Di Pierro, Giulia

Mini, Enrico

Roviello, Giandomenico

English

Florence Research

Page 1 of 4© Annals of Translational Medicine. All rights reserved.   Ann Transl Med 2019;7(Suppl 6):S229 | http://dx.doi.org/10.21037/atm.2019.07.70Editorial CommentaryCabozantinib in advanced non-clear-cell renal cell carcinoma: is it the way clearer now?Giulia Di Pierro1, Enrico Mini2, Giandomenico Roviello21School of Human Health Sciences, University of Florence, Florence, Italy; 2Department of Health Sciences, University of Florence, Florence, ItalyCorrespondence to: Giandomenico Roviello, MD. Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy. Email: giandomenicoroviello@hotmail.it.Provenance: This is an invited article commissioned by the Section Editor Dr. Xiao Li (Department of Urology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China).Comment on: Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol 2019;20:581-90.Submitted Jul 09, 2019. Accepted for publication Jul 19, 2019.doi: 10.21037/atm.2019.07.70View this article at: http://dx.doi.org/10.21037/atm.2019.07.70Martínez Chanzá et al. (1) investigated the activity of cabozantinib (an inhibitor of multiple tyrosine kinase receptors) in a multicentre, retrospective, cohort study carried out by 22 centres that involved 122 patients with metastatic renal cell carcinoma (RCC) with confirmed non clear cell histology treated in any line of therapy between 2015 and 2018. In particular, the histologies were divided as follows: 59% papillary histology, 15% Xp 11.2 translocation, 13% unclassified histology, 9% chromophobe histology and 4% collecting duct histology. About 27% among these patients had an objective response to treatment [defined as the best radiological complete or partial response (PR) according to RECIST criteria]. At a median follow up of 11 months the median progression-free survival (PFS) was 7.0 months with a median overall survival (OS) of 12.0 months. The median time to treatment failure was 6.7 months (discontinuation of cabozantinib occurred mainly because of progressive disease in 85% of patients and, secondly, because of toxicity in 7% of patients). Cabozantinib was administered at the approved dose of 60 mg one time a day to 83% of patients and the main side effects of any grade related to the treatment were similar to those seen with other TKIs (tyrosine kinase inhibitors) such as fatigue (52%), diarrhea (34%), rash and palmar-plantar erythrodysesthesia (31%), nausea (29%), hypertension (28%). In general, side effects were mostly mild to moderate and were generally manageable through the standard clinical practice. No deaths related to treatment were detected. Finally, next-generation sequencing (NGS) analysis were performed in 48% of patients which demonstrated that the most common somatic genetic alterations among all tumours were cyclin-dependent kinase Inhibitor 2A (CDKN2A) (22%) followed by mesenchymal epithelial transitions (MET) (20%). The authors concluded that cabozantinib showed encouraging activity and tolerable toxicity in all non-clear cell RCC, both in treatment-naïve patients and in heavily pretreated patients (24% of patients had had three or more previous systemic therapies) and the efficacy was maintained also in patients with poor-risk or intermediate-risk disease. These results connote that the antitumour efficacy of cabozantinib is not confined to clear cell histology only.Cabozantinib is a TKI that targets several receptors such as vascular endothelial growth factor receptors 1–3 (VEGFR 1–3), MET, AXL receptor tyrosine kinase (AXL) (2). Up to date, two large phase III trials (the METEOR trial (3) that compared cabozantinib with everolimus in patients progressed after previous VEGR-targeted therapy and the CABOSUN trial (4) that compared cabozantinib versus sunitinib as first-line therapy) evaluated the activity and safety of cabozantinib in renal cancer patients with clear cell histology or at least a clear cell component. Based on the result of these trials, it has been speculated that cabozantinib may be considered a valid option also for non-clear cell histologies, that account for 10–20% of all RCC.229Di Pierro et al. Cabozantinib in ncRCC© Annals of Translational Medicine. All rights reserved.   Ann Transl Med 2019;7(Suppl 6):S229 | http://dx.doi.org/10.21037/atm.2019.07.70Page 2 of 4However, the treatment of non-clear cell RCC is very challenging because non clear cell RCC involve many histologies which are profoundly different according to prognosis, morphological and clinical characteristics, and genetic features (5,6). Papillary RCCs is divided into type 1, often sporadic and associated with epidermal growth factor receptor or alternatively MET mutations, and type 2, mostly associated with SETD2 mutations, CDKN2A mutations, TFE3 fusions or fumaratehydratase (FH) mutations, and characterised by aggressive phenotype and often positive family history (7,8). In chromophobe RCCs the most commonly oncogenic pathway implicated is mammalian target of rapamycin (mTOR) associated with tumour suppressor protein 53 (TP53) alterations (8-10). It has been reported that papillary and chromophobe histology account for 80% of non-clear cell RCC (5,6). Collecting duct carcinoma (CDC) is a rare and extremely aggressive RCC that develop, as its name suggests, from the renal collecting ducts and is distinguished by an immune profile with a high percentage of tumour infiltrating lymphocytes (11). The optimal treatment strategy for metastatic non clear cell RCC is still generally inferred from the evidence available for metastatic clear cell RCC. Unfortunately, due to the rarity of non-clear cell RCC tumours, only few prospective randomised trials have been carried out to date. In 2016, the results of two prospective phase II randomised trials (ASPEN and ESPN) have compared the activity of the VEGF-TKIs (sunitinib) to the mTORi (everolimus); both studies have shown improved PFS in the first line in patients treated with sunitinib. On the other hand, this benefit was not confirmed as regards the OS (12,13). Concerning the comparison between the survival outcomes for the metastatic non clear cell RCC group compared to the metastatic clear cell RCC group, a large retrospective analysis of the International Metastatic RCC Database Consortium (IMDC) (14) showed that the entire non clear cell RCC group had a worse OS than the clear cell RCC group; the median OS was 12.8 months versus 22.3 months in clear cell RCC (P<0.0001). By contrast, the chromophobe non clear cell RCC subtype had a survival outcome which was comparable to clear cell RCC, except for the chromophobe tumours with sarcomatoid features which are associated with poor prognosis (15). In addition, a recent retrospective study, although involving only Asian patients (16), confirmed that the survival outcomes for the metastatic non clear cell RCC cohort were significantly inferior to the outcomes for the metastatic clear cell RCC cohort regarding to first-line PFS, total PFS, and cancer specific survival (CSS), except for the chromophobe and Xp 11.2 translocation groups that showed better survival outcomes compared to clear cell RCC. Contrariwise, first line PFS, total PFS and CSS for the other histologies evaluated in this study (like the collecting duct, papillary, and unclassified groups) were meaningfully poorer compared to those of the group clear cell RCC. Another retrospective study carried out by Koshkin et al., whose results were presented at the American Society for Clinical Oncology (ASCO) genitourinary (GU) conference in San Francisco in 2017, demonstrated the activity and safety of nivolumab in non-clear cell RCC subtypes (17). Twenty-three patients with metastatic non clear cell RCC were treated with nivolumab between 12/2015 and 01/2017. The most represented histologies were unclassified (48%) and papillary (44%) and most patients had been pretreated with systemic therapy (mainly sunitinib, pazopanib or axitinib). After a median follow up of 6.5 months, median PFS was 4.2 months and median OS was not reached. Twenty-nine percent patients had PR as the best radiological response and 19% had stable disease (SD). Median time to best response was 5.1 months (17). With regard to cabozantinib, a retrospective study demonstrated a promising efficacy in patients with metastatic non clear cell RCC with a 14.3% of patients who had confirmed PR, and 64.2% who had SD. The median PFS was 8.6 months and the median OS was 25.4 months at a median follow-up of 20.6 months (18). Despite its clear importance and value, the study by Martínez Chanzá et al. presents several limitations that we have to address. First of all, the retrospective analysis could cause possible selection bias. In addition, we have to mention the population heterogeneity regarding histology and clinical history, even if the cohort analyzed is correctly evocative of the actual population treated in clinical practice. It is quite important to mention the lack of central pathological and radiological review and the use of the time to treatment failure rather than the progression free survival as one of the main endpoint (by reason of the discontinuation of the treatment that was not necessarily due to tumour progression, but rather to the physician’s judgment based on patient tolerability and clinical benefit). To conclude, the ability to evaluate the efficacy of cabozantinib also in relation to the tumour genomic alterations, was possible only in a small number of patients (although this is the biggest series reported so far).In  conclus ion,  non-c lear  ce l l  RCC inc ludes  a Annals of Translational Medicine, Vol 7, Suppl 6 September 2019 Page 3 of 4© Annals of Translational Medicine. All rights reserved.   Ann Transl Med 2019;7(Suppl 6):S229 | http://dx.doi.org/10.21037/atm.2019.07.70heterogeneous group of tumours different from each other in terms of clinical features, genetic characteristics and prognostic variables, which are scarcely investigated due to their infrequency. It is crucial to define the efficacy of the available treatments and the best treatment sequence for this group of patients, because few studies have been carried out on the matter and it is not certain whether the data obtained for patients with clear cell histology can also be completely applied to patients with non-clear cells histology. For these reasons, the importance of the study carried out by Martínez Chanzá et al., and of the other studies that have been done with similar intent, is noteworthy. Acknowledgments None. Footnote Conflicts of Interest: The authors have no conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.References1. Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol 2019;20:581-90.2. Yakes FM, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011;10:2298-308. 3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-27. 4. Choueiri TK, Halabi S, Sanford BL, 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;35:591-7. 5. Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol 2016;70:93-105. 6. Ricketts CJ, De Cubas AA, Fan H, et al. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep 2018;23:3698.7. Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, et al. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 2016;374:135-45. 8. Durinck S, Stawiski EW, Pavía-Jiménez A, et al. Spectrum of diverse genomic alterations define non-clear cell renal carcinoma subtypes. Nat Genet 2015;47:13-21. 9. Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014;26:319-30. 10. Malouf GG, Monzon FA, Couturier J, et al. Genomic heterogeneity of translocation renal cell carcinoma. Clin Cancer Res 2013;19:4673-84. 11. Becker F, Junker K, Parr M, et al. Collecting duct carcinomas represent a unique tumor entity based on genetic alterations. PLoS One 2013;8:e78137. 12. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016;17:378-88. 13. Tannir NM, Jonasch E, Albiges L, et al. Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non-Clear Cell Renal Cell Carcinoma (ESPN): A Randomized Multicenter Phase 2 Trial. Eur Urol 2016;69:866-74. 14. Kroeger N, Xie W, Lee JL, et al. Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: characterization of survival outcome and application of the International mRCC Database Consortium criteria. Cancer 2013;119:2999-3006. 15. Ged Y, Chen YB, Knezevic A, et al. Metastatic Chromophobe Renal Cell Carcinoma: Presence or Absence of Sarcomatoid Differentiation Determines Clinical Course and Treatment Outcomes. Clin Genitourin Cancer 2019;17:e678-88. 16. Kim JK, Kim SH, Song MK, et al. Survival and clinical prognostic factors in metastatic non-clear cell renal cell carcinoma treated with targeted therapy: A multi-institutional, retrospective study using the Korean metastatic renal cell carcinoma registry. Cancer Med 2019;8:3401-10.17. Koshkin VS, Barata PC, Vogelzang NJ, et al. Nivolumab Di Pierro et al. Cabozantinib in ncRCC© Annals of Translational Medicine. All rights reserved.   Ann Transl Med 2019;7(Suppl 6):S229 | http://dx.doi.org/10.21037/atm.2019.07.70Page 4 of 4treatment for patients with non-clear cell renal cell carcinoma: A multicenter retrospective analysis. J Clin Oncol 2017;35:abstr 4586.18. Campbell MT, Bilen MA, Shah AY, et al. Cabozantinib for the treatment of patients with metastatic non-clear cell renal cell carcinoma: A retrospective analysis. Eur J Cancer 2018;104:188-94.Cite this article as: Di Pierro G, Mini E, Roviello G. Cabozantinib in advanced non-clear-cell renal cell carcinoma: is it the way clearer now? Ann Transl Med 2019;7(Suppl 6):S229. doi: 10.21037/atm.2019.07.70

Cabozantinib in advanced non-clear-cell renal cell carcinoma: is it the way clearer now?

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Cabozantinib in advanced non-clear-cell renal cell carcinoma: is it the way clearer now?

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