No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: Results from a large patient cohort
... The evident benefits produced by TKIs and mTOR inhibitors in terms of increased disease control has led up to 15% of patients initially diagnosed with recurrent or mRCC to be candidate to a third line treatment attempt [53]. Unfortunately, most of the evidences regarding this setting are based on retrospective studies, often with conflicting results [54,55]. Iacovelli [54]. ...
... Unfortunately, most of the evidences regarding this setting are based on retrospective studies, often with conflicting results [54,55]. Iacovelli [54]. Opposite findings were observed in a previous retrospective German study including 103 patients, of whom 62 received the sequence TKI-TKI-mTOR and 41 the sequence TKI-mTOR-TKI; in fact a trend (p=0.08) ...
... favoured the patients treated with the TKI-mTOR-TKI sequence [55]. No comparisons can be made between the studies, due to the retrospective nature of both of them and relative selection bias; however, while the type of sequence maintained a statistically significant predictive value for both PFS and OS either in univariate or multivariate Cox regression models in the Iacovelli's trial, it did not in the German trial [54,55]. This might play for a greater affordability of Iacovelli's findings. ...
Genitourinary cancers represent a heterogeneous group of malignancies arising from genitourinary tract, and are responsible for almost 359 000 newly diagnosed cases and 58 420 related deaths in USA. Continuous advances in cancer genetics and genomics have contributed towards changing the management paradigms of these neoplasms. Neoangiogenesis, through the activation of the tyrosine-kinase receptors signalling pathways, represents the key mediator event in promoting tumour proliferation, differentiation, invasiveness and motility. In the last decade, several treatments have been developed with the specific aim of targeting different cell pathways that have been recognized to drive tumour progression. The following review attempts to provide a comprehensive overview of the literature, focusing on new advances in targeted therapies for genitourinary tumours. Furthermore, the promising results of the latest clinical trials and future perspectives will be discussed.
... Therefore, alternating TT sequentially can improve therapeutic efficacy. The most commonly employed TT sequences are TKI-TKI-mTORi and TKI-mTORi-TKI [2,[5][6][7][8][9], but there is limited evidence for the optimal sequential TT use for mRCC, especially in Asian patients [5,6,9]. This study aimed to compare the survival outcomes of patients who underwent sequential treatment using double-or triple-TT, with or without immunotherapy (ITx). ...
... For third-line sequential TT, in the present study, TKI-mTORi-TKI doubled OS compared with TKI-TKI-mTORi. This finding is dissimilar to that of Iacoville et al. who indicated that TKI-TKI-mTORi resulted in superior outcomes compared with TKI-mTORi-TKI [8]. Such discrepancies could be due to the heterogeneity of data sources, confounding factors, selection bias due to the lack of randomization, and the small number of cases in the present study. ...
Objective
To evaluate the progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with double- and triple-sequence targeted therapy (TT) using tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORi).
Materials and Methods
Records of 292 patients with mRCC, treated with TT between January 2005 and July 2015, were analyzed retrospectively. Kaplan-Meier and log-rank analyses were used to calculate and compare the total PFS (tPFS) and OS when patients underwent double- or triple-TT using TKIs or mTORi.
Results
Eighty-one (27.7%) patients who underwent second-line TT were enrolled; 30 (10.3%) of whom underwent third-line TT. The tPFS and OS of double-TT using TKI-mTORi (5.4 and 30 months, respectively) were significantly better compared with TKI-TKI (0.3 and 2 months) or mTORi-TKI (2 and 6 months) (p <0.001). For triple-TT, the tPFS and OS of TKI-mTORi-TKI (22.8 and 25 months, respectively) were significantly superior compared with those for TKI-TKI-mTORi (4 and 9 months) (p <0.05).
For patients with intermediate-risk according to the Heng or Memorial Sloan-Kettering Cancer Center risk models, TKI-mTORi was associated with a significantly longer tPFS and OS compared with TKI-TKI [expect for OS in the Heng group (p = 0.086)]. For the triple TT group, TKI-mTORi-TKI resulted in improved tPFS and OS compared with TKI-TKI-TKI or TKI-TKI-mTORi (p <0.05).
Conclusion
In patients with mRCC, sequential administration of TKI-mTORi led to a significantly superior tPFS compared with any other TT sequence. By contrast, OS did not differ significantly according to TT sequence.
... Our data indicate that only 21% of patients are currently receiving TTT, which is similar to several studies performed using data from prior to 2012 that reported TTT ranging from 13% to 21% [5,[13][14][15][16]. Within these studies, the predominant TTT of choice varies greatly by location and year. ...
... The most recent study comes from 2012 in which everolimus (24.7%), bevacizumab (24.7%), and pazopanib (19.4%) were most common [14]. In contrast, an Italian study spanning from 2006 to 2011 identified that 51% of E U R O P E A N U R O L O G Y X X X ( 2 0 1 6 ) X X X -X X X their patients were treated with everolimus and 32.5% received sorafenib [15]. While these large incongruities may be troublesome, there is no robust data to suggest a superior third-line therapy, thus the consequence of such variation is unknown. ...
Background:
The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population.
Objective:
To evaluate the use and efficacy of targeted therapy in a third-line setting.
Design, setting, and participants:
Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis.
Outcome measurements and statistical analysis:
Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status.
Results and limitations:
Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study.
Conclusions:
TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS.
Patient summary:
Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease.
... The IMDC criteria can be also used as an adjustment method in retrospective studies. Iacovelli et al. [60] investigated the sequence of targeted therapy in patients with mRCC. All patients received 3 lines of targeted therapies in a sequence of VEGF-VEGF-mTOR or VEGF-mTOR-VEGF. ...
... When patients were stratified according to risk factors, the sequence of VEGF-VEGF-mTOR increased OS, particularly in patients with a good prognostic risk (HR ¼ 2.59, 95% CI: 1.59-4.22) [60]. As such, groups can be better balanced by stratification using prognostic factors in retrospective studies. ...
... However, this result cannot be generalized because temsirolimus and everolimus cannot be considered as comparable in this setting [30]. Simultaneously, several retrospective analyses tried to compare mTOR and TKIs with conflicting results [31][32][33]. ...
... Generally, 30% of new patients are diagnosed at an advanced stage and 20% become metastatic later on. Recent retrospective data reported that only 50% of patients who received first-line therapy will go to second-line of therapy and~13 --20% of those patients will reach a third one [31,32]. From a pharmaceutical company perspective, firstline is the highest expectation for a new drug to enter the market of systemic therapy in mRCC, but in this case head-to-head trial is required and sunitinib or pazopanib should be considered as standard comparators. ...
Introduction:
Since both cytotoxic and cytokine therapy were not able to improve the prognosis of advanced renal cell carcinoma (RCC), this tumor has been a good model for the development of new biological agents in the past decade. Five VEGF receptor (VEGFR) and two mammalian target of rapamycin (mTOR) inhibitors are currently available for treatment of this disease but several issues need to be resolved such as a better definition of prognosis, the overcome of resistance and the best therapy for less frequent histologies.
Areas covered:
This review focuses on new tyrosine kinase inhibitors (TKIs) under investigation in these patients. Study design, phase of investigation, result and emerging toxicities were reported for each molecule. Combination trials involving TKIs with other strategies such as immunotherapy were also covered.
Expert opinion:
Despite the development of more potent and more specific VEGFR TKIs, all tumors ultimately develop resistance to therapy and a plateau has been reached in terms of overall survival. Current research effort to develop new agents aims at overcoming both the primary and the acquired resistance to anti-VEGFR TKIs focusing on new molecular pathways. The ultimate goal is not only to improve patient outcome but to achieve durable complete remission. Several pitfalls that have been responsible for failure of other compounds remain, especially the lack of strong predictive biomarkers and the use of inappropriate tumor assessment criteria that may not accurately capture response to these new therapies.
... The importance of sequential treatment for patients with RCC was emphasized previously during the era when antiangiogenic agents were the only treatment option. 45 New data are now needed to confirm the best forms of secondline treatment after combination therapy. The vast majority of studies conducted so far involved the use of retrospective data, and thus prospective data are limited. ...
Cabozantinib is an oral tyrosine kinase inhibitor (TKI) with activity against several receptors involved in the angiogenesis pathway, including vascular endothelial growth factor receptor (VEGFR), c-MET and AXL. The antiangiogenic properties of cabozantinib led to its use as a monotherapy for the treatment of metastatic renal cell cancer (RCC), and quickly resulted in this treatment becoming part of the standard of care for these tumors. Since the advent of immune checkpoint inhibitors (ICIs), new standards of care have emerged in first-line settings, involving dual ICI or ICI–VEGF-TKI (including ICI–cabozantinib) combination treatments, and leading to a more complex algorithm of care. Cabozantinib remains an option in second-line settings and is still a first-line standard of care treatment in cases where the use of ICIs is contraindicated. This review focuses on the selection of patients who may benefit most from cabozantinib therapy, including those with bone and brain metastases and those with a non-clear cell RCC histology. The need to consider disease-related symptoms, comorbidities, age, drug interactions and biomarker analyses in the choice of therapeutic strategy is also highlighted. Finally, the perspectives for the use of cabozantinib in RCC treatment are discussed.
... До недавнего времени существовало 2 основных варианта терапии 2-й линии, которые чаще других назначались для лечения пациентов с ПКР: пероральный ингибитор mTOR эверолимус [5,6] и ингибитор рецепторов сосудистого эндотелиального фактора роста (vascular endothelial growth factor receptor, VEGFR) акситиниб [7]. В последнее десятилетие ингибиторы ангиогенеза и ингибиторы mTOR широко использовались последовательно после предшествующей монотерапии ингибиторами тирозинкиназ (ИТК), что способствовало увеличению общей выживаемости (ОВ) и повышению качества жизни пациентов [8,9]. Помимо комбинации ленватиниб + эверолимус (ЛЕНЭВЕ) [10,11] еще 2 препарата были недавно одобрены для лечения пациентов с ПКР после прогрессирования заболевания на фоне ингибиторов ангиогенеза (после как минимум одной линии терапии): ниволумаб -ингибитор рецептора программируемой смерти 1 (PD-1) [12], кабозантиниб -ИТК, действующий на VEGFR, рецептор фактора роста гепатоцитов (MET) и AXLрецептор [13,14]. ...
... PFS improved more with second-line VEGFR TKI if first-line VEFGR TKI was given for >8 months (11.3 vs. 5.1 months, p = 0.009), suggesting continued VEGF inhibition may be a pertinent strategy in this subset of patients. The duration of first-line PFS is an independent prognostic variable but it is not predictive for PFS associated with subsequent therapy (145). Other authors found that the response and the PFS to a firstline TKI correlated with longer PFS and OS using everolimus as second-line treatment (146). ...
In the last decades, the prognosis of metastatic renal cell carcinoma (mRCC) has remarkably improved following the advent of the “targeted therapy” era. The expanding knowledge on the prominent role played by angiogenesis in RCC pathogenesis has led to approval of multiple anti-angiogenic agents such as sunitinib, pazopanib, axitinib, cabozantinib, sorafenib, and bevacizumab. These agents can induce radiological responses and delay cancer progression for months or years before onset of resistance, with a clinically meaningful activity. The need for markers of prognosis and efficacy of anti-angiogenic agents has become more compelling as novel systemic immunotherapy agents have also been approved in RCC and can be administered as an alternative to angiogenesis inhibitors. Anti PD-1 monoclonal antibody nivolumab has been approved in the second-line setting after tyrosine kinase inhibitors failure, while combination of nivolumab plus anti CTLA-4 monoclonal antibody ipilimumab has been approved as first-line therapy of RCC patients at intermediate or poor prognosis. In this review article, biomarkers of prognosis and efficacy of antiangiogenic therapies are summarized with a focus on those that have the potential to affect treatment decision-making in RCC. Biomarkers predictive of toxicity of anti-angiogenic agents have also been discussed.
... These contrasting data do not help to clarify whether cross-resistance between sunitinib and sorafenib occurs in clinical practice, and if so, which TKI induces stronger cross-resistance. In a cohort of 281 patients, the sequence of TKI-TKI-mTORi, (TKIs, sorafenib or sunitinib; mTORi, everolimus) was reported to be associated with improved survival compared with TKI-mTORi-TKI (OS 50.7 versus 37.8 months, P = 0.004) 144 . On the basis of these data, it seems that even if cross-resistance between different TKIs exists, it is clinically insignificant and patients experience better outcomes after re-challenge with another TKI than a switch to mTORi, for which no data about cross-resistance with TKIs are available. ...
Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10–15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β–EIF4EBP1, PI3K–AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.
... The results of observational studies investigating the VEGFi-VEGFi versus VEGFi-mTORi sequences are inconclusive due to significant heterogeneity in the observed effect of second-line therapies and potential bias [18][19][20]. The only randomised study of secondline therapy directly comparing VEGFi with mTORi is the recently published METEOR trial. ...
Background:
It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC).
Methods:
This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test.
Results:
The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5-19.5 months), 17.1 months (95% CI 14.5-19.8), and 15.4 months (95% CI 11.0-19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second-line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus.
Conclusions:
In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib.
... From the third line onwards, treatments are not standardized, because much of our knowledge derives from retrospective analyses that have also shown a survival advantage with targeted agents in advanced lines, mostly in patients with favorable-and intermediate-prognostic criteria disease. The best sequence is still debated; some prospective trials [27,28] and retrospective analyses [29] are not conclusive in preferring one sequence rather than another, and this represents an open issue that would require a large prospective randomized trial to clarify. ...
Treatments for metastatic renal cell carcinoma are constantly changing thanks to the increasing knowledge of the molecular biology of this tumor. In fact, understanding the underlying genetic mechanisms has led to the development of new classes of drugs, known as molecularly targeted therapies that, to date, represent the standard treatment in the first-line setting. More recently, we have witnessed the resurgence of immunotherapy, which is providing significant benefit to patients with treatment-refractory disease. The use of all of the currently available agents, in sequence, has been shown to prolong survival to beyond 20 months, and to improve the quality of life of patients. Despite the recent progress, there is still a crucial need for further advances. The discovery of biomarkers that would allow the prediction of treatment response and therefore lead to better patient selection, as well as understanding the potential mechanisms of acquired resistance that might guide the choice of the optimal sequential use of the available drugs, together still represent an open challenge for both scientists and clinicians.
... However, despite the development of many types of TKIs, their effects are still limited and have been shown to be not curative [6]. A number of approved molecular targeted agents allow the sequential use of these drugs as empirical standard of care, although the optimum order of application has not been defined [7,8]. Moreover, treatment has been associated with the development of resistance after a median of 6-15 months [9]. ...
Metastatic renal cell carcinoma (RCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKI) represent the standard of care for RCCs, however a significant proportion of RCC patients develop resistance to this therapy. Interleukin-6 (IL-6) is considered to be associated with poor prognosis in RCCs. We therefore hypothesized that TKI resistance and IL-6 secretion are causally connected. We first analyzed IL-6 expression after TKI treatment in RCC cells and RCC tumor specimens. Cell proliferation and signal transduction activity were then quantified after co-treatment with tocilizumab, an IL-6R inhibitor, in vitro and in vivo. 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. Using a mouse xenograft model we can show that a combination therapy with tocilizumab and low dosage of sorafenib suppresses 786-O tumor growth, reduces AKT-mTOR pathway and inhibits angiogenesis in vivo more efficient than sorafenib alone. Furthermore FDG-PET imaging detected early decrease of maximum standardized uptake values prior to extended central necrosis.
Our findings suggest that a combination therapy of IL-6R inhibitors and TKIs may represent a novel therapeutic approach for RCC treatment.
... Currently, no known clinical or biological factors predict which type of treatment or specific agent might be optimal after the first-line setting. Previous studies have investigated parameters that emerge after initiation of first-line treatment, such as the development of toxicity [14], the duration of first-line therapy [15,16], the magnitude of the clinical response [17], and drug pharmacokinetics [18]. Preexisting hypertension appears to be associated with better cancer outcomes for patients receiving VEGFi [19,20]. ...
534
Background: Currently no predictive markers exist for choosing second-line targeted therapy (2L) in metastatic renal cell carcinoma (mRCC). A change in IMDC prognostic group when calculated at first-line therapy (1L) and 2L and its association with 2L efficacy was examined. Methods: The IMDC database was interrogated for patients who received 1L VEGF inhibitors (VEGFi) and then 2L with VEGFi or an mTOR inhibitor (mTORi). IMDC prognostic categories (Favorable, F; Intermediate, I; Poor, P) were defined prior to each line of therapy. Overall survival (OS), time to treatment failure (TTF) and response to 1L or 2L were assessed in relation to change in IMDC prognostic risk category. Results: Data for 1516 patients were analyzed; 89% had clear cell histology. Prognostic risk categories at 1L were F: 21.7%; I: 59.5%; P: 18.8%. 60.3% of patients remained in the same risk category at start of 2L; 9.0% improved (3% I→F; 6% P→I); 30.7% deteriorated (14% F → I or P; 16% I → P). Improvement in prognostic risk category was associated with better response and longer duration of 1L. Patients who improved prognostic risk (I → F or P → I), or maintained I or F grouping, had longer TTF if they remained on VEGFi for 2L compared to those who switched to mTORi (p < 0.05). In contrast, patients whose risk category deteriorated (F → I or P) may be more likely to benefit from switching to mTORi. Conclusions: Changes in IMDC prognostic category may predict the subsequent clinical course of patients with aRCC and provide a rational basis for selection of subsequent therapy. [Table: see text]
... Some studies have demonstrated that there is no clear demonstration of superiority between the various molecules of the TKI class [6,7]; there are few published data on the sequential use of two or more TKIs in the treatment of mRCC and most of them are the results of retrospective or phase III studies [8,9], which represent an idealized setting with stringent selection criteria. Yet, 35% of 'real-life' patients with mRCC are not eligible for clinical trials for several reasons, the most common being poor performance status and nonclear-cell histology [10]. ...
... Tolerance and toxicity of sequentially used drugs is similar to that encountered for each drug used alone. Furthermore, basing on growing number of retrospective analyses, each line of therapy was shown to have additive effect on PFS and prolong overall PFS [15][16][17][18][19][20][21][22][23][24][25][26]. Sequential use of the following regimen: TKI -m-TOR inhibitors -TKI could be a good choice in the treatment of mRCC but larger and appropriate studies are require to provide evidence for standard sequencing treatment [25][26][27][28]. ...
Efficacy of new molecularly targeted drugs in the treatment of renal cell carcinoma (RCC), confirmed in clinical studies in relation to survival and prolongation of time to progression, has became a big chance for patients with metastatic renal cell cancer. Axitinib is a potent and selective receptor tyrosine kinase for vascular endothelial growth factor (VEGFR-1, -2, -3), platelet-derived growth factor ? (PDGRF-?) and c-KIT.
This is a case report of a 57-year old female patient with a history of left nephrectomy due to clear cell renal cell carcinoma. The patient had received three prior systemic treatments (interferon ? sorafenib ? everolimus). After consecutive progression the patient was qualified to 4th line therapy ? axitinib at a dose of 5 mg twice daily. Partial response to treatment was achieved. After 6 months therapy was stopped due to the disease progression. The total time to progression was 37.5 months. The total survival time from the disease diagnosis was 45 months.
Based on literature date and own experience we showed that sequential treatment RCC is associated with improved survival. In summary, axitinib may be an effective drug after failure of tyrosine-kinase inhibitor (TKI) therapy in previous lines of therapy.
... Treatment with combination therapeutics has been deemed to be unfeasible due to toxicity profiles, or has not been shown to be more effective than sequential monotherapy. Several population-based studies have demonstrated that sequential targeted monotherapy improves overall survival [5][6][7]. Nevertheless, the optimal sequencing of targeted agents to treat mRCC and maximize the patients' survival is still under rigorous investigations [8,9]. ...
Background:
The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include pazopanib as a second-line treatment option. It would therefore be of interest to determine the efficiency of pazopanib in this setting in terms of the partial response rate (PRR), disease control rate (DCR), and progression-free survival (PFS).
Methods:
Peer-reviewed clinical reports without language restriction, both full papers and conference abstracts, which assessed the second-line use of pazopanib following failure of first-line non-cytokine-targeted therapy, were included. After the literature retrieval, we conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review of the literature and meta-analysis of the size of the effect of each outcome measure (PRR, DCR, and PFS). The effect size and 95 % confidence interval (CI) were calculated using fixed-effect or random-effects models based on the heterogeneity represented by I(2) of selected studies. Meta-analysis forest plots with a fixed-effect model showing the PRR and DCR were created.
Results:
Our results show that there are no available comparative studies on pazopanib second-line treatment. Only phase II trials or retrospective analysis reports were retrievable. Six studies (comprising 217 patients) were included in the qualitative and quantitative analysis. Pazopanib as a second-line treatment resulted in a PRR of 23 % (95 % CI, 17-31 %; I(2) = 52.6 %) and a DCR of 73 % (95 % CI, 65-80 %; I(2) = 0.00 %). The meta-analysis with fixed-effect model revealed that PFS was 6.5 months (95 % CI, 5.6-7.5 months; I(2) = 86.2 %).
Conclusions:
In conclusion, the effectiveness and indication of pazopanib for use in the second-line setting has not yet been examined in-depth; however, this meta-analysis has shown that the treatment effects in terms of PRR, DCR, and PFS may be similar to other well-studied second-line targeted therapies. Rigorous comparative phase III trials testing this hypothesis are required.
... A retrospective study suggests that patients receiving three lines of systemic therapy might benefit more from a TKI-TKI-mTOR sequence (two TKIs followed by an mTOR inhibitor) than from a TKI-mTOR-TKI sequence. 40 However, these data were reported only for patients reaching the third-line setting and do not provide strong enough evidence to recommend the use of a specific agent in the second-line setting. ...
Metastases are present in one third of renal cell carcinomas at diagnosis. The overall survival duration in metastatic renal cell carcinoma is approximately 22 months, which underlines the need for more effective systemic treatments. Therapies on the basis of antiangiogenic agents and inhibitors of the mammalian target of rapamycin have been approved for treatment of metastatic renal cell carcinoma, but only benefits for progression-free survival were demonstrated in the second-line setting. Fortunately, promising treatments are emerging, from new antiangiogenic agents to immune checkpoint inhibitors. For the first time, both an immune checkpoint inhibitor (nivolumab) and a dual inhibitor of the tyrosine kinases c-Met and vascular endothelial growth factor receptor-2 (cabozantinib) have demonstrated improvements in overall survival in the second-line setting. Finding the best sequence for these novel agents will be crucial to improving outcomes in patients with metastatic renal cell carcinoma. This article comprises both a systematic review of the literature and recommendations for second-line therapeutic strategies for patients with metastatic clear cell renal cell carcinoma in whom inhibitors of vascular endothelial growth factor have failed.
... To further complicate the picture, patients often become sicker as the disease progresses, forcing physicians to incorporate other considerations such as performance status, comorbidities, and preferences regarding end-of-life care into decisions about treatment options; in fact, evidence suggests that only about 50% of patients in the United States receive second-line therapy, as opposed to best supportive care (7). Italian analyses similarly showed that approximately 50% of patients received second-line therapy, and only 13% of patients received third-line therapy (8,9). ...
The treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network's Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future.
... Most data related to third-line treatments result from retrospective cohort studies and subgroup analysis: comparative retrospective assessment of the sequence TKI-TKI-mTORi versus TKI-mTORi-TKI suggests superiority of TKI-TKI-mTORi [58]; subgroup analysis within the RECORD-1 trial assessed everolimus as a third-line agent exhibiting a significant benefit regarding PFS versus placebo (4.0 mo PFS vs 1.8 mo; HR: 0.32; p < 0.01), and it is thus in favor of TKI-TKI-mTORi sequence [52]. ...
The recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC).
This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition.
Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidence-based data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC.
... Similarly, in the GOLD trial, patients previously treated with VEGFi-mTORi sequence and randomized to receive dovitinib or sorafenib as third-line therapy reached a median PFS of 3.7 versus 3.6 months, respectively [12]. Finally, Iacovelli et al. reported in thirdline setting a median PFS and OS of 6.1 and 44.7 months, respectively [13]. Interestingly, when patients were stratified according to MSKCC prognostic criteria, the median OS was 59.9, 38.8, and 24.6 months in the good, intermediate, and poor prognosis groups, respectively, regardless of the treatment sequence. ...
Renal cell carcinoma accounts for about 2-3% of all malignant tumors. The prevalence of brain metastases from RCC is less than 20% of cases. Traditionally, whole brain radiotherapy as well as the latest stereotactic radiosurgery improves both survival and local tumor control. These treatments also allow stabilization of clinical symptomatology. However, validated treatment guidelines for RCC patients with brain metastases are not yet available on account of the frequent exclusion of such patients from clinical trials. Moreover, limited data about the sequential use of three therapies, changing the class of agent, have been published up to now.
Case Report.
We report the case of a patient with metastatic RCC who developed disease progression after sunitinib and everolimus as first-line and second-line therapy, respectively. Thus, he underwent a multimodality treatment with pazopanib, as third-line therapy, to control systemic disease and radiosurgery directed on the new brain metastasis. To date, the patient is still receiving pazopanib, with progression-free survival and overall survival of 43 and 103 months, respectively.
Conclusion.
In a context characterized by different emerging options, with no general consensus on the optimal treatment strategy, the use of pazopanib in pretreated patients could be a suitable choice.
... Since RCTs on this issue will not be available in the near future, observational data from clinical practice are needed. (14.8 %) were identified with more than three lines of TT, which is comparable to other studies that suggest <20 % of patients proceed to third-line therapy [16][17][18]. Data on fourth-line TT are very limited. In a multicenter retrospective study, Maute et al. report 27 patients (33 %) receiving fourth-or fifth-line TT out of 81 selected patients receiving Ev in second-or third-line after failure of VEGFi TT [19]. ...
Introduction:
Evidence for sequencing targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) beyond third line is limited. Treatment decisions for these sequence options are largely based on individual preferences and experience. The aim of this study was to describe the efficacy and toxicity of fourth-line TT.
Materials and methods:
We retrospectively reviewed patients treated with fourth-line TT for mRCC after failure of previous treatment lines at a German academic high-volume center. Out of 406 patients treated in first line, 56 patients (14.8 %) were identified with more than three lines of TT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were applied to explore predictors of PFS and OS in uni- and multivariable analysis.
Results:
For the fourth-line treatment, disease control rate was 35.7 %. Median OS from beginning of first-line therapy was 47.4 months (IQR 31.0-76.5). Primary resistance at first-line TT, metastatic disease at initial diagnosis and an intermediate MSKCC score were independent predictors of shorter OS from start of first-line TT. Median OS from the time of initiation of fourth-line therapy was 10.5 months (IQR 5.6-22.6). The corresponding median PFS for fourth-line TT was 3.2 months (IQR 1.6-8.0) and was not correlated with treatment response in first-line TT. The rate of toxicity-induced treatment termination was 16.1 %. Limitations are the retrospective and unicentric design with a limited number of patients.
Conclusions:
Patients might benefit from subsequent treatment lines independently from treatment response in first line.
... A retrospective study analyzed data obtained from 23 centers in Italy involving 2065 patients treated with up to three consecutive lines of therapy in one of the following sequences: VEGF inhibitor-VEGF inhibitor-mTOR inhibitor or VEGF inhibitor-mTOR inhibitor-VEGF inhibitor [40]; this study was also included in the aforementioned systematic review. [39] VEGF inhibitors included sunitinib, sorafenib, pazopanib, axitinib and bevacizumab plus IFN-α; mTOR inhibitors included temsirolimus and everolimus. ...
Introduction:
The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries. Areas covered: The adoption of targeted therapies for the first-line treatment of mRCC in the region was slow and faced many obstacles. In order to evaluate the current status of treatment beyond the first-line setting in the CEE region, this review examines the availability and reimbursement of mRCC drugs and clinical practice in institutions that treat patients with mRCC. Expert opinion: This review highlights the need to raise awareness among physicians, payers and regulators on clinical trial and cost-effectiveness data regarding the treatment of mRCC beyond the first line. The obstacles to mRCC drug access highlighted in this review need to be overcome to ensure that patients are receiving the best treatment available.
... This is practically quite relevant as the present oncological practice is to treat patients affected by metastatic clear-cell RCC with targeted therapies independent of the molecular signature of the metastatic tissue. 13,14 Intratumor heterogeneity, associated with heterogenous protein function, may foster tumor adaptation and therapeutic failure. [15][16][17] Thus, we investigated the presence of losses of hot spots on chromosomal loci 9p and 14q in primary clear-cell RCC and the matched metastatic cancer tissue in patients treated with targeted therapies to check for possible heterogeneity of chromosomal aberrations. ...
Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
... Therefore, response or lack of response to prior VEGF-targeted therapy does not appear to affect further therapy with agents exhibiting similar mechanisms of action. Iacovelli et al (18) recently reported data from a cohort of patients who had received three lines of therapy, suggesting that the sequence of VEGF inhibitor followed by another VEGF inhibitor followed by a mechanistic target of rapamycin (mTOR) inhibitor may be associated with better survival compared with a sequence in which an mTOR inhibitor was sandwiched between two VEGF inhibitors. Phase III trials are required to further support this concept and may help define an optimal sequence on an individual patient basis. ...
The treatment of advanced renal cell carcinoma (RCC) has advanced significantly over the last two decades. This multicenter study was designed with the primary objective to evaluate the efficacy and safety of sorafenib as first-line treatment in patients with advanced or metastatic RCC in the Middle East, who were considered to be ineligible for other approved first-line therapies. A total of 75 eligible patients from 8 centers in the Middle East were included in this study. The patients comprised 48 men and 27 women, with a median age of 52 years (range, 19-78 years). A total of 50 patients had clear cell carcinoma, 17 had papillary carcinoma and 8 had other pathological subtypes. At enrollment, 55 of the 75 patients had undergone previous nephrectomy. A total of 67 patients presented with metastatic disease, while 8 patients had regional residual lesions or local recurrence. The patients were treated with 400 mg oral sorafenib twice daily on a continuous basis as a single agent. Treatment was discontinued upon disease progression, prohibitive toxicity, surgical complications, loss to follow-up, or refusal to continue therapy. The median treatment duration was 21 weeks (range, 1-137 weeks). Sorafenib was tolerated by the majority of the patients. Grade 3/4 hand-foot syndrome occurred in 17 patients; diarrhea, elevated liver enzymes and fatigue were observed in 3 patients each; and grade 3/4 vomiting, hypertension and anemia, in 1 patient each. Of the 75 patients included in this study, 60 were evaluable for response. One patient achieved a complete response for 91 weeks and 6 patients exhibited a partial response (median duration of 23 weeks) with an overall response rate of 11.7%. Disease stabilization occurred in 37 patients (61.7%). Thus, disease control was achieved in 44 of the 60 patientrs (73%). At a median follow-up period of 53.5 weeks (range, 8.5-192 weeks), an intention-to-treat analysis demonstrated a median time-to-disease progression of 25.7 weeks, with a median overall survival of 54.8 weeks. In conclusion, sorafenib was found to be tolerable and effective as first-line therapy in patients with advanced RCC.
... Following first-line VEGF-targeted therapy 33% of 645 patients received second-line VEGF-targeted therapy or mTOR inhibiting agents (123). Similarly, 13% of patients received third-line treatment in an Italian retrospective analysis of targeted therapies (124). The data suggests that MSKCC risk groups and first-line therapy may be predictive factors for receiving second-line treatment. ...
The spectrum of drugs that have shown activity in advanced or metastatic renal cell carcinoma (RCC) has led to a debate on the optimal sequence of treatments. There is agreement on recommending targeted agents as the standard of care in this disease. Uncertainty, however, remains on the best first-line drug choice. Physicians and patients may select sunitinib, bevacizumab in combination with interferon-alpha (IFN-a), pazopanib, or-in poor risk patients-temsirolimus. There are also a variety of therapies with proven efficacy on hand in the second-line setting: sorafenib, pazopanib, axitinib, and everolimus. While most randomized RCC trials assessed progression free survival (PFS) as primary endpoint, some agents were shown to improve median overall survival (OS), and given in sequence they have extended the life expectancy of RCC patients from 13 months in the cytokine era to over 30 months. Despite the progress made, there are sobering aspects to the oncologic success story in RCC, as the new treatments do not obtain an objective response or disease stabilization (SD) in all patients. There are also as yet no predictors to select patients who might benefit and those who are primary resistant to specific drugs, and ultimately almost all patients will experience disease progression. Bearing inevitable treatment failure in mind, availability of further drugs and switching therapy while the patient is in a condition to continue pharmacotherapy is essential. Of note, depending on the setting, only 33-59% of patients receive second-line treatment. In this review we present data on first-, second-, and third-line treatment in RCC, and discuss the difficulties in their interpretation in the context of treatment sequence. We summarize biological aspects and discuss mechanisms of resistance to anti-angiogenic therapy and their implications for treatment selection.
... A total of 281 mRCC patients treated with three lines of targeted therapies were screened. 16 Of these, 233 patients received EV or SO as third-line and included in the final analysis. The median age was 63.2 years (IQR 55.7-70.9); ...
Treatment of metastatic renal cell carcinoma (mRCC) has improved with the use of targeted therapies, but bone metastases continue to be negative prognostic factor.
Patients with mRCC treated with everolimus (EV) or sorafenib (SO) after two previous lines of targeted therapies were included in the analysis. Overall survival (OS) and progression-free survival (PFS) were assessed based on the presence of bone metastases and type of therapy; they were also adjusted based on prognostic criteria.
Of the 233 patients with mRCC, 76 had bone metastases. Of the 233 patients, EV and SO were administered in 143 and 90 patients, respectively. Median OS was 10.4 months in patients with BMs and 17.4 months in patients without bone metastases (p = 0.002). EV decreased the risk of death by 18% compared to SO (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.74-0.91; p < 0.001), with comparable effects in patients with or without bone metastases. In the same manner, EV decreased the risk of progression by 12% compared to SO (adjusted HR 0.88, 95% CI 0.82-0.96; p = 0.002), but this difference was not significant in patients without bone metastases. The major limitations of the study are its retrospective nature, the heterogeneity of the methods to detect bone metastases, and the lack of data about patients treated with bisphosphonates.
The relative benefit of targeted therapies in mRCC is not affected by the presence of bone metastases, but patients without bone metastases have longer response to therapy and overall survival.
... No significant differences between the two strategies were found and the PFS for 65 patients treated with everolimus was 4.3 months and the OS was 35.8 months, with a disease control rate of 60%. The results in terms of OS were consistent with other data reported by the same author in a previous study [Iacovelli et al. 2013]. ...
Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR-I) and is currently approved for the treatment of metastatic renal cell carcinoma (mRCC) after failure of first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI).
In this narrative review, we aim to report the available evidence about the use of everolimus as second-line therapy for mRCC. A literature search was performed using PubMed/MEDLINE and abstracts from major conferences on clinical oncology as sources. We report data from prospective as well as retrospective and real world data studies and we analyze the safety and efficacy profile of everolimus as second-line therapy for mRCC.
Although different drugs are currently available for the second-line treatment of mRCC, everolimus represents a feasible and safe option in this setting, especially for patients who have experienced high-grade toxicity or are still carrying TKI-related toxicities from first-line treatment.
... The MSKCC classification and first-line agent were significant predictors for receiving second-line treatment. Similarly, in an Italian retrospective analysis of targeted therapies, only 13% of patients received third-line treatment [45].This suggests that the first choice of drugs could be crucial and decisive. This might be especially relevant in the patient group with ZZ, in which additional disease progression will disable the patient to undergo further treatments owing to the deterioration of clinical conditions. ...
Background:
With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field.
Materials and methods:
Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified.
Results:
The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria).
Conclusion:
In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts.
Implications for practice:
The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated.
... First, it must be noticed that by using targeted agents sequentially, improvements in overall survival have been achieved [42,43], to then move the debate up to the third-line of treatment. In fact, for the first time the ESMO clinical guidelines show recommendations, albeit weak, on the third-line treatment [44]. ...
ABSTRACT 2014 has been a year of significant innovations on kidney cancer treatments, the most relevant of which will be shown below. In particular, we analyzed the consolidated knowledge regarding the role of surgery in localized and advanced renal cell carcinoma and the targeted therapies already approved for metastatic renal cell carcinoma. Furthermore, we examined the outstanding issues, with particular reference to the choice of the second-line and the role of adjuvant and neoadjuvant treatments. Finally, we outlined the future therapeutic perspectives and those definitely abandoned.
... A recently published retrospective analysis investigated the efficacy of sequential VEGFR-TKI, VEGFR-TKI, and mTOR inhibitor and of sequential VEGFR-TKI, mTOR inhibitor, and VEGFR-TKI in Italy [5]. Median PFS ranged from 36.5 to 29.3 months, and median overall survival (OS) ranged from 50.7 to 37.8 months. ...
Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings.
Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed.
In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered.
This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/ ).
Immune checkpoint inhibitor combinations have reshaped the treatment landscape of metastatic clear-cell renal cell carcinoma. As four regimens are now approved in the first-line setting, including nivolumab plus ipilimumab in intermediate and poor-risk patients, and pembrolizumab plus lenvatinib, nivolumab plus cabozantinib and pembrolizumab plus axitinib in all-comers, the choice of subsequent therapies is becoming a novel challenge for physicians. Such choices now rely on several compounds used as monotherapy which have demonstrated sustained activity after previous immune checkpoint or tyrosine kinase inhibitors. Future strategies may lie in novel targets, including hypoxia-inducible factor inhibitors, as well as further exploration of combinations in more advanced settings. Here we review the current evidence regarding treatment activity after immune checkpoint inhibitor combinations, the underlying biological and clinical challenges that may impact patient selection and the optimal sequencing strategies for clinical practice.
Background
Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy.
Objective
To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy.
Design, setting, and participants
A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled.
Intervention
Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward.
Outcome measurements and statistical analysis
Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest.
Results and limitations
The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71–98%). The median PFS after SRT was 9.3 mo (95% CI 7.5–15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32–68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6–17.4 mo). One-year OS was 92% (95% CI 82–100%). There were no grade 3–5 SRT-related toxicities.
Conclusions
LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr.
Patient summary
The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy.
Background:
The aim of this study was to compare the efficacy and safety of nivolumab as second-line and later-line (third-line or thereafter) therapy in metastatic renal cell carcinoma (mRCC).
Methods:
Sixty-seven patients who received nivolumab after the failure of at least one molecular-targeted therapy were evaluated. The patients were divided into two groups based on the line of nivolumab: second-line and later-line groups. Efficacy was assessed using progression-free survival and overall survival (OS) after nivolumab initiation, and objective response rate. Safety was assessed using the incidence of immune-related adverse events. These outcomes were compared between the second-line and later-line groups.
Results:
Forty-two patients (62.7%) received nivolumab as second-line therapy. There was no significant difference in the progression-free survival (median: 5.06 vs. 6.28 months, p = 0.691) or objective response rate (35.7% vs. 32.0%, p = 0.757) between the second-line and later-line groups. The OS tended to be longer in the second-line group (not reached vs. 26.0 months, p = 0.118), and the rate of patients who received subsequent therapy after nivolumab failure was significantly higher in the second-line group (90.9% vs. 55.0%, p = 0.0025). There was no difference in the incidences of immune-related adverse events between the second-line and later-line groups (any grade: 54.8% vs. 48.0%, p = 0.592; grade ≥ 3: 19.1% vs. 20.0%, p = 0.924).
Conclusions:
The efficacy of nivolumab did not deteriorate and the tolerability was also maintained even in later-line therapy. However, a tendency of longer OS and a higher chance of subsequent therapy after nivolumab failure were observed with nivolumab as second-line therapy.
Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.
Sunitinib has been shown to offer clinical benefits during the treatment of advanced renal cell carcinoma. However, molecular targeting drugs are expensive and can have a significant impact on medical expenses. The purpose of this study was to assess the cost-effectiveness of sunitinib as a first-line therapy compared with interferon-alpha (IFN-α) in metastatic renal cell carcinoma patients. A Markov model was used to show the clinical courses of patients with metastatic renal cell carcinoma who received sunitinib or IFN-α. The transition probabilities and utilities employed in this Markov model were derived from two sources. This study focused on the perspective of public healthcare payer, as only direct medical costs were estimated from the treatment schedule for metastatic renal cell cancer. In the cost-effectiveness analysis, outcomes were valued in terms of life years (LYs) and quality-adjusted life years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) during the cost-effectiveness analysis. The results were tested using Monte Carlo simulations. Sunitinib and IFN-α treatment resulted in LYs of 2.40 years and 2.03 years, QALYs of 1.58 and 1.25, and expected costs of 13,572,629 yen and 6,083,002 yen, respectively. As a result, the ICER associated with replacing IFN-α with sunitinib was 22,695,839 yen/QALYs. Our results suggest that compared with IFN-α, sunitinib prolongs LYs and QALYs, but the increases in quality achieved by sunitinib are more expensive than those produced by IFN-α.
Objectif : Le traitement médical du cancer du rein métastatique (CRM) a été profondément bouleversé par l'émergence des thérapies ciblées (TC). Cependant, si ces molécules ont permis d'améliorer le pronostic des patients traités, leur utilisation actuelle n'est pas optimale. Aussi l'identification de marqueurs pronostiques permettant de guider l'utilisation des TC dans le cadre d'une prise en charge personnalisée s'avère nécessaire. L'objectif de notre travail était d'étudier les facteurs pronostiques cliniques, biologiques, et moléculaires au sein d'une population de patients traités par TC pour un CRM. Matériel et méthodes : Une étude a été réalisée chez les patients traités par TC pour un CRM dans notre centre entre 2006 et 2012. L'ensemble des données cliniques et biologiques ont été collectées rétrospectivement. L'analyse des facteurs pronostiques a été réalisée selon 4 axes : étude de l'impact de la toxicité induite par le traitement et de la fonction rénale, étude de l'impact de l'âge à l'initiation du traitement, étude des facteurs pronostiques en deuxième ligne de TC. Le quatrième axe a consisté en une analyse moléculaire chez les patients pour lesquels du tissu tumoral congelé était disponible. La technique de QMPSF a été adaptée au rein et utilisée pour identifier les altérations génomiques quantitatives (AGQ), et déterminer leur intérêt pronostique. Résultats : 102 patients ont été inclus dans l'étude. L'âge médian était de 62 [38-87] ans. Une toxicité induite sévère et une altération de la fonction rénale sont apparues comme associées à une meilleure survie globale (SG) et sans progression (SSP) p < 0,05. La toxicité sévère a également été identifiée comme facteur indépendant pour la SG (HR=0,52 p=0,03) et la SSP (HR=0,54 P=0,03) et l'altération de la fonction rénale comme facteur de survenue de toxicité sévère (OR=3,9 p=0,01). Concernant le deuxième axe, les patients de plus de 70 ans présentaient significativement plus de toxicités sévères (73% vs. 41%, p=0,002), plus de réduction de doses des TC (79% vs. 51%, p=0,006) et plus d'arrêt du traitement (50% vs. 21%, p=0,004), cependant, ces différences de tolérance n'impactaient pas la survie. Pour le 3e axe, les facteurs pronostiques usuels ont été identifiés comme gardant un intérêt pronostique en 2e ligne. De plus, une toxicité sévère a de nouveau été identifiées comme associée à une meilleure SG et SSP (p < 0,05). L'analyse moléculaire a inclus 50 patients et a permis d'adapter avec succès la QMPSF pour l'étude du cancer du rein. Un intérêt pronostique potentiel a été identifié pour certaines AGQ, notamment les délétions des gènes CDKN2A, PLG, et ALDOB associées à des facteurs de mauvais pronostic (p < 0,05). Conclusion : Cette étude nous a permis de mettre en avant l'intérêt pronostique de la toxicité induite par les TC, ainsi que le potentiel rôle sous-jacent d'une altération de la fonction rénale. L'analyse moléculaire a également mis en évidence l'intérêt pronostique de certaines AGQ. Ces résultats doivent désormais être confirmés par de nouvelles études.
Introduction: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic.
Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm.
Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.
Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.
Background:
We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response.
Objective:
To assess outcomes of 2L according to type of therapy and change in IMDC prognostic category.
Design, setting, and participants:
We performed a retrospective review of the IMDC database for mRCC patients who received first-line (1L) VEGF inhibitors (VEGFi) and then 2L with VEGFi or mTOR inhibitors (mTORi). IMDC prognostic categories were defined before each line of therapy (favorable, F; intermediate, I; poor, P). Data were analyzed for 1516 patients, of whom 89% had clear cell histology.
Intervention:
All included patients received targeted therapy for mRCC.
Outcome measurements and statistical analysis:
Overall survival (OS), time to treatment failure, and response to 2L were analyzed using Cox or logistic regression.
Results and limitations:
At start of 2L, 60% of patients remained in the same prognostic category; 9.0% improved (3% I → F; 6% P → I); 31% deteriorated (15% F → I or P; 16% I → P). Patients with the same or better IMDC prognostic category had a longer time to treatment failure if they remained on VEGFi compared to those who switched to mTORi (adjusted hazard ratio [AHR] ranging from 0.33 to 0.78, adjusted p<0.05). Patients who deteriorated from F to I appeared more likely to benefit from switching to mTORi (median OS 16.5 mo, 95% confidence interval [CI] 12.0-19.0 for VEGFi; 20.2 mo, 95% CI 14.3-26.1 for mTORi; AHR 1.53, 95% CI 1.04-2.24; adjusted p=0.03).
Conclusions:
Changes in IMDC prognostic category predict the subsequent clinical course for patients with mRCC and provide a rational basis for selection of subsequent therapy.
Patient summary:
The pattern of treatment failure might help to predict what the next treatment should be for patients with metastatic renal cell carcinoma.
The application of targeted and pathogenetically sound medicational approaches could considerably improve the results of therapy in patients with metastatic renal-cell carcinoma (mRCC). To date, VEGF/VEGFR inhibitors continue to remain a basic and most effective drug treatment in patients with mRCC and the choice of a drug for first-line therapy is based on the following factors: disease prognosis, a patient’s general somatic state, and the understanding of immediate therapy goals, anticipated toxicity and tolerability.Most patients develop resistance to VEGFR inhibitors within 6–11 months after treatment initiation. The basis for resistance development may be the following mechanisms: activation of alternative proangiogenic signaling pathways, that of angiogenesis-independent progression pathways, a microenvironment-induced phenotypic change of tumor cells to form their resistance to targeted drugs, and pharmacokinetic and pharmacodynamic changes in the drug itself during therapy. To overcome resistance to VEGFR inhibitors, there are 2 possible options: 1) switching to a drug having another mechanism of action (the mTOR inhibitor everolimus); 2) that to a more selective and potent tyrosine kinase inhibitor (axitinib) that selectively affects and suppresses the activityof the same targets – VEGFR (Vascular Endothelial Growth Factor Receptor) 1–3. As before, there is scanty convincing evidence for unique benefits in a particular succession of targeted drugs: a VEGFR inhibitor – a VEGFR inhibitor or a VEGFR inhibitor – an mТOR inhibitor. In a number of cases, the succession of prescribing of targeted drugs may be practically determined by clinical criteria, specifically by the possibility of controlling toxic complications that may be typical for VEFGR inhibitors and may accumulate in case of their successive use. It must be also remembered that VEGFR inhibitors may be successfully reused in patients who have received second- or more line therapy with targeted drugs in different succession.
Background:
The treatment of metastatic renal cell carcinoma (mRCC) has largely improved over the last decade, due to the availability of several targeted agents (TAs). Sorafenib was the first TA to report a benefit in terms of PFS in this disease, and it has largely been used as a comparator in randomized trials. We tested its activity compared to other TAs by performing a systematic review and meta-analysis.
Methods:
MEDLINE/PubMed, the Cochrane library, and the ASCO university websites were searched for randomized phase II or III trials that compared other TAs to sorafenib in mRCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The measured outcomes were progression free survival (PFS), overall survival (OS), and the overall response rate (ORR). Sub-analyses were performed for MSKCC prognostic groups and lines of therapy.
Results:
A total of 3094 patients were evaluable for PFS. Other TAs significantly reduce the risk of progression compared to sorafenib (HR=0.78; 95% CI, 0.72-0.85; p<0.001). This difference remains significant in patients in a good prognostic group with respect to both first- (HR=0.61; 95%CI, 0.44-0.85; p=0.003) and second-line therapy (HR=0.58; 95% CI, 0.42-0.79; p<0.001). No significant differences were, however, found in patients with an intermediate prognosis in terms of both first- (HR=0.80; 95% CI, 0.60-1.00; p=0.05) and second-line treatment (HR=0.89; 95% CI, 0.73-1.07; p=0.21). In 2922 patients evaluable for OS, no significant difference was found between other TAs and sorafenib (HR=1.07; 95% CI, 0.97-1.18; p=0.18). A benefit was also not identified when the analysis was limited to patients treated with first or subsequent lines of therapy or in patients previously treated with sunitinib. Significant differences were found in terms of the ORR in the 2963 evaluable patients favoring other TAs (RR=1.48; 95% CI, 1.24-1.76; p<0.001). This difference remain significant when a sub-analysis was performed per line of therapy.
Conclusions:
Other TAs improve PFS but not OS when compared to sorafenib. The use of sorafenib in patients with an intermediate prognosis, especially in second-line therapy, does not have a detrimental effect on PFS and might be an option for certain patients.
Advanced or metastatic inoperable renal cell carcinoma (mRCC) remains an incurable disease despite significant advances in systemic treatment. Currently, there are seven targeted agents available in the Czech Republic. Sunitinib, pazopanib, temsirolimus, or bevacizumab/interferon-α can be used as first-line therapy, everolimus, axitinib, sorafenib, or (in selected patients) sunitinib can be used in the second line. Everolimus can also be used for third-line treatment. The choice of a first-line targeted agent is influenced by results of prospective randomised clinical trials as well as clinical status of the patient and therapeutic intent. Recommendations for second-and third-line therapy contain many areas of uncertainty although there are some randomised and non-randomised studies that have provided guidance into optimal treatment selection. Nevertheless, sequential therapy of mRCC remains hotly debated in the oncology community.
Background:
Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice.
Patients and methods:
Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib, (57.2% due to progression), 47.9% had received 2nd-line targeted therapy, and 48.9% had died.
Results:
According to IMDC prognostic model, 19.4% had favourable-risk (FR), 57.2% intermediate-risk (IR), and 23.4% poor-risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1% respectively, (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model.
Conclusion:
Our results validate the IMDC model for first-line pazopanib in mRCC, and confirm the effectiveness and safety of this treatment.
Introduction:
Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients. Areas covered: Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies. Expert opinion: Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.
The introduction of agents targeting vascular endothelial growth factor has radically changed the approach to metastatic renal cell carcinoma (mRCC): sunitinib and pazopanib are now the standard first-line therapy in mRCC. At sunitinib failure, second-line axitinib or everolimus or sorafenib should be considered to improve the clinical outcome. No data are available for a third-line tyrosine kinase inhibitor (TKI) after 2 previous lines of therapy with TKIs. At pazopanib failure, no prospective data are available.
The TOKIO study was designed to evaluate progression-free survival, safety, and efficacy of third-line therapy with TKI in 44 patients already treated with 2 previous lines of TKIs in 10 Italian centers, and relapsed from sunitinib-axitinib (group A) or pazopanib-sorafenib (group B). Standard treatment is sorafenib in group A and sunitinib in group B, administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety, and quality of life.
Hintergrund
Patienten mit metastasiertem Nierenzellkarzinom haben eine ungünstige Prognose. Allerdings konnte in den letzten Jahren die Prognose durch neue sog. zielgerichtete Therapien verbessert werden.
Ergebnisse
Insgesamt wurden 7 neue Substanzen, Tyrosinkinaseinhibitoren (TKI), mTOR-Inhibitoren und der VEGF-Antikörper Bevacizumab eingeführt, die zu einer Verlängerung des progressionfreien Überlebens (PFS) und einem medianen Gesamtüberleben (OS) von 2–3 Jahren führen. Für die Erstlinientherapie sind die TKI Sunitinib und Pazopanib sowie die Kombination von Bevazizumab mit Interferon-α (IFN-α) und der mTOR-Inhibitor Temsirolimus für Patienten mit ungünstiger Prognose zugelassen. Sunitinib und Pazopanib können auch in der Zweitlinie eingesetzt werden, wobei Pazopanib auf Patienten nach Zytokinversagen beschränkt ist. Axitinib zeigte verglichen mit Sorafenib nach Zytokinvortherapie oder nach Sunitinib eine Verbesserung des PFS. Weitere Therapieoptionen in der Zweitlinie sind Everolimus und Sorafenib.
Diskussion
Durch die neuen zielgerichteten Substanzen, die in mehreren Therapielinien eingesetzt werden können, hat sich die Prognose für Patienten mit metastasiertem Nierenzellkarzinom signifikant verbessert. Die Frage nach der optimalen Sequenz ist trotz Phase-III-Studien bei fehlenden prädiktiven Faktoren noch nicht definitiv geklärt. Mögliche neue vielversprechende Therapieoptionen eröffnen sich mit den „Immunecheckpoint-Inhibitoren“.
Currently, 7 agents are approved for the first- and second-line therapy for metastatic renal cell carcinoma. In contrast, data supporting their use beyond second line are limited. Here we summarize our experience in patients treated with more than 4 lines of therapy.
We retrospectively assessed the outcome of 24 patients treated at our institution with at least 4 lines of therapy. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimates.
Median OS from the initiation of first-line therapy for the whole cohort is 64.7 months. Up to 96% of the patients received a tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitor (mTOR-I) within the first 3 lines of treatment. In the fourth or following lines, patients were treated with TKI, mTOR-I, bevacizumab/interferon, or experimental drugs. Seven patients continued treatment with a sixth-line agent; one has been treated up to the ninth line. Sixteen percent of the patients receiving fourth-line therapy and 13% receiving fifth-line therapy experienced a partial remission, which was independent from response to previous therapies. Median OS from fourth and fifth line was 30.8 and 26.2 months, respectively. Median PFS for fourth-line therapy was 5.8 months. No significant difference in PFS was observed for patients with disease that responded or did not respond to first-line therapy.
Despite the limitations of a retrospective analysis, our study suggests that selected patients benefit from multiple lines of treatment, independent of response to first-line therapy. However, the optimal sequence of treatment with regard to later lines remains to be determined.
Copyright © 2015 Elsevier Inc. All rights reserved.
To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer.
We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression.
In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003).
The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use.
Targeted therapies have improved survival in patients with metastatic renal cell cancer (RCC); however, expert opinion on the optimal therapeutic strategy is divided. This retrospective study evaluates different sequential schemes of targeted therapies in 310 patients with advanced/metastatic RCC who received different systemic agents - sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and axitinib - alone or in different sequences, until disease progression or intolerable toxicity (median follow-up: 37 months). The median overall survival (OS) was 22 months and the 5-year OS was 23.4%; differential therapeutic schemes were not associated with differences in OS. A worse performance status, no nephrectomy and a poor-risk classification according to the Motzer criteria was associated with a shorter OS. These findings support the use of targeted therapies in the treatment of RCC, even in a large unselected population from a single institution, and suggest that treatment should be tailored to meet individual circumstances and needs.
Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.
To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.
One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.
PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).
Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.
Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.
Anticancer cytotoxic agents go through a process by which their antitumor activity—on the basis of the amount of tumor shrinkage they could generate—has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma.
From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005.
At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo.
As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).
Since sunitinib malate has shown activity in two uncontrolled studies in patients with metastatic renal-cell carcinoma, a comparison of the drug with interferon alfa in a phase 3 trial is warranted.
We enrolled 750 patients with previously untreated, metastatic renal-cell carcinoma in a multicenter, randomized, phase 3 trial to receive either repeated 6-week cycles of sunitinib (at a dose of 50 mg given orally once daily for 4 weeks, followed by 2 weeks without treatment) or interferon alfa (at a dose of 9 MU given subcutaneously three times weekly). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, patient-reported outcomes, and safety.
The median progression-free survival was significantly longer in the sunitinib group (11 months) than in the interferon alfa group (5 months), corresponding to a hazard ratio of 0.42 (95% confidence interval, 0.32 to 0.54; P<0.001). Sunitinib was also associated with a higher objective response rate than was interferon alfa (31% vs. 6%, P<0.001). The proportion of patients with grade 3 or 4 treatment-related fatigue was significantly higher in the group treated with interferon alfa, whereas diarrhea was more frequent in the sunitinib group (P<0.05). Patients in the sunitinib group reported a significantly better quality of life than did patients in the interferon alfa group (P<0.001).
Progression-free survival was longer and response rates were higher in patients with metastatic renal-cell cancer who received sunitinib than in those receiving interferon alfa (ClinicalTrials.gov numbers, NCT00098657 and NCT00083889 [ClinicalTrials.gov]).
Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.
In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.
Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).
As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).
4501
Background: Tivozanib, a potent, selective, long half-life tyrosine kinase inhibitor targeting all three VEGF receptors, showed activity and tolerability in a Phase II trial (JCO 2011;29[18S]:4550). Methods: Patients (pts) with clear cell advanced renal cell carcinoma (RCC), prior nephrectomy, RECIST-defined measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 were randomized 1:1 to tivozanib (T) 1.5 mg once daily for 3 weeks (wks) followed by 1 wk rest, or sorafenib (S) 400 mg twice daily continuously in a 4-wk cycle. Pts were treatment naïve or received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. The primary endpoint was progression-free survival (PFS) per blinded, independent radiological review. 500 pts were to be enrolled to observe 310 events, yielding 90% power to detect medians of 9.7 and 6.7 months (m) with 5% type I error (2-sided). Results: A total of 517 pts were randomized to T (n=260) or S (n=257). Demographics were well balanced between the 2 groups, except ECOG 0 (T: 45% vs S: 54%, p=0.035). Median PFS was 11.9 m for T vs 9.1 m for S (HR=0.797, 95% CI 0.639–0.993; p=0.042). In the treatment-naïve stratum (70% of pts enrolled in each arm), the median PFS was 12.7 m for T vs 9.1 m for S (HR 0.756, 95% CI 0.580–0.985; p=0.037). In all pts, objective response rate (ORR) for T was 33% vs 23% for S (p=0.014). The most common adverse event (AE; all grades/≥grade 3) for T was hypertension (T: 46%/26% vs S: 36%/18%) and for S was hand-foot syndrome (T: 13%/2% vs S: 54%/17%). Other important AEs included diarrhea (T: 22%/2% vs S: 32%/6%), fatigue (T: 18%/5% vs S: 16%/4%), and neutropenia (T: 10%/2% vs S: 9%/2%). Patient-reported outcome data are being analyzed. Overall survival data are not mature. Conclusions: Tivozanib demonstrated significant improvement in PFS and ORR compared with sorafenib as initial targeted treatment for advanced RCC. The safety profile of tivozanib is favorable, and includes a low incidence of fatigue, diarrhea, myelosuppression, and hand-foot syndrome.
305
Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population are poorly understood.
Methods: Data from patients with mRCC treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers.
Results: One thousand fifty-six evaluable patients were treated with VEGF-inhibitors as their first-line antiangiogenic therapy. Of those, 272 (26%) patients had PD as best response. Their initial treatment was sunitinib (n=203), sorafenib (n=51), or bevacizumab (n=18). Six percent of patients were favorable risk, 55% intermediate risk, and 39% poor risk as per Heng et al JCO 2009 prognostic factors. On multivariable analysis, predictors of PD at first restaging were KPS < 80% (OR 2.3, p < 0.0001), diagnosis to treatment < 1 year (OR 2.1, p < 0.0001), neutrophilia (OR 1.9, p = 0.0021), thrombocytosis (OR 1.7, p = 0.0068), and anemia (OR 1.6, p = 0.0058). The median progression-free survival (PFS) and overall survival (OS) in patients with primary refractory disease vs. patients without (i.e., partial response or stable disease) was 2.4 vs. 11 months (p<0.0001) and 6.8 vs. 29 months (p<0.0001), respectively. Only 108 (40%) VEGF-refractory patients proceeded to receive 2 nd line VEGF inhibitors (sunitinib (n=32), sorafenib (n=44), axitinib (n=2), bevacizumab (n=4)), mTOR inhibitors (temsirolimus (n=14), everolimus (n=11)), or interferon (n=1). The response rate, PFS and OS of this second-line therapy was 9%, 2.5 months and 7.4 months, respectively. The response rate, PFS and OS of those receiving second-line VEGF vs. mTOR inhibitors was 10% vs. 6% (p=NS), 2.8 vs. 2.0 months (p=0.069) and 7.9 vs. 4.7 months (p=0.40), respectively.
Conclusions: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR agents may not be better than alternate anti-VEGF agents after primary anti-VEGF failure. Investigation into the mechanism of primary resistance and alternative therapeutic strategies are needed.
[Table: see text]
Background
The optimal sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been defined.Objective
To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy.Design, setting and participantsRetrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n = 62) or VEGFi-mTORi-rTKI (n = 41) at two German academic centers.InterventionSequence of systemic targeted treatment.Outcome measurements and statistical analysisResponse was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression.Results and limitationsSequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8–5.4), 4.1 mo (95% CI, 3.4–4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7–8.1) for mTORi treatment (p = 0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p = 0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4–37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4–52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases.Conclusions
The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.
Prognosis of metastatic renal cell carcinoma (mRCC) has markedly improved in the recent years. Several factors such as precocious diagnosis, better supportive care, and an increased number of targeted therapies are responsible for this progress. From 2006 to date, 7 drugs have been approved for treatment of mRCC, and among these only 2 are recommended for the second line of therapy with grade 1 evidence. Tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors are the strategies with more evidence, but no comparative studies are available and what is the best second line remains an open issue. Herein, we review the available evidence on the second-line treatment focusing mainly on prospective studies. We identify a special population of patients in whom more evidence is available, and we propose a possible strategy for the management of progressed mRCC and for primary resistant lesions as well as for patients who need a rapid response in lesions. In the majority of patients, several factors should be considered: toxicity reported during first-line therapy, performance status, the absence of correlation between the length of first-line therapy and the probability to respond to second-line therapy, and the lack of comparative trials between mTOR inhibitors and TKI. When an mTOR inhibitor is selected, everolimus must be preferred, although in the RECORD1 trial only the increase in progression-free survival has been reported and the increase in terms of overall survival has not been reached. When another TKI is the choice, there are no strong pieces of evidence that favor the use of a defined molecule. In every case, we recommend to start the selected targeted agents at standard dosage and to pursue therapy as long as possible because the control of disease should be the primary endpoint for the management of mRCC.
The advent of targeted therapies in the past 7 years has extended median survival for metastatic renal-cell carcinoma. This improvement in clinical outcome has created a need for new, more accurate prognostic measures. We assessed the use of conditional survival--a measure that accounts for elapsed time since treatment initiation--for prognostication in patients with metastatic renal-cell carcinoma treated with first-line VEGF-targeted therapies.
We obtained data for patients with metastatic renal-cell carcinoma who were treated with a first-line VEGF-targeted therapy between April 7, 2003, and Oct 12, 2010, from our large multi-institutional International mRCC Database Consortium (centres in Canada, the USA, Singapore, Denmark, and South Korea). All histologies, performance statuses, and prognostic risk groups were included. The primary outcome was 2-year conditional survival, defined as the probability of surviving an additional 2 years from a given timepoint since the start of targeted therapy. Secondary analyses included 1-year and 3-year conditional survival, along with stratification of patients by Heng prognostic risk criteria and Karnofsky performance score, and conditional survival based on length of time on therapy. We used the Kaplan-Meier method and a landmark analysis to calculate conditional survival.
In the 1673 patients analysed, median follow-up for alive patients was 20·1 months (IQR 9·0-34·4). We recorded an increase in the 2-year conditional survival probability from 44% (95% CI 41-47) at 0 months to 51% (46-55) at 18 months since beginning targeted therapy. When stratified by the Heng prognostic risk criteria defined at therapy initiation, 2-year conditional survival changed little in the favourable and intermediate groups, but in the poor-risk group, 2-year conditional survival improved from 11% (8-15) at 0 months to 33% (18-48) after 18 months. When conditioned on time on targeted therapy from 0 months to 18 months, 2-year conditional survival improved from 44% (41-47) to 68% (60-75) in the overall population and from 74% (68-79) to 90% (77-96) in the favourable group, 49% (45-53) to 57% (45-67) in the intermediate group, and 11% (8-15) to 73% (43-89) in the poor risk group.
Conditional survival is a clinically useful prediction measure that adjusts prognosis of patients with metastatic renal-cell carcinoma on the basis of survival since treatment initiation or therapy duration. Conditional survival might be especially relevant to adjust prognosis for poor-risk patients.
The Trust Family Fund for Kidney Cancer Research.
Sequential treatment with targeted therapies is the current standard of care for patients with metastatic renal cell carcinoma (mRCC). Most patients are initially treated with a first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI), but will eventually develop resistance and subsequent disease progression. Patients with mRCC whose disease progresses during initial VEGFr-TKI therapy may continue treatment with a different VEGFr-TKI or they may switch to treatment with a mammalian target of rapamycin (mTOR) inhibitor which has a different mechanism of action. Based on positive results of the phase III RECORD-1 trial, clinical guidelines in the United States and Europe recommend use of everolimus, an mTOR inhibitor, in patients with VEGFr-TKI-refractory mRCC. Positive results of the phase III AXIS trial led to recent approval in the United States of the VEGFr-TKI axitinib for use in patients with mRCC who failed one previous therapy. VEGFr-TKIs and mTOR inhibitors have distinct clinical effects with differing safety profiles, but to date, no head-to-head comparisons in the post-VEGFr-TKI second-line setting are available. This review discusses multiple factors that should be considered when selecting a second-line therapy for patients with VEGFr-TKI-refractory mRCC, including evidence-based guidelines, efficacy, safety, patient profile, and clinician familiarity with available agents.
Background:
Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.
Methods:
Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent.
Results:
Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P=.016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P=.061).
Conclusions:
The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.
Background
The aim of this study was to evaluate the use of sunitinib as third-line therapy for metastatic renal cell carcinoma (mRCC).
Methods
This study included a total of 35 consecutive Japanese patients with mRCC who were treated with third-line sunitinib after sequential use of cytokine therapy (interferon-α and/or interleukin-2) and sorafenib between September 2008 and December 2010. The clinical outcomes of third-line sunitinib in these patients were retrospectively reviewed.
Results
Of the 35 patients, 3 (8.6%), 28 (80.0%) and 4 (11.4%) were judged to have a partial response, stable disease and progressive disease, respectively, as the best response to sunitinib. The median progression-free survival (PFS) and overall survival (OS) of these patients following the introduction of sunitinib were 10.9 and 14.2 months, respectively. Of several factors examined, response to sorafenib and performance status appeared to be independently associated with PFS and OS, respectively, on multivariate analyses. The common grade 3–4 adverse events related to third-line sunitinib were thrombocytopenia (51.4%), neutropenia (42.9%) and hypertension (14.3%).
Conclusion
Despite the low response rate, third-line sunitinib is well tolerated and could provide comparatively favorable prognostic outcomes in Japanese patients with mRCC after first-line cytokine therapy and second-line sorafenib; therefore, treatment with sunitinib could be one on the therapeutic options for patients with mRCC even after the failure of sequentially performed systemic therapies, such as cytokine therapy and sorafenib.
Background
The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer.
Methods
We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392.
Findings
A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544–0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.
Interpretation
Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.
Funding
Pfizer Inc.
The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.
To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.
Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.
Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11).
We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).
Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.
The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.
A better understanding of the molecular biology of renal cell carcinoma (RCC) has led to a dramatic paradigm shift in the treatment of patients with metastatic disease. Historically, a nonspecific immune approach using cytokines was employed, but recently this has transitioned to a molecularly-targeted approach against vascular endothelial growth factor (VEGF) and related pathways. Several anti-VEGF agents, including ligand-binding agents such as bevacizumab and the small molecule inhibitors of VEGF and related receptors such as sunitinib and sorafenib, have demonstrated clinical activity in patients with metastatic RCC. Other agents that inhibit alternative targets such as the mammalian target of rapamycin (mTOR) have also demonstrated activity. This generation of novel molecular targeted therapies continues to show great promise. The purpose of this review is to summarize the current management and to discuss potential future directions in the management of metastatic RCC.
•To conduct a retrospective, multicentre, cohort analysis to assess the sequential use of the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib.
•Records of 189 patients with renal-cell carcinoma (RCC) who were treated with sorafenib and sunitinib sequentially between March 2004 and April 2009 at 12 Italian study centres were analysed. •Patients were treated under European Expanded Access Programmes or, following market approval, in general clinical practice. •Interventions were sorafenib (800 mg/day) and sunitinib (50 mg every day; 4 weeks on and 2 weeks off). •Progression-free survival (PFS) during treatment with the first and second TKI was evaluated.
•In all, 99 patients were treated with sunitinib followed by sorafenib (SuSo) and 90 were treated with sorafenib followed by sunitinib (SoSu); 104 (55%) patients had received prior systemic therapy, mostly with cytokines. •The median (range) PFS on the first TKI was similar between treatment groups [sorafenib 8.4 (1.1-28.9) months; sunitinib 7.8 (0.5-30.4) months; hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.78-1.40, P=0.758]. Multivariate analysis showed that good Memorial Sloan-Kettering Cancer Center status was associated with increased PFS. •After the second TKI, patients in the SoSu group had a longer median PFS than those in the SuSo group (7.9 months vs 4.2 months, respectively; HR 0.54, 95% CI 0.39-0.74, P<0.001). •Multivariate analysis showed only treatment and Eastern Cooperative Oncology Group performance status (and not age, gender, study centre or previous treatment) were significantly associated with duration of PFS.
•Our findings suggest a limited cross-resistance between sorafenib and sunitinib and that the sequence SoSu may result in a longer combined PFS than SuSo. This is the largest retrospective study to date, though its findings are limited in part by the retrospective nature.
A phase 3 trial demonstrated superiority at interim analysis for everolimus over placebo in patients with metastatic renal cell carcinoma (mRCC) progressing on vascular endothelial growth factor receptor-tyrosine kinase inhibitors. Final results and analysis of prognostic factors are reported.
Patients with mRCC (N = 416) were randomized (2:1) to everolimus 10 mg/d (n = 277) or placebo (n = 139) plus best supportive care. Progression-free survival (PFS) and safety were assessed to the end of double-blind treatment. Mature overall survival (OS) data were analyzed, and prognostic factors for survival were investigated by multivariate analyses. A rank-preserving structural failure time model estimated the effect on OS, correcting for crossover from placebo to everolimus.
The median PFS was 4.9 months (everolimus) versus 1.9 months (placebo) (hazard ratio [HR], 0.33; P < .001) by independent central review and 5.5 months (everolimus) versus 1.9 months (placebo) (HR, 0.32; P < .001) by investigators. Serious adverse events with everolimus, independent of causality, in ≥ 5% of patients included infections (all types, 10%), dyspnea (7%), and fatigue (5%). The median OS was 14.8 months (everolimus) versus 14.4 months (placebo) (HR, 0.87; P = .162), with 80% of patients in the placebo arm crossed over to everolimus. By the rank-preserving structural failure time model, the survival corrected for crossover was 1.9-fold longer (95% confidence interval, 0.5-8.5) with everolimus compared with placebo only. Independent prognostic factors for shorter OS in the study included low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).
These results established the efficacy and safety of everolimus in patients with mRCC after progression on sunitinib and/or sorafenib.
To characterize and evaluate the efficacy of second-line therapy in patients who had progressed on initial anti-vascular endothelial growth factor (VEGF) therapy.
Between 2005 and 2007, patients with mRCC who received second-line therapy after 1st-line VEGF-targeted therapy were identified across 7 cancer centers.
A total of 645 mRCC patients received first-line VEGF-targeted therapy, of which 216 patients received second-line VEGF-targeted therapy (sunitinib, n = 93; sorafenib, n = 80; bevacizumab, n = 11; axitinib, n = 8) or mammalian target of rapamycin (mTOR)-inhibiting agents (temsirolimus, n = 21; everolimus, n = 3). On multivariate analysis, a higher baseline Karnofsky performance status score before first-line therapy predicted which patients were more likely to receive second-line therapy (P <.0001). The median time to treatment failure of second-line therapy was 4.9 months for anti-VEGF therapy and 2.5 months for mTOR inhibitors (P = .014) (HR: 0.52, CI: 0.29-0.91 and HR: 0.495, CI: 0.27-0.9 after adjusting for Memorial Sloan-Kettering Cancer Center prognostic factors and histology, respectively). Overall survival from start of second-line therapy was not significantly different (14.2 vs 10.6 months respectively; P = .38).
Baseline Karnofsky performance status is an independent predictor of receiving second-line targeted therapy. Patients who receive a second-line anti-VEGF drug appear to have a similar overall survival to those who receive a second-line anti-mTOR drug.
There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy.
Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS.
The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73.
This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
An open-label, phase II study to evaluate progression-free survival (PFS), overall best response, adverse events (AEs), and patient-reported outcomes with sorafenib versus interferon alfa-2a (IFN-alpha-2a) in patients with untreated, advanced renal cancer.
A total of 189 patients were randomly assigned to oral sorafenib 400 mg twice daily or to subcutaneous IFN-alpha-2a 9 million U three times weekly (period 1). Sorafenib patients who progressed were dose-escalated to 600 mg twice daily; IFN-alpha-2a patients who progressed were switched to sorafenib 400 mg twice daily (period 2).
In period 1 PFS was similar for sorafenib-treated (n = 97; 5.7 months) and IFN-alpha-2a-treated patients (n = 92; 5.6 months); more sorafenib-treated patients had tumor shrinkage (68.2% v 39.0%). Common drug-related AEs (Grades > or = 3) for sorafenib were hand-foot skin reaction (11.3%), diarrhea (6.2%), and rash/desquamation (6.2%); for IFN-alpha-2a, these were fatigue (10.0%), nausea (3.3%), flu-like syndrome (2.2%), and anorexia (2.2%). Sorafenib-treated patients reported fewer symptoms, better quality of life (QOL), and greater treatment satisfaction. In period 2, 41.9% of patients who received sorafenib 600 mg twice daily (n = 43) experienced tumor reduction (median PFS, 3.6 months). After the switch to sorafenib 400 mg twice daily, tumors were reduced in 76.2% of 50 patients (median PFS, 5.3 months). AEs were mostly grade 1 to 2; no increase in AEs of grades > or = 3 occurred after sorafenib dose escalation.
In this study, sorafenib resulted in similar PFS as IFN-alpha-2a in patients with untreated RCC. However, sorafenib-treated patients experienced greater rates of tumor size reduction, better QOL, and improved tolerability. Both dose escalation of sorafenib after progression and a switch to sorafenib after progression on IFN-alpha-2a resulted in clinical benefit.
Sunitinib and sorafenib are small-molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.
Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first-line therapy with either sunitinib or sorafenib and subsequently receiving second-line therapy with the other TKI agent.
Twenty-nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P=.016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P=.061).
The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation.
To identify prognostic factors and a model predictive for survival in patients with metastatic renal-cell carcinoma (RCC).
The relationship between pretreatment clinical features and survival was studied in 670 patients with advanced RCC treated in 24 Memorial Sloan-Kettering Cancer Center clinical trials between 1975 and 1996. Clinical features were first examined univariately. A stepwise modeling approach based on Cox proportional hazards regression was then used to form a multivariate model. The predictive performance of the model was internally validated through a two-step nonparametric bootstrapping process.
The median survival time was 10 months (95% confidence interval [CI], 9 to 11 months). Fifty-seven of 670 patients remain alive, and the median follow-up time for survivors was 33 months. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status (<80%), high serum lactate dehydrogenase (> 1.5 times upper limit of normal), low hemoglobin (< lower limit of normal), high "corrected" serum calcium (> 10 mg/dL), and absence of prior nephrectomy. These were used as risk factors to categorize patients into three different groups. The median time to death in the 25% of patients with zero risk factors (favorable-risk) was 20 months. Fifty-three percent of the patients had one or two risk factors (intermediate-risk), and the median survival time in this group was 10 months. Patients with three or more risk factors (poor-risk), who comprised 22% of the patients, had a median survival time of 4 months.
Five prognostic factors for predicting survival were identified and used to categorize patients with metastatic RCC into three risk groups, for which the median survival times were separated by 6 months or more. These risk categories can be used in clinical trial design and interpretation and in patient management. The low long-term survival rate emphasizes the priority of clinical investigation to identify more effective therapy.
Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.
Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted.
In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E.
325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10.2 months vs 5.4 months; HR 0.63, 95% CI 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]).
The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.
Recent progress in the management of advanced renal cell carcinoma Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study
- Ja Garcia
- Rini
- Lc Harshman
- W Xie
- Bjarnason
- Ga
Garcia JA, Rini BI. Recent progress in the management of advanced renal cell carcinoma. CA Cancer J Clin 2007;57:112–25. 3. Harshman LC, Xie W, Bjarnason GA, et al. Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study. Lancet Oncol 2012;13:927–35.
Retrospective comparison of triple-sequence therapies in metastatic renal cell carcinoma http://dx.doi.org/10.1016/j.eururo
- J Busch
- C Seidel
- B Erber
Busch J, Seidel C, Erber B, et al. Retrospective comparison of triple-sequence therapies in metastatic renal cell carcinoma. Eur Urol 2012. http://dx.doi.org/10.1016/j.eururo.2012.09.004, pii: S0302-2838(12)01027-5.
Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): clinical characteristics, risk factors, and subsequent therapy
- Heng
- Mackenzie Mj Dy
- Vaishampayan
- Un
Heng DY, MacKenzie MJ, Vaishampayan UN, et al. Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): clinical characteristics, risk factors, and subsequent therapy. J Clin Oncol 2011;29(Suppl. 7; abstr. 305).
Sorafenib in advanced clear cell renal-cell carcinoma
- B Escudier
- T Eisen
- Wm Stadler
Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced
clear cell renal-cell carcinoma. N Engl J Med 2007;356:125–34.