poor-risk disease.¹⁵ These recommendations are based on the outcomes of various pivotal trials, some of which have also looked into the outcomes in patients with sarcomatoid features on biopsy.^16-21 Subgroup analysis of Checkmate 214 has made ipilimumab and nivolumab (IOIO) a standard of care in renal cancers with sarcomatoid differentiation, however, IOTKI (immunotherapy and tyrosine kinase inhibitor) combinations may reduce the primary progression rate that can occur with IOIO combination.¹⁶

Management of advanced renal cancers has taken significant strides in the last decade. However, outcome data of renal cancers with sarcomatoid differentiation treated with these new protocols remains relatively sparse. Here, we report the results from our collaborative study which explored survival outcomes in sarcomatoid metastatic renal cancer patients with different first-line treatments in the real world.

METHODS

A multicentre retrospective review was conducted including patients commencing systemic anti-cancer therapy for mRCC between 01/01/2018 and 30/06/2021 at 17 UK NHS trusts. Inclusion criteria for this study were: patients aged 18 years or older, treatment-advanced renal cell carcinoma patients with histological confirmation of sarcomatoid differentiation and having received at least one line of treatment. The analysis of patients having sarcomatoid differentiation on histology was pre-planned. Participants were characterised according to IMDC risk stratification (favourable [score of 0], intermediate [score of 1 or 2], or poor [score of 3 to 6]). IMDC risk stratification was done based on the following clinical and laboratory parameters: a Karnofsky performance-status score of 70, a time from initial diagnosis to randomization of less than one year, a haemoglobin level below the lower limit of normal range, a corrected serum calcium concentration of more than 10 mg/dL (2.5 mmol/L), an absolute neutrophil count above the upper limit of the normal range, and a platelet count above the upper limit of the normal range.¹²

Outcomes and Assessments

Patient demographics, tumour histology, IMDC group, treatment choices in the first line and outcomes in the form of overall survival (OS) and progression-free survival (PFS) were analysed. Treatment options used in successive lines were also recorded. Overall survival was defined as the time from diagnosis of renal cancer to death from any cause. Progression-free survival (PFS) was defined as the time from initiation of treatment to the occurrence of disease progression or death. Reasons for discontinuation of treatment in the first line were also recorded.

Statistical Analysis

Outcomes were analysed for sarcomatoid changes based on first-line treatment type. Means were used to summarise quantitative data, whereas proportion/percentage was used to summarise qualitative data. Survival data was compared using Kaplan-Meier curves with 95% CIs between treatment arms for OS and PFS (sarcomatoid versus non-sarcomatoid histology). A stratified log-rank test at a two-sided 5% significance level was used to compare the distributions of OS and PFS between the different treatment groups (IMDC favourable, intermediate and poor risk).

RESULTS

Demographics

A total of 1319 patients were included in the overall analysis of which 106 (8.04%) patients had sarcomatoid changes in their histology. The median age for the cohort was 62 years (IQR: 38-71 years) and the M:F ratio was 2.2:1. A majority of 73 (68.87%) patients had prior nephrectomies. Other baseline characteristics have been summarised in Table 1.

Table 1: Demographic characteristics of the cohort

Characteristics	n (%)
Predominant histological subtype
Clear cell	85 (80.2%)
Sarcomatoid	10 (9.4%)
Papillary	5 (4.7%)
Undifferentiated	4 (3.8%)
Chromophobe	1 ((0.9%)
Not recorded	1 (0.9%)
IMDC risk group
Favourable	8 (7.5%)
Intermediate	62 (58.5%)
Poor	35 (33.0%)
Not recorded	1 (0.9%)
IMDC scoring
Time from initial diagnosis to systemic therapy <1 year	81 (76.4%)
Karnofsky Performance status <80%	13 (12.3%)
Haemoglobin less than lower limit of normal	48 (45.3%)
Corrected serum calcium more than upper limit of normal	19 (17.9%)
Neutrophilia	26 (24.5%)
Thrombocytosis	22 (20.8%)
Metastasis at presentation
Lung	72 (67.9%)
Nodal	55 (51.9%)
Bone	26 24.5%)
Others	21 (19.8%)
Adrenal	16 (15.1%)
Liver	14 (13.2%)
Brain	6 (5.7%)
Pancreas	6 (5.7%)
Presentation of Brain metastasis
<3 months from metastatic diagnosis	9 (8.5%)
>3 months from metastatic diagnosis	2 (1.9%)

IMDC, International Metastatic Renal Cell Carcinoma Database Consortium

Treatment

The median number of lines of treatment received was two. Overall, 49 (46.2%) patients received IOIO combination in the first-line setting followed by TKI monotherapy in 44 (41.5%) patients and IOTKI in 12 (11.3%) patients. Treatment received, classified according to IMDC risk group, is depicted in Table 2. The most commonly used TKI for monotherapy in the first line was Sunitinib (16, 15.1%) and in subsequent lines was Cabozantinib (35, 33.0%). Avelumab-axitinib was the most commonly used IOTKI in any line in 7 (6.6%) patients. Lenvatinib-everolimus was the most commonly used combination not falling into any of the above categories in 4 (3.8%) patients.

Table 2: Treatment choices for different lines stratified according to IMDC risk classification.

IMDC Risk Group	n (%)	First Line	Second Line	Third Line	Fourth Line
Favourable	IOIO	0	0	0	0
	TKI	2 (25.0%)	4 (66.7%)	2 (100%)	0
	IOTKI	6 (75.0%)	0	0	0
	IO	0	2 (33.3%)	0	0
	Other	0	0	0	0
	Total	8 (100%)	6 (75%)	2 (25%)	0
Intermediate	IOIO	33 (53.2%)	1 (3.33%)	0	0
	TKI	23 (37.1%)	20 (66.7%)	6 (54.5%)	1 (100%)
	IOTKI	6 (9.7%)	0	0	0
	IO	0	8 (26.7%)	2 (18.2%)	0
	Other	0	1 (3.33%)	3 (27.3%)	0
	Total	62 (100%)	30 (48.4%)	11 (17.7%)	1 (1.6%)
Poor	IOIO	16 (45.7%)	0	0	0
	TKI	15 (42.9%)	15 (88.2%)	6 (75.0%)	0
	IOTKI	4 (11.4%)	0	0	0
	IO	0	1 (5.9%)	2 (25.0%)	1 (50.0%)
	Other	0	1 (5.9%)	0	1 (50.0%)
	Total	35 (100%)	17 (48.6%)	8 (22.9%)	2 (5.7%)

IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IOIO, Immunotherapy combination; IOTKI, Immunotherapy and Tyrosine Kinase Inhibitor combination; TKI, Tyrosine Kinase Inhibitor monotherapy

Outcomes

Patients having sarcomatoid differentiation had a reduced median OS of 21.7 months (95% CI: 11.9-24.5 months) compared with patients lacking a sarcomatoid differentiation having a median OS of 26.6 months (95% CI: 24.1-28.7 months). This difference of about 4.9 months was statistically significant with a P value of 0.019 calculated by Chi-square test. (Figure 1) Patients having sarcomatoid differentiation also had a statistically significantly worse median PFS of 4.9 months (95% CI: 3.5-6.2 months) compared to 8.7 months (95% CI: 8.1-9.6 months) in patients lacking a sarcomatoid differentiation [p=0.002]. (Figure 1)

Figure 1: Figure showing that both the overall survival (left) and progression-free survival (right) were worse for patients with RCC with sarcomatoid differentiation versus those who lacked sarcomatoid differentiation (P value 0.019 and 0.002, respectively)



IOIO, IOTKI and TKI had a median OS of 25.0 months (95% CI: 12.7-30.9 months), NR (not reached) and 16.8 months (95% CI: 6.6-38.5 months) respectively [p= 0.666]. IOIO, IOTKI and TKI had a median PFS of 5.8 months (95% CI: 3.4-12.5 months), 6.0 months (95% CI: 3.0-17.5 months), 4.0 months (95% CI: 3.1-4.9 months) respectively [p= 0.367]. The OS and PFS stratified based on treatment received is depicted in Figure 2.

Figure 2: Figure showing overall survival (left) and progression-free survival (right) for patients with RCC with sarcomatoid differentiation based on first-line treatment received (P value 0.666 and and 0.367, respectively)



IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IOIO, Immunotherapy combination; IOTKI, Immunotherapy and Tyrosine Kinase Inhibitor combination; TKI, Tyrosine Kinase Inhibitor monotherapy

Toxicities

Permanent discontinuation in first-line treatment due to toxicity was documented in 21 (20%) patients. Discontinuation IOIO, IOTKI and TKI in the first line were noted in 10 (9.5%), 10 (9.5%) and 1 (0.9%) patients, respectively.

DISCUSSION

Historically, conventional treatment options have lacked efficacy in the management of mRCC with sarcomatoid features. The survival in most cases has been quite dismal and ranges between 6-13 months.^5,9,22,23 Recently, several trials have established the benefit of immune checkpoint inhibitors (ICI) in combination either with other ICI or tyrosine kinase inhibitors (TKI) as first-line options in the management of mRCC. Introduction of immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical benefit for patients with renal cancers with sarcomatoid features as well with median overall survival now reaching over 20 months.²⁴

Biologically, the benefit in overall survival with ICI in patients with mRCC with sarcomatoid differentiation could be attributed to increased programmed death ligand-1 (PD-L1) expression in this subgroup of tumours.²⁵ Genetic studies have also documented that renal cancers with sarcomatoid differentiation have heavily inflamed tumour microenvironments facilitating the action of ICI.²⁶ The biological spectrum of this subtype of renal cancers favouring the use of ICI in the first-line setting has been shown to translate into clinical benefit in various phase III and prospective phase II trials.^16-21 A comprehensive review of these practice-changing trials with respect to mRCC with sarcomatoid differentiation has been performed by Mario et. al.²⁴

In the majority of the trials, sarcomatoid features have been documented in 5 to 15% of the study population, which is congruent to our subgroup of about 8% of patients.^16-21 However, the actual number of mRCC patients with sarcomatoid features in the trial arm in each of these studies has been well under 100. To the best of our knowledge, this study documents the outcomes of the largest group of patients with mRCC having sarcomatoid differentiation, treated with the current standard of care for mRCC, and their outcomes in the real-world setting. In the current study, ICI (in combination with another ICI or a TKI) was the preferred option in the first line in a majority of 61 (57.5%) patients. Throughout the course of their treatment 78 (73.6%) patients had received ICI, with 12 (11.3%) receiving ICI in the second line and 5 (4.7%) in further lines of treatment.

On progression with ICI, VEGFR-targeted therapies are an option as documented in various studies. ^27-29 In the current study, out of a total of 53 patients who had received second-line treatment, 39 (73.6%) patients received TKI monotherapy in the second line. Cabozantinib was the most commonly used TKI in 24 (45.3%) patients in the second line, followed by Sunitinib in 7 (13.2%) patients. This is very similar to the findings of Hahn et. al. wherein Cabozantinib was the most preferred option as well. The median time on TKI in our study was 11 months which was more than the 6.1 months noted by Hahn et.al. in mRCC patients with sarcomatoid differentiation.²⁷

The limitations of the current study include the fact that it is a retrospective study and prone to recall bias. The identification of specific toxicities and specifically the grading of toxicities was difficult to document. Also, some of the data collection was during the COVIS period which may have impacted decision making.

CONCLUSION

The current multi-institutional study represents the practice of the majority of the United Kingdom with respect to treatment choices in mRCC with sarcomatoid features. This dataset agrees with existing literature that sarcomatoid changes in patients with mRCC confer a worse prognosis compared with mRCC patients without sarcomatoid changes. Immunotherapy-containing regimens improve survival outcomes compared to TKI monotherapy alone in this group of patients. Allowing for the small number of patients receiving IOTKI, observed OS was longer for IOIO compared with TKI monotherapy. Based on this real-world data set, IOIO should remain the standard of care for mRCC patients with sarcomatoid change.

FUNDING

No funding was received for this work.

REFERENCES

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et. al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi: 10.3322/caac.21834
2. Cancer Research UK. Kidney cancer statistics [Internet], Accessed June
   2024; Available from:
   https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer
3. Dudani S, de Velasco G, Wells JC, Gan CL, Donskov F, Porta C, et. al. Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival. JAMA Netw Open. 2021;4(1):e2021869. doi: 10.1001/jamanetworkopen.2020.21869
4. Blum KA, Gupta S, Tickoo SK, Chan TA, Russo P, Motzer RJ, et. al. Sarcomatoid renal cell carcinoma: biology, natural history and management. Nat Rev Urol. 2020;17(12):659-678. doi: 10.1038/s41585-020-00382-9
5. Kim T, Zargar-Shoshtari K, Dhillon J, Lin HY, Yue B, Fishman M, et. al. Using percentage of sarcomatoid differentiation as a prognostic factor in renal cell carcinoma. Clin Genitourin Cancer. 2015;13(3):225-30. doi: 10.1016/j.clgc.2014.12.001
6. Shuch B, Said J, La Rochelle JC, Zhou Y, Li G, Klatte T, et. al. Cytoreductive nephrectomy for kidney cancer with sarcomatoid histology--is up-front resection indicated and, if not, is it avoidable? J Urol. 2009;182(5):2164-71. doi: 10.1016/j.juro.2009.07.049
7. de Peralta-Venturina M, Moch H, Amin M, Tamboli P, Hailemariam S, Mihatsch M, et. al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol. 2001;25(3):275-84. doi: 10.1097/00000478-200103000-00001
8. Mian BM, Bhadkamkar N, Slaton JW, Pisters PW, Daliani D, Swanson DA, et. al. Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma. J Urol. 2002;167(1):65-70.
9. Zhang BY, Thompson RH, Lohse CM, Leibovich BC, Boorjian SA, Cheville JC, et. al. A novel prognostic model for patients with sarcomatoid renal cell carcinoma. BJU Int. 2015;115(3):405-11. doi: 10.1111/bju.12781
10. Adibi M, Thomas AZ, Borregales LD, Merrill MM, Slack RS, Chen HC, et. al. Percentage of sarcomatoid component as a prognostic indicator for survival in renal cell carcinoma with sarcomatoid dedifferentiation. Urol Oncol. 2015;33(10):427.e17-23. doi: 10.1016/j.urolonc.2015.04.011
11. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 2017;376:354-366. doi: 10.1056/NEJMra1601333
12. Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, 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(34):5794-9. doi: 10.1200/JCO.2008.21.4809
13. Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, et. al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-8. doi: 10.1016/S1470-2045(12)70559-4
14. Powles T, Albiges L, Bex A, Comperat E, Grünwald V, Kanesvaran R, et. al. on behalf of the ESMO Guidelines Committee, Renal cell carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2024;35(8):692-706. doi: https://doi.org/10.1016/j.annonc.2024.05.537
15. Tannir NM, Signoretti S, Choueiri TK, McDermott DF, Motzer RJ, Flaifel A, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res 2021;27(1):78–86. Doi: 10.1158/1078-0432.CCR-20-2063
16. Tannir NM, Signoretti S, Choueiri TK, McDermott DF, Motzer RJ, George S, et al. Efficacy and safety of nivolumab plus ipilimumab (N+I) versus sunitinib (S) for first-line treatment of patients with advanced sarcomatoid renal cell carcinoma (sRCC) in the phase 3 CheckMate 214 trial with extended 5-year minimum follow-up. J Clin Oncol. 2022;40(6):suppl 352. doi: https://doi.org/10.1200/JCO.2022.40.6_suppl.352
17. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380(12):1116–27. doi: 10.1056/NEJMoa1816714
18. Choueiri TK, Larkin JMG, Pal SK, Motzer RJ, Venugopal B, Alekseev BY, et al. Efficacy and biomarker analysis of patients (pts) with advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC): Subgroup analysis from the phase III JAVELIN renal 101 trial of first-line avelumab plus axitinib (A + Ax) vs sunitinib (S). Ann Oncol 2019;30:v361. doi: 10.1016/j.annonc.2020.04.010
19. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. The Lancet 2019;393:2404–15. doi: 10.1016/S0140-6736(19)30723-8
20. Motzer RJ, Choueiri TK, Powles T, Burotto M, Bourlon MT, Hsieh JJ, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin. Oncol. 2021;39(6):suppl 308. doi: 10.1200/JCO.2021.39.6_suppl.308
21. Choueiri TK, Eto M, Kopyltsov E, Rha SY, Porta CG, Motzer R, et al. 660P Phase III CLEAR trial in advanced renal cell carcinoma (aRCC): Outcomes in subgroups and toxicity update. Ann Oncol 2021;32(Suppl 5):S683–685.
22. Cheville J.C., Lohse C.M., Zincke H., Weaver A.L., Leibovich B.C., Frank I., et. al.: Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J Surg Pathol 2004;28:435-441. doi: 10.1097/00000478-200404000-00002
23. Leibovich B.C., Blute M.L., Cheville J.C., Lohse C.M., Frank I., Kwon E.D., et. al.: Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: A stratification tool for prospective clinical trials. Cancer 2003;97:1663-1671. doi: 10.1002/cncr.11234
24. Fontes-Sousa M, Calvo E. First-line immune checkpoint inhibitors in advanced or metastatic renal cell carcinoma with sarcomatoid features. Cancer Treat Rev. 2022;105:102374. doi: 10.1016/j.ctrv.2022.102374
25. Motzer R.J., Banchereau R., Hamidi H., Powles T., McDermott D., Atkins M.B., et. al.: Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell 2020;38:803-817.e4. doi: 10.1016/j.ccell.2020.10.011
26. Bakouny Z, Braun DA, Shukla SA, Pan W, Gao X, Hou Y, et. al. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nat Commun. 2021;12(1):808. doi: 10.1038/s41467-021-21068-9
27. Pal SK, Albiges L, Tomczak P, Suárez C, Voss MH, de Velasco G, Chahoud J, Mochalova A, Procopio G, Mahammedi H, Zengerling F, Kim C, Osawa T, Angel M, Gupta S, Khan O, Bergthold G, Liu B, Kalaitzidou M, Huseni M, Scheffold C, Powles T, Choueiri TK. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi: 10.1016/S0140-6736(23)00922-4
28. Hahn AW, Surasi DS, Viscuse PV, Bathala TK, Wiele AJ, Campbell MT, et. al. Treatment Outcomes in Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid and/or Rhabdoid Dedifferentiation After Progression on Immune Checkpoint Therapy. Oncologist. 2024;29(5):392-399. doi: 10.1093/oncolo/oyad302
29. Albiges L, Powles T,  Sharma A, Venugopal B, et al. CaboPoint: Interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC). J of Clin Oncol. 2023;41(6):suppl 606. doi: https://doi.org/10.1200/JCO.2023.41.6_suppl.606

 

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Posted on 17 October 202417 October 2024