**Rationale** Several novel renal tumor entities were classified as “emerging or provisional” in the “2016 WHO classification of tumours of the urinary system and male genital organs”, including renal cell carcinoma (RCC) associated with anaplastic lymphoma kinase (ALK) gene rearrangements (ALK-RCC) [1]. ALK is a receptor protein kinase encoded by the ALK gene located on the 2p23 chromosome and belongs to the superfamily of insulin receptors [2]. The role of ALK in tumorigenesis was initially shown in anaplastic large-cell lymphoma by Morris et al. in 1994 [3]. Nowadays, several ALK alterations have been detected in multiple solid tumors such as non-small cell lung cancer, inflammatory myofibroblastic tumor and neuroblastoma [4]. In parallel, the identification of ALK-positive tumors caused the development of a new class of anticancer agents, named ALK-inhibitors (ALK-i). Crizotinib was the first ALK-i drug approved, followed by the second generation of ALK-i (alectinib, brigatinib, and ceritinib) and, recently, the third generation of ALK-i (lorlatinib) [5]. ALK-RCC accounts for < 1% of all renal neoplasms and has been diagnosed in both adults and children [6]. Since its first description in 2010 [7], several publications assessing the clinical presentation and histological characteristics of patients affected by ALK-RCC have been published, mainly in case reports and case series [6]. In contrast, the activity of ALK-i in ALK-RCC patients has been reported only in a few publications. To our best knowledge, the impact of ALK-i in this population has never been reviewed. **Review question** This systematic review aims to evaluate the reported activity of ALK-i in adult ALK-RCC patients published in the scientific literature. We will summarize and report data adhering to the “preferred reporting items for systematic reviews and meta-analyses” (PRISMA) standards [8]. **Search strategy** MEDLINE will be systematically searched from inception to 7 January 2022 for studies without any filters. All references of included studies will be hand-searched later. **Inclusion Criteria** Case reports and case series on adult patients affected by ALK-RCC will be evaluated. Only papers written in English or European languages will be considered. The case series will have to provide single descriptions of the reported cases otherwise they will not be selected. Letters to the editor providing single-case descriptions will be included, subject to all the previous criteria. Subsequently, we will include only patients treated with ALK-i whose therapeutical outcomes were described. **Data extraction (selection and coding)** The literature search, the title, and abstract filtering will be conducted independently by two Authors using reference management software. Firstly, all titles and abstracts will be initially evaluated for potential relevance. Secondly, full texts of results considered eligible will be searched and further assessed for eligibility. A third Author will be required to resolve disagreements on study selection by consensus. Subsequently, two Authors will develop a data-charting form using Microsoft Excel to define the variables to extract. They will independently chart the data and discuss the results in an interactive process. A third Author will verify all the data extracted. The following data will be extracted: - **Study characteristics**: first author name, publication date, journal of publication, study design, number of patients reported; - **Patient characteristics**: age, gender, presenting symptoms and signs, tumor staging, histotype of renal cancer, metastatic sites, type of ALK alteration, previous surgical and medical treatments; - **Exposure characteristics**: type of ALK-i with the related therapeutical outcome described in terms of either best response according to the response evaluation criteria in solid tumors (RECIST) or survival (if available). We will report aggregated data obtained from the variables extracted from included publications. Due to the expected limited sample size, no inferential or predictive statistics analyses will be performed. **Risk of bias assessment** Publications included in the review will be assessed for bias with a tool proposed by Murad et al. [9] to evaluate the methodological quality of case series and case reports. This tool comprises eight different questions categorized in four domains: selection, ascertainment, causality, and reporting. A binary response will be assigned to every question, and then an aggregate score will be formulated for every publication. **References** [1] Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM. 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. https://doi.org/10.1016/j.eururo.2016.02.029. [2] Gorczyński A, Prełowska M, Adam P, Czapiewski P, Biernat W. ALK-positive cancer: still a growing entity. Future Oncol 2014;10:305–21. https://doi.org/10.2217/fon.13.184. [3] Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994;263:1281–4. https://doi.org/10.1126/science.8122112. [4] Mano H. ALKoma: a cancer subtype with a shared target. Cancer Discov 2012;2:495–502. https://doi.org/10.1158/2159-8290.CD-12-0009. [5] Gristina V, La Mantia M, Iacono F, Galvano A, Russo A, Bazan V. The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2020;13:E474. https://doi.org/10.3390/ph13120474. [6] Kuroda N, Sugawara E, Kusano H, Yuba Y, Yorita K, Takeuchi K. A review of ALK-rearranged renal cell carcinomas with a focus on clinical and pathobiological aspects. Pol J Pathol 2018;69:109–13. https://doi.org/10.5114/pjp.2018.76693. [7] Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol 2011;24:430–42. https://doi.org/10.1038/modpathol.2010.213. [8] PRISMA - Transparent Reporting Of Systematic Reviews And Meta-Analyses. Available online: http://prisma-statement.org/ (accessed on 28 Dec 2021) [9] Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med 2018;23:60–3. https://doi.org/10.1136/bmjebm-2017-110853.