Sunitinib for Metastatic Renal Cell Carcinoma: Real-World Data from the STAR-TOR Registry and Detailed Literature Review.

INTRODUCTION: We evaluated the effectiveness and safety profile of the tyrosine kinase inhibitor sunitinib in patients with advanced or metastatic renal cell carcinoma (a/mRCC) in a real-world setting. METHODS: We analyzed data of adult a/mRCC patients treated with sunitinib. Data were derived from the German non-interventional post-approval multicenter STAR-TOR registry (NCT00700258). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated using descriptive statistics and survival analyses for the entire cohort and patient subgroups. RESULTS: A total of 116 study sites recruited 702 patients treated with sunitinib (73.1% male; median age 68.0 years; median Karnofsky index 90%) between November 2010 and May 2020. The most frequent histological subtype was clear cell RCC (81.6%). Sunitinib was administered as first-line treatment in 83.5%, as second line in 11.7%, and as third line or beyond in 4.8% of the patients. Drug-related AEs and serious AEs were reported in 66.3% and 13.9% of the patients, respectively (most common AE: gastrointestinal disorders; 39.7% of all patients). CONCLUSIONS: This study adds further real-world evidence of the persisting relevance of sunitinib for patients with a/mRCC who cannot receive or tolerate immune checkpoint inhibitors. The study population includes a high proportion of patients with unfavorable MSKCC poor-risk score, but shows still good PFS and OS results, while the drug demonstrates a favorable safety profile. The STAR-TOR registry is also registered in the database of US library of medicine (NCT00700258).

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass).

BACKGROUND: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. OBJECTIVE: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. DESIGN, SETTING, AND PARTICIPANTS: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function. INTERVENTION: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. RESULTS AND LIMITATIONS: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36-4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. CONCLUSIONS: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. PATIENT SUMMARY: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.

A Prospectivly Randomized Phase-II Trial of Axitinib versus Everolimus as Second-Line Therapy in Metastatic Renal Cell Carcinoma (BERAT Study).

INTRODUCTION: Inhibition of neo-angiogenesis is a cornerstone of medical treatment in metastatic renal cell carcinoma (mRCC). While 1st line therapies were previously dominated by inhibitors of the vascular endothelial growth factor axis, 2nd line options were less clearly defined. We investigated the role of everolimus (EVE) or a tyrosine kinase inhibitor (TKI) in 2nd line treatment of mRCC patients. METHODS: Key inclusion criteria were measurable mRCC, ECOG 0-1, IMDC risk: good or intermediate and adequate organ function. Patients who progressed on or were intolerant to bevacizumab + interferon were subject for randomization between TKI and EVE treatment. Cross-over occurred at time of progression during 2nd line treatment. Improvement of 2nd line progression-free survival (PFS) rate (PFR) at 6 months from 50% to 65% was the primary endpoint. Secondary endpoints were PFS, total PFS, objective response rate (ORR), overall survival (OS), safety, and patient reported outcomes. RESULTS: In 2012-2015, a total of 22 patients were included. The study was stopped for poor accrual. Ten patients (46%) were randomized to receive 2nd line treatment with EVE (n = 5) or axitinib (n = 4)/sunitinib (n = 1). ECOG 0 was recorded in 20% (EVE) and 60% (TKI). Severe adverse events occurred in approx. 60% in each arm. ORR was 1/5 (20%) for TKI and 0/5 (0%) for EVE. PFR at 6 months was 20% in each arm. Median PFS was 3.7 months (EVE) and 2.2 months (TKI) (hazard ratio [HR] 1.0 [95% confidence interval [CI]: 0.26-3.85]). The OS was comparable between arms HR 1.12 (95% CI: 0.27-4.61). CONCLUSION: The rapid change of the treatment landscape, the limited use of bevacizumab and interferon in 1st line and the duration of 1st line treatment jeopardized BERAT trial recruitment. The small number of patients is a major limitation of our trial. Our observation indicated the poor prognosis in progressive patients and the limited efficacy of TKI or mTOR inhibitors in 2nd line treatment.

[Interdisciplinary recommendations for the treatment of advanced renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des fortgeschrittenen Nierenzellkarzinoms.

In the treatment of advanced renal cell carcinoma, anti-VEGFR tyrosine kinase inhibitors (TKI) have been replaced mostly by immunotherapy combinations with checkpoint inhibitors (CPI), especially in first line therapy. Due to these novel therapies, the prognosis of patients has been improved further. In pivotal studies a median overall survival of 3-4 years has been achieved. TKI monotherapy remains important for patients with low risk, a contraindication against immunotherapy and with regard to the SARS-CoV-2 pandemic.Selection of the correct first line therapy is difficult to answer because there are two CPI-TKI combinations and one CPI-combination. Temsirolimus and the combination bevacizumab + interferon alfa have become less important. In second line therapy, nivolumab and cabozantinib have demonstrated superior overall survival compared to everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second line and further settings. TKI are an option as well, but they have lower supporting evidence. Everolimus has been replaced in the second line setting by these new options. Biomarkers are not available. The German S3 guideline has been updated recently to give better orientation in clinical practice.The question of the optimal sequence is still unanswered. Most second line options were evaluated after failure of anti-VEGF-TKI, but these are only applicable for a minority of patients.The purpose of an interdisciplinary expert meeting in november 2020 was to debate which criteria should influence the therapy. The members discussed several aspects of treating patients with advanced or metastatic RCC, including the SARS-CoV-2 pandemic. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

Pathology and systemic therapy of non-clear cell renal cell carcinoma: an overview.

Introduction: Non-clear cell renal cell carcinoma (nccRCC) represents a highly heterogenous group of kidney cancer entities. As most clinical trials predominantly include patients with clear cell RCC (ccRCC), nccRCC treatment guidelines are mainly extrapolated from recommendations in ccRCC. Here, we review and elucidate current data on the pathologic classification and treatment of nccRCC.Areas covered: This article gives an overview of the WHO classification of RCC, showing the histological diversity of nccRCC and focusing particularly on entities first characterized since 2016, their specific molecular behavior and their role as indicators for hereditary cancer syndromes. In this context, we discuss the available data on nccRCC treatment oprtions such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, cytotoxic chemotherapy, and immune checkpoint inhibitors.Expert opinion: Although nccRCCs are relatively uncommon, entities of this type account for a subgroup of up to 20-25% of all RCCs. Advances in histopathology and molecular genetics, together with evidence gained from retrospective and prospective clinical data, have improved understanding of these tumors in recent years. Nevertheless, selective trials of current and novel therapies including new targeted agents in patients with nccRCC are urgently needed to further improve treatment guidelines.

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Aim: Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients & methods: Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Results: Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Conclusion: Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).

[Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des fortgeschrittenen Nierenzellkarzinoms.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry.

Aim: Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Materials & methods: Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Results: Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Conclusion: Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.

[What is new in the diagnosis and therapy of renal cell carcinoma?] / Was ist neu bei der Diagnostik und Therapie des Nierenzellkarzinoms?

Renal cell carcinomas (RCC) include different tumor entities, of which clear cell RCC is the most common tumor with approx. 75 % followed by the papillary RCC with 10-15 %. RCC are increasingly being diagnosed incidental in the context of abdominal diagnostics from other indications using sonography or cross-sectional imaging.The prognosis of metastatic RCC has improved significantly due to new therapy options, especially through the use of immune checkpoint inhibitors (IO). In the first line, combination therapies of the tyrosine kinase inhibitor (TKI) axitinib with the PD-1 antibody pembrolizumab or the PDL-1 antibody avelumab apply regardless of the risk profile and histological entity, as well as the combination of the CTLA4 antibody ipilimumab with the PD-1 antibody nivolumab in patients with intermediate and high risk as new standards in therapy. The combinations lead to a higher response rate and longer survival. In the second line and subsequent lines, there is no evidence-based data after combination therapies, but drugs can be used that were not yet part of the first-line therapy.

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society.

BACKGROUND: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. METHODS: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. RESULTS: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival. CONCLUSIONS: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.

Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma.

BACKGROUND: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC. METHODS: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65-74 (n = 201) and ≥75 years (n = 63). RESULTS: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and 0.38 (95% CI: 0.18-0.79) for <65, 65-74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54-0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups. CONCLUSIONS: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma has improved significantly. A median overall survival of more than two years is a realistic goal. Immunotherapies with checkpoint inhibitors are new first-line and second-line options. Sunitinib, Pazopanib, Tivozanib and the combination of Bevacizumab + interferon alpha are approved for first-line therapy, regardless of the progression risk score. The use of both the combination Nivolumab + Ipilimumab and Cabozantinib is limited to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with Sunitinib. Temsirolimus is only approved for high-risk patients. Sunitinib and Pazopanib can also be used as second-line options, with the use of Pazopanib being limited to the event of cytokine failure. Nivolumab and Cabozantinib demonstrated superior overall survival compared to Everolimus. Furthermore, the combination of Lenvatinib + Everolimus and Axitinib are approved treatment options in second-line and further settings. Everolimus monotherapy has been replaced by the new options. The question regarding the optimal sequence of treatments is still unanswered. An interdisciplinary expert meeting aimed to discuss the criteria that should be used for therapy. The members discussed several aspects of treating patients with RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented here.

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options.

Non-clear cell renal cell carcinomas (nccRCC) are rare diseases with heterogeneous histopathologically and genetically defined entities. The clinical data on optimal systemic treatments of nccRCC is rather limited. In this review, the current World Health Organization (WHO) classification of nccRCC based on histopathologic and genetic findings is reported. Regarding systemic treatment options, the most commonly used agents are mTOR inhibitors like everolimus or temsirolimus, or tyrosine kinase inhibitors like sunitinib. 2 small randomized clinical trials with nccRCC comparing sunitinib with everolimus revealed a trend towards a better progression-free survival (PFS) and overall survival (OS) in favor of sunitinib. In RCC with predominant sarcomatoid features, both chemotherapy and targeted agents are reported without any preference for outcome. For subsequent lines of therapy, some case reports describe promising effects of PD-1 or PD-L1 inhibitors in nccRCC including sarcomatoid subtype and Bellini duct carcinoma. Currently, nccRCCs are treated similarly to clear cell RCC or, whenever possible, within clinical trials. Clinical trials with immune checkpoint inhibitors are ongoing.

Final Results of a Non-Interventional Study Evaluating the Quality of Life in Second-line Treatment of Metastatic Renal Cell Carcinoma With Everolimus: The EVERPRO Study.

BACKGROUND: This study assessed the quality of life (QoL) and the implication of time effort of everolimus treatment in patients with metastatic renal cell carcinoma (mRCC). METHODS: Adult patients with mRCC were eligible for everolimus treatment after first-line vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors or bevacizumab therapy. The primary end-point, QoL, was assessed by means of the NCCN-FACT FKSI-19 questionnaire. RESULTS: In total, 202 patients (24% of female patients; median age, 71 years) were evaluable for QoL analyses. The median treatment duration was 4.4 months (95% CI, 3.8-5.3) and the median time to progression was 6 months (95% CI, 5.4-7.5). The median FKSI-19 total score remained stable during treatment (52.0 at therapy start, 55.0 at observation end). The median time effort spent on total therapy was 20 hours per patient. Most of the patients stated to have "no limitations," "a little" or "moderate" limitations in their daily, social, and professional lives. Two months after the start of treatment, 65 patients reported none or a little time burden due to therapy. CONCLUSIONS: QoL was maintained during the everolimus therapy and limitations as well as time effort were acceptable for most of the patients. The study supports previous findings on switching mode of action after anti-VEGFR-targeted therapy to a mammalian target of rapamycin inhibitor.

[Interdisciplinary Recommendations for the Treatment of Metastatic Renal Cell Carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms .

Thanks to the use of targeted therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved significantly. A median overall survival of more than 2 years is a realistic claim. These improvements are also reflected in recent discussions about 3 and more lines of therapy.Sunitinib, pazopanib, the combination of bevacizumab and interferon alpha, and temsirolimus are approved for first-line therapy of mRCC. Sunitinib and pazopanib are also approved for second-line therapy, which, for pazopanib, is confined to the use after cytokine failure. Everolimus (after tyrosine kinase inhibitor (TKI) treatment), sorafenib (after cytokines) and axitinib (after treatment with sunitinib or cytokines) are other compounds available for second-line therapy.3 new substances have recently been approved for second-line therapy: Nivolumab, cabozantinib, and lenvatinib combined with everolimus can be used after VEGF-targeted treatment has failed. It is for the first time that targeted immunotherapy and a combination of targeted substances are available for the treatment of mRCC.There is no new insight as to an optimal sequence therapy. Study results from a phase III trial suggest that the sequences sorafenib-sunitinib and sunitinib-sorafenib are equally effective.The purpose of an interdisciplinary expert meeting on RCC was to work out joint treatment recommendations based on current data and clinical experience and to integrate them into clinical routine practice. The results are presented in this publication.

[Systemic therapy of metastatic renal cell carcinoma]. / Systemtherapie des metastasierten Nierenzellkarzinoms.

In metastatic ccRCC , the treatment options in 1st line treatment are still the tyrosinkinase inhibitors (TKI) pazopanib and sunitinib, for patients with low or intermediate risk additionally IFNα/bevacizumab and for high risk patients the mTOR inhibitor temsirolimus. In 2nd line following cytokine therapy, axitinib or pazopanib and following TKI /VEGF directed therapy axitinib or everolimus may be administered. New upcoming agents in RCC are the PD1 antibody nivolumab and the multikinase inhibitor Cabozantinib, which both showed an OS advantage compared to everolimus. After marketing authorization in Europe, these agents should therefore be preferred in 2nd and 3rd line therapy. Further agents are under investigation.

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

BACKGROUND: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option. MATERIALS AND METHODS: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks. RESULTS: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection. CONCLUSION: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu). IMPLICATIONS FOR PRACTICE: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: results of a pooled analysis of non-interventional studies.

AIM: To assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies. PATIENTS AND METHODS: Data from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression). RESULTS: The overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3months (95% confidence interval [CI], 5.9-6.8) for the overall population and 6.4months (95% CI, 5.8-6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5months (95% CI, 5.0-6.1) for the overall population and 5.8months (95% CI, 5.0-6.4) for second-line everolimus population. Best tumour response (n=349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2months (95% CI, 9.0-not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%). CONCLUSIONS: Results of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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/).