What is the optimal therapy for patients with metastatic renal cell carcinoma who progress on an initial VEGFr-TKI?

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.     

Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma

In a comparison of tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin inhibitor (mTORi) in patients with metastatic clear-cell renal cell carcinoma who received a 1st-line TKI for at least 6 months, the TKI-TKI sequence was favored over the TKI-mTORi. Long-term 2nd-line responders were more likely to have received a second TKI and to have been long-term responders to a 1st-line TKI.BackgroundAlthough sequential targeted therapy is standard in patients with metastatic clear-cell renal cell carcinoma (m-ccRCC), the choice of drugs and optimal administration sequence have yet to be established. The objective of this study was to explore whether it is preferable to rechallenge a long-term responder to a first-line tyrosine kinase inhibitor (TKI) with a TKI or whether to switch to a mammalian target of rapamycin inhibitor (mTORi); to determine whether second-line treatment response depends on duration of first-line response (TD1).Patients and methodsRetrospective multicenter study (2004–2011) of 241 consecutive mRCC patients (clear-cell histology) who received a first-line TKI for ≥6 months followed by a second-line TKI (n = 118) or mTORi (n = 123). End points: Progression-free survival (PFS) and time-to-treatment failure (TTF) on second-line therapy. Multivariable full-model: second-line drug, TD1, ECOG-PS before first- and second-line, best objective response (first-line), Fuhrman grade, number of metastatic sites, and presence of bone metastases. Adjustment covariable: International mRCC Database Consortium (IMDC) risk score. Multiple propensity score and missing data methods were used. Any correlation between first-line and second-line PFS was investigated using censored quantile regression models (CQRM).ResultsSequence effect in the overall cohort was in favor of the TKI–TKI sequence over the TKI–mTORi sequence on using TD1 as continuous covariable (HR ≈ 0.75 for PFS and TTF). TKI–TKI superiority was attributed in large part to the 11–22 month (TD1) subgroup of patients which displayed significantly better outcomes [HR ≈ 0.5; median PFS (months): 9.4 (5.9–12.2) versus 3.9 (3.0–5.5), P = 0.003; TTF(months): 8.0 (5.5–11.0) versus 3.6 (3.0–4.6), P = 0.009]. Upon full CQRM, long-term second-line responders were more likely to have received a second TKI than an mTORi and to have been long-term responders to first-line TKI.Conclusionsm-ccRCC patients who remained on first-line TKI between 11 and 22 months benefited from a TKI rechallenge rather than from second-line mTORi.     

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

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

Management of adverse events of targeted therapies in normal and special patients with metastatic renal cell carcinoma

Treatment options for metastatic renal cell carcinoma (mRCC) have evolved very rapidly, as reflected by the approval of the many drugs that have shown efficacy in phase III studies. Approved drugs include tyrosine kinase inhibitors (TKI) such as sunitinib, sorafenib and pazopanib, vascular endothelial growth factor inhibitors such as bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus and everolimus. These biological agents have toxicity profiles that differ from those accompanying current chemotherapeutic agents, but their novelty leads to a lack of exhaustive clinical data regarding related adverse events (AEs), whose symptoms may overlap with those of the chronic illnesses of patients with mRCC such as hypertension, hyperglycemia, and pneumonitis. Hypertension, hypothyroidism, hand-foot syndrome, and fatigue are AEs frequently associated with TKIs; whereas immunosuppression, stomatitis, metabolic alterations, and non-infectious pneumonitis are AEs of mTOR inhibitors. Recommendations for treating these adverse events in patients with mRCC are usually the same as those for the general population. Mild to moderate toxicities may be managed with supportive and pharmacologic interventions, but higher-grade toxicities usually require external specialist consultation, dose reductions, and treatment interruption or discontinuation. Some groups of patients with mRCC, such as frail, elderly patients, and patients with renal or liver dysfunction, require special management of AEs.     

The Efficacy of Lenvatinib Plus Everolimus in Patients with Metastatic Renal Cell Carcinoma Exhibiting Primary Resistance to Front-Line Targeted Therapy or Immunotherapy

BackgroundPatients with primary refractory metastatic renal cell carcinoma (mRCC) have a dismal prognosis and poor response to subsequent treatments. While there are several approved second-line therapies, it remains critical to choose the most effective treatment regimen.Patients and MethodsWe identified 7 patients with clear cell mRCC who had primary resistance to vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) combination therapy. The patients were treated with lenvatinib (a multitargeted TKI) plus everolimus (a mammalian target of rapamycin inhibitor). Among these 7 patients, 2 had prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. We collected the patients' clinical characteristics, molecular profiles, treatment durations, and toxicity outcomes.ResultsThe median time to progression on prior therapies was 1.5 months. Lenvatinib plus everolimus was used either as a second-line (n = 4) or third-line (n = 3) therapy. As best responses, 3 patients had partial responses and 3 achieved stable disease. Patients were followed for ≥17 months; progression-free survival ranged from 3 to 15 months, and overall survival ranged from 4 to 17 months.ConclusionThese 7 cases provide real-world data for the use of lenvatinib plus everolimus in patients with mRCC with primary resistance to first-line VEGF-targeted TKIs or ICI combination therapy.     

Sequential therapy with targeted agents in patients with advanced renal cell carcinoma: Optimizing patient benefit

Multiple targeted agents are now available for the treatment of patients with metastatic renal cell carcinoma (mRCC). Although targeted agents offer improvements over previous treatments and significantly prolong progression-free survival, most patients eventually experience disease progression. For these patients, sequential treatment with multiple lines of therapy may afford sustained clinical benefit. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) are recommended as first-line therapy for most patients with mRCC. Current clinical practice guidelines uniformly recommend treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus after initial VEGFr-TKI failure. Recent results of the AXIS phase 3 trial demonstrated improved efficacy with second-line axitinib compared with sorafenib in patients who progressed on a variety of first-line therapies, including the VEGFr-TKI sunitinib. Available clinical evidence, individual patient profile, and toxicity concerns should be carefully evaluated when deciding whether to administer an mTOR inhibitor or a second VEGFr-TKI after progression on a first-line VEGFr-TKI. In patients who progress on a VEGFr-TKI and an mTOR inhibitor, retrospective analyses indicate that treatment with a second VEGFr-TKI in the third-line setting provides additional clinical benefit. Recent results from a prospective phase 1/2 trial indicate that third-line therapy with the investigational TKI, dovitinib, may have promising efficacy in patients who progress on a VEGFr-TKI and an mTOR inhibitor; a phase 3 trial of dovitinib versus sorafenib in this patient population is ongoing. This review discusses and evaluates current clinical evidence for sequential therapy with targeted agents in patients with mRCC.     

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

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

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

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

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC

BackgroundRECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points.Patients and methodsPatients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored.ResultsAt final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1–26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus [hazard ratio (HR)_{EVE-SUN/SUN-EVE}, 1.2; 95% CI 0.9–1.6]. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HR_{EVE-SUN/SUN-EVE}, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences.ConclusionsResults of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals.Clinical Trials numberClinicalTrials.gov identifier, NCT00903175     

Efficacy and safety of axitinib in elderly patients with metastatic renal cell carcinoma

The objective of this study was to analyze the impact of age on clinical outcomes of metastatic renal cell carcinoma (mRCC) patients receiving axitinib. This study included 144 consecutive mRCC patients who received axitinib for at least 12 weeks as second-line therapy in a routine clinical setting. The efficacy, safety and quality of life (QOL) were compared between patients aged <75 (n = 116) and ≥75 (n = 28) years. No significant differences in the clinicopathological characteristics were noted between younger and older patients. There was no significant difference in the response rate, clinical benefit rate or proportion of patients going on to receive third-line therapy between these two groups. In addition, the progression-free and overall survivals in older patients were similar to those in younger patients. There were no significant differences in the incidences of adverse events between these two groups, except for that of fatigue, which was significantly more frequent in older than younger patients. There was no significant difference in the incidence of the discontinuation of axitinib due to adverse events between the two groups. QOL assessment at 12 weeks after the introduction of axitinib using the Medical Outcomes Study 36-Item Short Form showed no significant differences in any of the eight scale scores between the two groups. Taken together, it might be possible to achieve clinical outcomes in older patients receiving axitinib comparable to those in younger patients, suggesting that advanced age should not be a contraindication to treatment with axitinib as a second-line setting in mRCC patients.     

Activity of Systemic Treatments After Cabozantinib Failure in Advanced Metastatic Renal Cell Carcinoma

BackgroundCabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated.Materials and MethodsWe conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pretreated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR).ResultsAmong 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and 2 patients with axitinib and 2 patients treated with Immune checkpoint inhibitors achieved a partial response.ConclusionOverall, activity of systemic therapies after cabozantinib was limited.     

Are Tyrosine Kinase Inhibitors Still Active in Patients With Metastatic Renal Cell Carcinoma Previously Treated With a Tyrosine Kinase Inhibitor and Everolimus? Experience of 36 Patients Treated in France in the RECORD-1 Trial

BackgroundBecause the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence.Patients and MethodsData were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence.ResultsThirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease) was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months), and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting.ConclusionsAdministration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.     

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial

BackgroundAxitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.Patients and MethodsAXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.ResultsOf 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.ConclusionIn patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.     

索拉非尼治疗转移性肾癌的疗效与安全性观察

目的:评估63例转移性肾细胞癌（metastatic renal cell carcinoma,mRCC）患者服用索拉非尼的疗效及安全性。方法:前瞻性观察2010年6月至2018年6月就诊于西安交通大学第一附属医院肿瘤内科及中华慈善总会索拉非尼援助赠药项目mRCC患者共计71例,其中63例可评价疗效及安全性。使用SPSS 18.0 软件进行K-M单因素生存分析,所得阳性因素导入COX回归模型进行多因素分析,明确影响索拉非尼治疗mRCC疗效的因素。结果:63例可评价mRCC患者中,无CR患者,PR 18例,SD 22例,PD 23例,ORR为28.57%（18/63）,DCR为63.49%（40/63）;中位PFS为14月（3~51月）,中位OS为29月（6~69月）;所有不良反应均可控或随剂量减少而降低。索拉非尼作为mRCC一线治疗者39例,二线及以上治疗者24例。一线和二线及以上治疗的ORR及DCR均无统计学差异,且中位PFS分别为24月（4~51月）和13月（3~42月）（P=0.021）。COX回归分析示,索拉菲尼是否为一线治疗是影响PFS的独立危险因素（P=0.030）。结论:索拉非尼治疗mRCC疗效确切,不良反应较少,并且是否为一线治疗是影响患者中位PFS的独立预测因素。     

Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer

Lenvatinib is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors 1–3, fibroblast growth factor receptors 1–4, RET, KIT, and platelet-derived growth factor receptor-α. Lenvatinib is approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the second-line treatment of advanced renal cell carcinoma. Lenvatinib is also under investigation for the treatment of several malignancies including unresectable hepatocellular carcinoma. Although lenvatinib is associated with favorable efficacy, it is associated with adverse events (AEs) that the clinician will have to closely monitor for and proactively manage. Most of these AEs are known class effects of VEGF-targeted therapies, including hypertension, diarrhea, fatigue or asthenia, decreased appetite, and weight loss. This review summarizes the safety profile of lenvatinib and offers guidance for the management of both frequent and rare AEs. We discuss the potential mechanisms underlying these AEs and present practical recommendations for managing toxicities. The development of treatment plans that include prophylactic and therapeutic strategies for the management of lenvatinib-associated AEs has the potential to improve patient quality of life, optimize adherence, minimize the need for dose reductions, treatment interruptions, or discontinuations, and maximize patient outcomes.     

Everolimus: side effect profile and management of toxicities in breast cancer

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.     

Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)

BackgroundRECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting.MethodsPatients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis.ResultsEnrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7–11.0]; in the cohorts, it was 5.7 months (95% CI 3.7–11.3) with previous sunitinib, 7.8 months (95% CI 5.7–11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6–not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0–NE) and, in the cohorts, it was 23.8 months (95% CI 13.7–NE) with previous sunitinib, 17.2 months (95% CI 11.9–NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9–NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug).ConclusionsThese results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience.Clinical trial name and identifierEverolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.     

Comprehensive overview of the efficacy and safety of sorafenib in advanced or metastatic renal cell carcinoma after a first tyrosine kinase inhibitor

We performed a literature search that shed light on the signaling pathways involved in the sorafenib activity as first- or subsequent-line treatment, taking into account its toxicity profile. Sorafenib appears to have better tolerability when compared with other agents in the same indication. Cross-resistance between tyrosine kinase inhibitors (TKIs) may be limited, even after failure with a previous VEGFR inhibitor, but the optimal sequence with TKIs remains to be determined. Randomized trials of second-line treatment options have showed either modest or no differences in terms of progression-free and overall survival (OS). Direct comparison between sorafenib and axitinib demonstrated differences in terms of PFS in favor of axitinib, but not in terms of OS as second-line treatment. In contrast, a phase III study showed a benefit in OS, favoring sorafenib when compared with temsirolimus. In conclusion, after using other VEGF inhibitor such as sunitinib, sorafenib is active and safe for the treatment of patients with advanced or metastatic RCC.     

Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre

BackgroundAxitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials.MethodsA prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored.ResultsOne-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in 38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n = 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF.ConclusionEfficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy.     

Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma

Purpose

In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities.

Results

The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit.