4th International Symposium on Leukemia and Lymphoma – Molecular Pharmacology and New Treatment Modalitie

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.     

Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement

With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.     

Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action

Few types of cancer have had their treatment evolve as rapidly as metastatic renal cell carcinoma (mRCC). Since 2005, six new targeted therapies with proven efficacy have been approved for the treatment of mRCC. The downside is that our knowledge about the mechanisms of action of these therapies and the intrinsic and extrinsic mechanism of resistance has not evolved equally fast, and many questions remain unanswered. The only approved agent to date in the European Union for patients who progress on sunitinib or sorafenib is everolimus. The results of the phase III trial comparing axitinib vs. sorafenib after failure on sunitinib, bevacizumab, temsirolimus, or cytokines have recently been published, and axitinib has recently been licensed by the Food and Drugs Administration. Other phase III trials that are being conducted include a comparison between everolimus plus bevacizumab and everolimus after failure on tyrosine kinase inhibitors, and between temsirolimus and sorafenib after failure on sunitinib. In this article, we will review the available evidence from clinical studies on sequential therapy for mRCC, including those that are still in progress. In addition, information on the mechanism of resistance or tolerance to first-line therapy, recommendations of the main practice guidelines for second-line treatment, potential therapies for third or successive treatment lines, and the major reasons why patients who progress may benefit from a change of mechanism of action will also be discussed.     

Oral and intravenously administered mTOR inhibitors for metastatic renal cell carcinoma: Pharmacokinetic considerations and clinical implications

Identification of the role of biological pathways in metastatic renal cell carcinoma (mRCC) has led to the development of targeted agents for its treatment, in particular those that inhibit the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin (mTOR). mTOR is central to signalling pathways that regulate cellular growth, proliferation and survival, and this paper focuses on the two currently licensed mTOR inhibitors, temsirolimus and everolimus. These agents are administered via different routes (intravenously and orally, respectively), and this has an impact on their pharmacokinetics; intravenous temsirolimus is not affected by variable absorption in the gastrointestinal tract or by food intake, unlike the orally administered mTOR inhibitor everolimus. Temsirolimus is administered weekly, whereas everolimus is currently approved for daily dosing. In general, intravenous administration is likely to ensure better control of plasma drug concentrations, greater treatment adherence, and more regular monitoring of toxicity and therapeutic response, although it can be uncomfortable and inconvenient for patients. Oral administration is preferred by patients for its convenience, but can be associated with suboptimal adherence to treatment, and poor and variable bioavailability. Temsirolimus and everolimus have both been associated with improved outcomes in patients with mRCC but, as reviewed in this paper, the pharmacokinetic characteristics of these agents differ in many respects.     

Current options for the treatment of locally advanced and metastatic renal cell carcinoma: focus on sunitinib

Recent developments in molecular biology have increased our understanding of the biology and genetics of renal cell carcinoma (RCC) and identified pathways for novel targeted therapy. Several targeted therapies are now available that show promising activity in this disease. Sunitinib, an oral multitargeted tyrosine kinase inhibitor (TKI), has recently been approved for first-line treatment of metastatic RCC (mRCC) and is the new reference standard for the treatment of clear-cell disease. Three other promising TKIs are temsirolimus, approved for the treatment of advanced RCC, sorafenib, approved for the treatment of patients with advanced RCC who have failed or are considered unsuitable for cytokine therapy and bevacizumab, effective in combination with immunotherapy for first-line therapy of mRCC. Several other agents are under investigation as single-agent or combination therapy for mRCC. These include the TKIs axitinib, pazopanib, everolimus, erlotinib, gefitinib and lapatinib. Use of these agents is leading to the development of treatment paradigms that will transform the management of mRCC.     

“Real World” Treatment of Metastatic Renal Cell Carcinoma in a Joint Community-Academic Cohort: Progression-Free Survival Over Three Lines of Therapy

BackgroundNew targeted therapeutics approved for metastatic renal cell carcinoma (mRCC) offer multiple options in each line of therapy; however, there are few prospective data beyond the first-line settings, and overall comparative effectiveness data are limited. In the targeted therapy era, progression-free survival (PFS) has been the most common regulatory end point for demonstrating the benefit of new therapies.Patients and MethodsDrawing on a joint community-academic retrospective mRCC registry, we analyzed all patients who had undergone at least 1 line of systemic therapy (N = 325) for PFS. Patients were grouped according to treatment choice (sorafenib, sunitinib, temsirolimus, everolimus, and “other”) for up to 3 lines of therapy. PFS by treatment choice and line of therapy was evaluated using Kaplan-Meier and Cox regression analyses.ResultsPFS was longest in patients treated with sunitinib in the first and second lines of therapy. First-line PFS for sorafenib, sunitinib, temsirolimus, everolimus, and “other” was 6.9, 8.9, 4.2, not analyzed (too few patients), and 10.8 months, respectively. Second-line PFS was 4.6, 7.0, 3.2, 3.8, and 4.1 months, respectively. Third-line PFS was 4.5, 4.6, 9.9, 4.2, and 2.9, months, respectively. The risk of progression in patients treated with temsirolimus was about twice that of patients treated with sunitinib in the first and second lines of therapy.ConclusionPatients treated with sunitinib had the longest PFS in the first and second lines of therapy. PFS from practice-based data appear consistent with trial-based expectations; however, practice variation was still evident.     

Future directions of mammalian target of rapamycin (mTOR) inhibitor therapy in renal cell carcinoma

With an explosion of available treatments for metastatic renal cell carcinoma (mRCC) in recent years, it is important to recognize that approved targeted therapies fall broadly into only two mechanistic categories. The first category, vascular endothelial growth factor (VEGF)-directed therapies, includes sunitinib, pazopanib, sorafenib and bevacizumab. The second category includes inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. A pivotal trial of everolimus supports use of the agent in patients with mRCC refractory to VEGF- tyrosine kinase inhibitors (TKI) therapy, while pivotal data for temsirolimus supports use in poor-prognosis patients as first-line therapy. Multiple reviews exist to delineate the laboratory and clinical development of mTOR inhibitors. This paper will outline the future applications of these therapies. It will explore ongoing trials evaluating combinations of mTOR inhibitors with other targeted therapies, along with sequencing strategies and biomarker discovery efforts. The application of mTOR inhibitors in unique populations is also described.     

Quality of life and supportive care for patients with metastatic renal cell carcinoma

In recent years, a key issue in the management of patients with metastatic renal cell carcinoma (mRCC) has been the assessment of health-related quality of life (HRQoL), particularly following the introduction of targeted therapies that have brought significant improvements in progression-free survival and quality of life in these patients. HRQoL is becoming one of the main factors influencing choice of therapy, and HRQoL experienced during first-line treatment may affect the choice of the second-line therapy. Consequently, several trials have been conducted to evaluate the impact of approved targeted therapies for mRCC on HRQoL, and this measure is being introduced with increasing frequency in the trial design. With respect to agents used after progression on cytokines, sunitinib and temsirolimus have yielded better HRQoL scores, and sorafenib and pazopanib have shown stable HRQoL scores compared with placebo. Regarding targeted agents approved for patients who progress on a first-line tyrosine kinase inhibitor, everolimus has shown to delay and reduce the degree of Karnofsky performance status deterioration compared with placebo. Moreover, evidence obtained from these trials shows that tumor response and delay in disease progression affect HRQoL. In this article, we review the different HRQoL scales used to evaluate patients with mRCC along with the results obtained in clinical trials. Given that HRQoL is determined not only by treatment-related effects but also by mRCC symptoms and its clinical complications, the characteristics and appropriate treatment of the most commonly experienced symptoms, including anorexia, fatigue, pain, anemia, and venous thromboembolism, are also reviewed.     

Addition of Salvage Immunotherapy to Targeted Therapy in Patients with Metastatic Renal Cell Carcinoma

There have been significant advances in the treatment of metastatic renal cell carcinoma (mRCC), with immunotherapy (IO)-based combinations as the standard-of-care treatment in the front-line setting. IO in this setting is paired with another IO agent or with a vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitor (TKI). One IO/IO combination and four IO/TKI combinations are currently approved. However, the role of the salvage IO in patients with disease progression on TKI monotherapy is uncertain. Here, we present a case series of five patients who were on single-agent TKI therapy for treatment-refractory mRCC and upon disease progression had an IO agent added to their TKI. The median duration of TKI monotherapy was 11.2 months (range, 1.7–31.1 months), and the median duration of response after the addition of IO was 4 months (range, 2.8–10.5 months). Although IO salvage therapy has a plausible rationale, this case series did not show a clear benefit to this approach. Further clinical trials are needed to determine the clinical utility of IO salvage therapy in mRCC.     

Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells

Temsirolimus (CCI-779), a recently synthesized analogue of rapamycin, specifically inhibits mTOR and has been approved for clinical use in renal cell carcinoma. Recent reports have indicated the growth inhibitory effect of temsirolimus in some cancers including non-small-cell lung carcinoma (NSCLC). In this study, we aimed to explore the potential therapeutic use of temsirolimus as a treatment for NSCLC. Using cultured NSCLC cells (A549, H1299, and H358), we determined the effect of temsirolimus on cell proliferation and its antitumor effects on subcutaneous tumors, as well as its contribution to the survival of mice having pleural dissemination of cancer cells, mimicking advanced NSCLC. Temsirolimus suppressed proliferation of NSCLC cells in a dose-dependent manner, with an IC(50) of <1 nM. Western blot analysis revealed that temsirolimus treatment specifically inhibited the phosphorylation of mTOR and its downstream effectors in 1 h, accompanied by an increased cell population in the G(0) /G(1) phase, but according to flow cytometry, the cell population did not increase in the sub-G(0) phase. When NSCLC subcutaneous tumor-bearing mice were treated with temsirolimus, tumor volume was significantly reduced (tumor volume on day 35: vehicle vs temsirolimus = 1239 vs 698 cm(3) ; P < 0.05). Furthermore, prolonged survival was observed in pleural disseminated tumor-bearing mice with temsirolimus treatment (median survival: vehicle vs temsirolimus = 53.5 vs 72.5 days; P < 0.05). These results suggest that temsirolimus could be useful for NSCLC treatment, due to its antiproliferative effect, and could be a potential treatment for advanced NSCLC, giving prolonged survival.     

First-Line Mammalian Target of Rapamycin Inhibition in Metastatic Renal Cell Carcinoma: An Analysis of Practice Patterns From the International Metastatic Renal Cell Carcinoma Database Consortium

Introduction/BackgroundApproval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting.Patients and MethodsWe performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS).ResultsWe identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients.ConclusionPoor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.     

Everolimus vs. Temsirolimus for Advanced Renal Cell Carcinoma: Use and Use of Resources in the US Oncology Network

BackgroundThe National Comprehensive Cancer Network (NCCN) guidelines suggest the use of inhibitors of mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus, as first- and second-line therapy, respectively, for advanced or metastatic renal cell carcinoma (mRCC). However, adherence to this recommendation in clinical practice and the use of these 2 agents in mRCC is unknown.Patients and MethodsWe determined the prescribing patterns of temsirolimus and everolimus in a retrospective longitudinal cohort study of patients with mRCC receiving clinical care within The US Oncology Network. Outpatient health care use in patients with mRCC was derived for the categories of laboratory visits, acute care visits, minor procedures, radiation therapy, drug/medication use, and other services.ResultsAmong 462 patients with mRCC, 144 (31%) were treated with everolimus and 318 (69%) were treated with temsirolimus. The use of temsirolimus vs. everolimus as first-, second-, and third-line therapy was 50.7% vs. 16.7%, 30.1% vs. 42.1%, and 19.3% vs. 83.2%, respectively. Despite similarities in disease stage and demographic features, compared with temsirolimus, everolimus use was independently associated with lower use of outpatient health care resources, regardless of the line of therapy.ConclusionNotwithstanding the potential limitation that this was an observational retrospective study, our results indicate that everolimus results in substantial savings in the use of resources relative to temsirolimus. In a large geographically dispersed network of community-based oncology practices, both of these agents are used frequently outside of NCCN guidelines. A direct comparison of the efficacy and costs of everolimus vs. temsirolimus for mRCC is warranted.     

Immunotherapy: A new standard in the treatment of metastatic clear cell renal cell carcinoma

Renal cell cancer (RCC) represents 2%-3% of all adulthood cancers and is the most common malignant neoplasm of the kidney (90%). In the mid-nineties of the last century, the standard of treatment for patients with metastatic RCC was cytokines. Sunititib and pazopanib were registered in 2007 and 2009, respectively, and have since been the standard first-line treatment for metastatic clear cell RCC (mccRCC). Renal cell cancer is a highly immunogenic tumor with tumor infiltrating cells, including CD8+ T lymphocytes, dendritic cells, natural killer cells (NK) and macrophages. This observation led to the design of new clinical trials in which patients were treated with immunotherapy. With the growing evidence that proangiogenic factors can have immunomodulatory effects on the host’s immune system, the idea of combining angiogenic drugs with immunotherapy has emerged, and new clinical trials have been designed. In the last few years, several therapeutic options have been approved [immunotherapy and immunotherapy/tyrosine kinase inhibitors (TKI)] for the first-line treatment of mccRCC. Nivolumab/ipilimumab is approved for the treatment of patients with intermediate and poor prognoses. Several checkpoint inhibitors (pembrolizumab, nivolumab, avelumab) in combination with TKI (axitinib, lenvatinib, cabozantinib) are approved for the treatment of patients regardless of their International mRCC Database Consortium prognostic group and PD-L1 expression. There is no specific and ideal biomarker that could help in selecting the ideal patient for the appropriate first-line treatment.     

Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents

The medical treatment of metastatic renal cell carcinoma (mRCC) has undergone a paradigm shift during the last decade with the approval of five drugs targeting vascular endothelial growth factor (VEGF) or its receptors (bevacizumab, sunitinib, sorafenib, pazopanib and axitinib) and of two drugs inhibiting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway (temsirolimus and everolimus). Median survival has now reached 2 years in mRCC patients receiving first-line targeted treatment. A considerable body of work was conducted on the identification of prognostic factors of survival in the earlier era of immunotherapy of mRCC. The current challenge is to pursue this work on biomarkers of prognosis for targeted therapy and, even more importantly, to identify predictive factors of response to such therapy. This review provides an overview of recent key work on prognostic and predictive factors in patients with advanced clear cell RCC treated with VEGF-targeted agents.     

The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma

Introduction

Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC.

Materials and Methods

This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry–liquid chromatography method.

Results

We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups.

Conclusion

In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC.

Implications for Practice

Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.

     

Overcoming resistance to tyrosine kinase inhibitors in renal cell carcinoma

Targeted agents have substantially improved patient outcomes in metastatic renal cell carcinoma (mRCC) and have now replaced cytokines as standard of care. Despite the clinical benefits observed, resistance to targeted agents has been shown to develop after a median of 5-11months of treatment. Furthermore, a small subset of patients does not experience any clinical benefit from targeted therapy. Two general modes of resistance have been proposed: intrinsic (pre-existing) and evasive (adaptive). Evasive resistance is thought to be the mechanism involved when patients progress after initial clinical benefit. It has been suggested that upregulation of alternative pro-angiogenic factors and/or downregulation of angiostatic factors may be involved. Several strategies have been shown to enable clinical benefit in patients who have experienced disease progression during prior therapy. These strategies include: adjusting the dose of the drug, combination therapy or switching to an alternative agent, with or without a different mechanism of action. Improvements in our understanding of the mechanisms of resistance associated with targeted agents and refinement of management strategies may help to improve patient outcomes further. In this article, we review the available evidence supporting mechanisms of resistance to targeted agents in mRCC, with a focus on tyrosine kinase inhibitors, and consider the potential management strategies which may allow further clinical benefit to be achieved.     

Differenzialtherapie beim metastasierenden Nierenzellkarzinom

In 2006 the new compounds Sorafenib and Sunitinib were approved in Europe for the treatment of advanced renal cell carcinoma (mRCC). Additional innovative substances are to be expected on the market for which data have not yet been published and will provide physicians with a whole array of individual therapeutic options. Principles of primary surgical procedures for tumor and metastasis resection remain untouched. An accepted algorithm for the new drug entities has, however, been missing and it is felt that recommendations on how mRCC should be treated in clinical practice are needed. The suggested treatment algorithm is based on results from evidence-based medicine together with parameters which resulted in the approval of recent data announced at the ASCO congress in 2007 and, last but not least, on wide experience in treating mRCC patients.     

Impact of anti-angiogenic treatments on metastatic renal cell carcinoma

Patients with metastatic renal cell cancer (mRCC) have traditionally had poor responses to systemic therapies. Recent developments in molecular biology have increased our understanding of the oncogenic processes and pathways in clear-cell mRCC. The development of drugs that target these pathways has expanded treatment options, improved prognosis and changed standard management of patients with clear-cell mRCC. Sunitinib, sorafenib and pazopanib (oral tyrosine kinase inhibitors) as well as everolimus and temsirolimus (mTOR inhibitors) and interferon with bevacizumab (an antibody to VEGF) have improved patient outcomes in large Phase III trials. These drugs have been incorporated into standard practice. Sunitinib has been adopted as first-line standard of care. Many agents are in development for treatment of mRCC, including axitinib in Phase III trials. We will review these treatments, their toxicities and how these targeted agents have impacted on mRCC.     

Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor,against sunitinib‐resistant renal cell carcinoma

Sunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first‐line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink‐1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink‐1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink‐1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib‐naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E‐binding protein 1 (4EBP1) and AKT. In addition, Rapalink‐1 had greater tumor suppressive effects than temsirolimus against the sunitinib‐resistant 786‐o cell line (SU‐R 786‐o), which we had previously established, as well as 3 additional SU‐R cell lines established here. RNA sequencing showed that Rapalink‐1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib‐sensitive or sunitinib‐resistant.