Scholarly article on topic 'mRCC management: past, present and future'

mRCC management: past, present and future Academic research paper on "Clinical medicine"

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{"Metastatic renal cell carcinoma" / mRCC / "Therapy management" / "Targeted agents" / Sunitinib / Temsirolimus}

Abstract of research paper on Clinical medicine, author of scientific article — Manuela Schmidinger, Martin Gore, Camillo Porta, Sylvie Négrier, Bernard Escudier

Aims and scope Over the last six years, the use of targeted agents has revolutionised the treatment of metastatic renal cell carcinoma (mRCC) and dramatically improved outcomes for patients. Multiple effective first-and second-line agents are now available or are in development, raising key questions and new challenges around the long-term management of mRCC. These topics were the focus of a Pfizer meeting held at the 7th European International Kidney Cancer Symposium (EIKCS) in Vienna (4–5 May 2012), where leading European oncology experts discussed recent advances and ongoing issues in mRCC clinical practice. ‘It is important for clinicians who see large numbers of patients with this rare disease to get together and share their experience and observations, for the benefit of those who only see few patients in their practice’, said Professor Manuela Schmidinger, Chair of the meeting. This report offers an overview of the critical evidence and the issues of long-term mRCC management debated at the meeting. It also presents key conclusions from the recently launched report ‘Europe 2012: is kidney cancer management at a crossroad?’, written by a selected panel of European kidney cancer experts to highlight current barriers to the optimal treatment of mRCC patients and the development of solutions to address these.

Academic research paper on topic "mRCC management: past, present and future"

ELSEVIER

available at www.sciencedirect.com

•J' ScienceDirect

mRCC management: past, present and future

Highlights of the 'Long-term management of mRCC: Recent advances and ongoing debates' meeting, held at the 7th European International Kidney Cancer Symposium (EIKCS) on 4th May, 2012 in Vienna, and a summary of the 'Europe 2012: is kidney cancer management at a crossroad?' report

Manuela Schmidingera *, Martin Goreb, Camillo Portac, Sylvie Négrierd, Bernard Escudiere

aMedical University of Vienna, Vienna, Austria bRoyal Marsden Hospital, London, UK

cIRCCS San Matteo University Hospital Foundation, Pavia, Italy dUniversity of Lyon 1 and Leon Berard Cancer Centre, Lyon, France eInstitut Gustave Roussy, Villejuif, France

Contents

1. Introduction...................................................................................................... 2

2. Efficacy and experience: key considerations in first-line treatment selection

Presented by Martin Gore (UK) and Manuela Schmidinger (Austria)...................................................... 3

3. Difficult-to-treat mRCC patients: available first-line options and remaining questions

Presented by Camillo Porta (Italy) .................................................................................... 5

4. Optimal sequencing strategies for achieving long-term survival

Presented by Sylvie Negrier (France) .................................................................................. 6

5. Europe 2012: is kidney cancer management at a crossroad? Overview of the report from a panel of European kidney cancer experts.................................................................................................... 8

6. Conclusions...................................................................................................... 9

Acknowledgements ................................................................................................. 9

Conflict of interest statement ....................................................................................... 9

References.......................................................................................................... 10

ARTICLE INFO AIMS AND SCOPE

Keywords: Over the last six years, the use of targeted agents has revolutionised the treatment of

Metastatic renal cell carcinoma metastatic renal cell carcinoma (mRCC) and dramatically improved outcomes for patients. mRCC Multiple effective first- and second-line agents are now available or are in development,

Therapy management raising key questions and new challenges around the long-term management of mRCC.

Targeted agents These topics were the focus of a Pfizer meeting held at the 7th European International

Sunitinib Kidney Cancer Symposium (EIKCS) in Vienna (4-5 May 2012), where leading European

Temsirolimus oncology experts discussed recent advances and ongoing issues in mRCC clinical practice.

'It is important for clinicians who see large numbers of patients with this rare disease to get together and share their experience and observations, for the benefit of those who only see few patients in their practice', said Professor Manuela Schmidinger, Chair of the meeting.

This report offers an overview of the critical evidence and the issues of long-term mRCC management debated at the meeting. It also presents key conclusions from the recently launched report 'Europe 2012: is kidney cancer management at a crossroad?', written by a selected panel of European kidney cancer experts to highlight current barriers to the optimal treatment of mRCC patients and the development of solutions to address these.

© 2012 Elsevier Ltd. All rights reserved.

* Correspondence: Manuela Schmidinger, Medical University of Vienna, Department of Medicine I, Clinical Division of Oncology and Comprehensive Cancer Center, Waehringer Guertel 18-20, A-1090 Vienna, Austria. manuela.schmidinger@meduniwien.ac.at

1359-6349/$ - see front matter © 2012 Elsevier Ltd. All rights reserved.

1. Introduction

The treatment of mRCC has been revolutionised by the development of targeted therapies that have significantly improved progression free survival (PFS) as well as overall survival (OS) for patients compared with the previous standard of care, immunotherapy treatments (Fig. 1).

Targeted agents have revolutionised

patient outcomes in mRCC

THE PAST

High efficacy,

Immunotherapy ^^^^ ONLY 5% of ^^^ Palliative care

patients

THE PRESENT

Multiple targeted Overall survival New era in

greater than 2 ^^^^ kidney cancer

agents ^^^^^ yearsa management

Longer-term survival is becoming a realistic goal

for many patients and their carers

Fig. 1 - Targeted agents have revolutionised patient outcomes in mRCC. In the past, when immunotherapy was the standard of care, only a minority of patients (~5%) derived benefit from it in terms of long-term outcome. Once the disease progressed, there was no other treatment left for those patients. Today, based on an improved understanding of the molecular characteristics of this disease, multiple targeted agents are available, which have been shown to benefit the majority of patients, in terms of response rates and extension of overall survival. a Motzer and Molina1, 2009. Slide courtesy of Manuela Schmidinger, 2012.

Long-term survival is now becoming a realistic goal and as a consequence, the clinical focus is shifting towards maximising the long-term benefits of such therapies by optimising the selection and management of treatment for each individual patient.

On this basis, the Pfizer sponsored meeting at the

7th European International Kidney Cancer Symposium in Vienna (4-5 May 2012) aimed to review the key factors that should guide treatment selection and effective management of the available agents in both first- and second-line treatment settings.

Achieving long-term survival requires careful selection of treatment for each individual patient. What are the most important factors that should guide clinicians in the selection of the most appropriate therapy?

Focusing on optimal first-line treatment, Martin Gore and Manuela Schmidinger, from the Royal Marsden Hospital (London) and the Medical University of Vienna, respectively, highlighted the critical importance of

efficacy and clinical experience as the key drivers of treatment selection. In addition, they reviewed evidence of how practical and effective therapy management strategies are equally critical to ensuring optimal clinical benefit and envisaged the use of certain clinical biomarkers to predict treatment efficacy and further optimise long-term clinical outcomes.

Based on data from currently available agents and results from ongoing studies, Camillo Porta from the IRCCS San Matteo University Hospital Foundation (Pavia) reviewed first-line treatment options for difficult-to-treat patients, such as those with a poor prognosis or non-clear cell histology.

Finally, Sylvie Negrier from the University of Lyon illustrated second-line treatment selection criteria in mRCC patients and discussed the benefits that implementation of rational sequencing approaches can provide to achieving a long-term continuum of care.

As important as treatment selection is ensuring that patients have equal access to the new treatments for mRCC across Europe. In November 2011, an independent panel of European experts in kidney cancer met to discuss the major barriers currently involved in the management of mRCC across Europe. Optimal treatment sequencing, equal access to treatments and education of healthcare professionals emerged as key challenges. Following their meeting, the group published a report entitled 'Europe 2012: is kidney cancer management at a crossroad?' (Fig. 2), with the aim of increasing

Fig. 2 - 'Europe 2012: is kidney cancer management at a crossroad?'

This report is available at www.lh-nierenkrebs.org

the understanding of these challenges, and facilitating improvements in patient treatment, outcomes and experience.

Recommended targeted agents for firstline treatment: Results from pivotal trials

Median PFS Median OS

Agent n (months) (months) ORR (%)

Sunitinib vs IFN-aa 750 11 vs 5 26.4 vs 21.8 47 vs 12

p<0.001 p=0.051 p<0.001

Bevacizumab + IFN-a vs IFN-ab,c 649 10.2 vs 5.4 23.3 vs 21.3 31 vs 13

p<0.0001 p=0.1291 p=0.0001

Bevacizumab + IFN-a vs IFN-ad,e 732 8.5 vs 5.2 18.3 vs 17.4 26 vs 13

p<0.0001 p=0.069 p<0.0001

Pazopanib* vs placebo's 435 11.1 vs 2.8 22.9vs20.5t 30 vs 3t

p<0.0001 p=0.224 p<0.001

Poor-risk patients

Temsirolimusvs IFN-ccht 626 5.5 vs 3.1 10.9 vs 7.3 8.6 vs 4.8

p<0.001 p=0.008 NS

Conditionally approved; includes cytokine refractory and treatment-naive patients; ^Poor-risk patients (modified MSKCC criteria)

Fig. 3 - Recommended targeted agents for first-line treatment: results from pivotal trials. Targeted agents enabled significant improvements in progression free survival compared to immunotherapy, which used to be the standard of care. a Motzer and Molina1, 2009; b Escudier et al.2, 2007;c Escudier et al.3, 2010; d Rini et al.4, 2008; e Rini et al.5, 2010;f Sternberg et al.6, 2010; g Sternberg et al.7, 2010; h Hudes et al.8, 2007. Slide courtesy of Martin Gore, 2012.

2. Efficacy and experience: key considerations in

first-line treatment selection

Martin Gore, Royal Marsden Hospital, London, UK

Martin Gore is the Medical Director of the Royal Marsden Hospital and Professor of Cancer Medicine at the Institute of Cancer Research in London. His main research interests include the development of novel therapeutics in ovarian cancer, melanoma and renal cell carcinoma, particularly in the area of biologics, gene therapy

and novel targeted agents. He is a Medical Advisor to the US Kidney Cancer Association and co-founder of the annual European International Kidney Cancer Symposium.

Manuela Schmidinger, Department of Oncology, Medical University of Vienna, Vienna, Austria Manuela Schmidinger is a Medical Oncologist and Professor of Medicine at the University of Vienna. She is currently Programme Director for mRCC, leading the research programme in the field of kidney cancer and the care of patients with RCC. Her research interests include prognostic factors

and treatment in RCC, mechanisms of tyrosine kinase inhibitor-

related side effects and management of side effects.

What are the key drivers to deciding which agent to use

in the first-line treatment of mRCC? Martin Gore opened his presentation by stating that, for most oncologists, the key driver is clinical efficacy, represented by improved tumour control and prolonged survival.

A wealth of randomised clinical trials investigating the efficacy of targeted agents in the last few years has provided the basis for the creation of first-line treatment

algorithms (Fig. 3).

Guidelines from the European Society for Medical

Oncology (ESMO) and the European Association of Urology (EAU) indicate sunitinib, bevacizumab + IFN-a

and pazopanib (which is conditionally approved in the European Union) as the most efficacious treatments for favourable/intermediate-risk patients, whereas tem-sirolimus is recommended as the current standard of care for poor-risk patients.9,10

A number of new studies will release results in the next 12-18 months and add information on the efficacy and toxicity of targeted agents. First, a phase III study of tivozanib in first- or second-line settings (TIVO-1, n = 517),11 in which the primary endpoint has been reached, showed statistically significant improvement in PFS with tivozanib compared with sorafenib. 12 The COMPARZ study (n = 927),13 a non-inferiority trial of pazopanib versus sunitinib in previously untreated mRCC patients, will provide data in relation to toxicity, although, being a non-inferiority study, it will not provide definitive data on the efficacy of pazopanib in relation to sunitinib. Another upcoming phase III study, PISCES,14 has compared continuous dosing of pazopanib with sunitinib given with a 50 mg 4/2 schedule (4 weeks on treatment followed by 2 weeks off treatment) over a ten week period, assessing patient preference based on toxicity profile (n = 169). Finally, the AGILE phase III study (n = 492),15 comparing axitinib with sorafenib, is expected to produce interesting information on the use of these two agents in both first- and second-line settings.

With a growing number of available first-line targeted agents, how do clinicians achieve optimal therapy? Professor Gore emphasised that the achievement of long-term survival is the combined result of optimal dosing schedules, appropriate management of side effects and treatment duration (Fig. 4).

Q: How can we optimise outcomes and prolong survival with current first-line therapies?

■ A: Effective therapy management

Fig. 4 - How can we optimise outcomes and prolong survival with current first-line therapies? Optimal therapy is the result of (i) optimal treatment dosing; (ii) effective management of side effects; (iii) optimal treatment duration. Schmidinger M, Arnold D, Szczylik C, Wagstaff J, Ravaud A.16 Optimizing the use of sunitinib in metastatic renal cell carcinoma: an update from clinical practice. Cancer Invest 2010;28:856-64. Slide courtesy of Martin Gore, 2012.

'The most critical issue in mRCC clinical practice is the active management of side effects', commented Professor Gore.

'Physicians must carefully assess each individual patient for baseline comorbidities, pre-empt side effects by treating them before the cancer therapy starts, and teach their patients how to best manage the toxicity so that they can achieve long-term results'. In the case of sunitinib, recent studies indicate that dosing adjustments that allow prolonged treatment duration are associated with improved responses.17 This underlies the importance of maintaining long-term exposure to targeted agents that show activity in order to obtain long-term outcomes. Long-term exposure to targeted agents in patients who experience clinical benefit was recently investigated in a multicentre, retrospective analysis looking specifically at a group of mRCC patients who obtained complete remission (CR) during treatment with tyrosine kinase inhibitors (TKIs) sunitinib or sorafenib.18 The majority of CR cases were in patients treated with sunitinib (n = 59, 92%) and the study shows that CR was obtained after at least 12.6 months of treatment (TKI treatment alone), or even longer for patients receiving TKI therapy plus local treatment. 18

When looking at the most frequent side effects associated with targeted agents, there is a real commonality of adverse events (AEs) shared by the firstline agents sunitinib,1 bevacizumab,2,5 pazopanib6 and temsirolimus8 (Fig. 5). These are fatigue, hypertension, diarrhoea and gastrointestinal disorders. Emerging data show that some of the AEs appear to behave as clinical

Most common AEs (>20%) reported with targeted agents for first-line treatment of mRCC

■ Most are mild-to-moderate in intensity

■ Manageable with therapy management strategies

Fatigue, gastrointestinal disorders, decreased appetite, hypertension, HFS, skin discolouration, mucosal inflammation

Bevacizumab/IFN-ab

Anorexia, fatigue/asthenia, haemorrhage, hypertension, influenza-like illness, headache, diarrhoea

Pazopanibd

Diarrhoea, hypertension, hair colour changes, nausea, anorexia, vomiting

Temsirolimus6

(Asthenia, anaemia, rash, gastrointestinal disorders, oedema, metabolic disorders, dyspnoea, cough, bacterial infections

Fig. 5 - Most common side effects of first-line targeted agents. The most common adverse events (>20%) reported with all targeted agents for first-line treatment of mRCC are gastrointestinal disorders, hypertension and fatigue. a Motzer and Molina AM1, 2009; b Rini et al.5, 2010;c Escudier et al.2, 2007; d Sternberg et al.6, 2010; e Hudes et al.8, 2007. Slide courtesy of Martin Gore, 2012.

Summary Box 1

• The development of targeted agents has revolutionised the treatment of mRCC

• Efficacy and clinical experience are both key drivers of treatment selection in the first-line setting

• It is important that targeted agents are effectively managed to obtain optimal clinical outcomes by:

optimising dosing maximising treatment duration effective management of adverse events

• In the future, certain clinical biomarkers may be used to predict treatment efficacy, and thus further optimise clinical outcomes

biomarkers for tumour control as well as OS, in particular hypertension,19 but also myelosuppression,20 hand-foot syndrome,21 and fatigue.22 PFS was shown to be longer in mRCC patients with hypertension treated with sunitinib. 19 Interestingly, the same study also showed that management of hypertension did not affect the efficacy of the treatment. 19 These clinical markers are awaiting validation, but in the future they may be used to predict treatment efficacy and allow further optimisation of clinical outcomes.

Along with efficacy, it is important not to underestimate the role of clinical experience when making appropriate treatment decisions. Professor Schmidinger emphasised that experience plays a critical role when, in addition to Memorial Sloan Kettering Cancer Centre (MSKCC) risk criteria,23 clinicians need to take into account factors that are individual to each patient with the aim of individualising treatment and improving outcomes. These factors include patient lifestyle, quality of life, expectations of therapy, as well as 'real world' clinical and disease-related factors, such as comorbidities, symptoms, and aggressiveness of the disease.

Since the first mRCC targeted agents were introduced back in 2006, growing clinical experience has become crucial when clinicians have to decide when to start first-line treatment, which agent to select, and when to implement effective therapy management, resulting in optimal patient outcome. 'Current treatment guidelines do not tell us when to commence targeted therapy', commented Professor Schmidinger, 'clinical experience allows us to establish the optimal time for each individual patient'.

The case of a 44-year-old patient diagnosed with RCC served to illustrate the importance of clinical experience in first-line treatment selection. The patient was diagnosed with primary metastatic disease in 9 different sites and classified as being at an intermediate risk level, according to MSKCC criteria.23 Based on clinical experience-related considerations, the patient underwent nephrectomy and started therapy with

sunitinib (50 mg, schedule 4/2), which enabled a PFS of more than 16 months and CR of most metastatic lesions.

In conclusion, appropriate therapy management is largely based on real-life clinical experience. 'Management of specific side effects can be challenging for the patients', said Professor Schmidinger 'but clinical experience now enables clinicians to avoid discontinuation of treatment by controlling most side effects with appropriate supportive and prophylactic measures, so as to achieve long-term outcomes'. Importantly, improved outcomes observed in phase III clinical trials of targeted agents are reproducible in the 'real world' clinical practice, where years of clinical experience can now be used to benefit the real patient population.

3. Difficult-to-treat mRCC patients: available first-line options and remaining questions

Camillo Porta, IRCCS San Matteo University Hospital Foundation, Pavia, Italy

Camillo Porta is a Senior Staff Member of the Unit of Medical Oncology at the IRCCS San Matteo University Hospital Foundation in Pavia and Adjunct Professor of Medical Oncology at the School of Biotechnology and the Postgraduate Schools of Medical Oncology and General Surgery at the University of Pavia. His clinical interests include clinical trials in advanced kidney cancer and hepatocellular carcinoma, and the development of new targeted agents.

Optimal treatment options for poor-risk patients, or those with non-clear histologies, are often not widely known or are under-investigated. Temsirolimus is the only agent that has been investigated in a large poor-risk patient population (n = 626), demonstrating impressive benefits in both PFS and OS8 (Fig. 6).

Approximately 20% of all patients with mRCC are categorised as poor-risk according to the MSKCC criteria,23 and temsirolimus is currently the only agent recommended for first-line treatment in poor-risk mRCC patients (ESMO/EAU guidelines), based on the results of the phase III ARCC clinical trial. 8 The ARCC study showed a 49% increase in median OS with temsirolimus compared with IFN-a,8 demonstrating that temsirolimus can significantly improve the OS in patients with such

Phase III evidence: Temsirolimus is efficacious in poor-risk patients with advanced RCC

Time from randomization (months)

Fig. 6 - Phase III evidence: temsirolimus is efficacious in poor-risk patients with advanced RCC. The ARCC study showed a 49% increase in median overall survival with temsirolimus compared with IFN-«. Slide courtesy of Camillo Porta, 2012, from Hudes G, Carducci M, Tomczak P, et a I.; Global ARCC Trial.8 Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N EngI J Med 2007;356:2271-81. © Massachusetts Medical Society.

Summary Box 2

• Temsirolimus is the only agent to date to demonstrate a significant improvement in median overall survival in the poor-risk patient population

• Ongoing studies will help to further optimise first-line treatment in these difficult-to-treat patients

• Promising clinical biomarkers await further development and validation

poor prognosis. The efficacy of other targeted agents in these patients remains largely unproven, although moderate PFS increases have been reported in a small sample population of poor-risk patients following firstline treatment with sunitinib.24

As discussed for intermediate-risk patients, the identification and validation of biomarkers to predict treatment outcomes could also help the implementation of individualised therapy for poor-risk patients. As yet, a few promising clinical biomarkers predictive of temsirolimus efficacy have been reported, including specific molecular components of the mTOR pathway,25 as well as levels of serum LDH,26 cholesterol27 and pneumonitis28. 'It is imperative to concentrate forces into the identification of predictive markers', commented Dr Porta. 'The ability to predict efficacy of treatment would not only limit patient exposure to unnecessary toxicity, but would also enable clinicians to provide patients with more reliable information on the potential benefit of a given treatment'.

4. Optimal sequencing strategies for achieving long-term survival

Sylvie Négrier, University of Lyon 1 and Leon Berard Cancer Centre, Lyon, France

Sylvie Négrier is Professor of Medicine at the University of Lyon and a Medical Oncologist and Director of the Leon Berard Cancer Centre. Her main research interest is the treatment of malignant melanoma and mRCC. She is a member of many organisations, including the European Society for Medical Oncology and is particularly involved with Groupe d'Etudes Francais des Cancers du Rein, where she has acted as principal investigator for several multicentre trials investigating the use of immunotherapy and targeted therapies in solid tumours.

For most mRCC patients, resistance to first-line therapy eventually develops, leading to disease progression. At that stage, clinicians face the very important question of when is the right time to start second-line treatment. Professor Negrier explained that 'disease progression' includes a wide range of clinical scenarios, and therefore

AXIS: Axitinib significantly prolonged PFS vs sorafenib

0 2 4 6 8 10 12 14 16 18 20

Time (months)

Subjects at risk, n

Axitinib 361 256 202 145 96 64 38 20 10 1 0

Sorafenib 362 224 157 100 51 28 12 6 3 1 0

*Axitinib is not currently approved in Europe

Fig. 7 - Axitinib significantly prolonged progression free survival when compared with sorafenib. The AXIS trial investigated the efficacy of the VEGFR inhibitor axitinib versus sorafenib in 723 patients who had previously received sunitinib as firstline treatment. Slide courtesy of Sylvie Negrier, 2012, from The Lancet, Vol. 378, Rini BI, Escudier B, Tomczak P, et a 1.40, Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial, Pages 1931-9, Copyright 2011, with permission from Elsevier.

clinicians need to use a combination of pathological data, clinical assessment and patient individual factors to decide whether disease progression has occurred and a second-line treatment is needed.

Recent evidence suggests that, whereas Response Evaluation Criteria In Solid Tumours (RECIST) are valid to compare drugs in clinical trials and identify primary resistance to targeted therapies, they are not sufficient to define disease progression in real-life clinical practice,29 or to evaluate the efficacy of anti-angiogenic therapies that induce necrosis often without changes in tumour size. 30 Recently developed alternatives to RECIST include functional imaging techniques and dynamic contrast-enhanced ultrasonography, 30 which should allow more precise monitoring of disease progression.

Determining optimum treatment sequencing may help patients to overcome resistance that develops after treatment with first-line agents. Therapy sequencing allows full dosages of targeted agents to be administered, 31 and to avoid toxicity issues that have been observed in combination therapies.32,33 'Optimal sequences have not been identified yet', commented Professor Negrier, 'but a number of ongoing trials investigating different sequence combinations will provide results over the next two years that will hopefully enable clinicians to apply optimal sequencing in reallife clinical practice'. Optimal sequencing strategies also involve ensuring prolonged treatment duration for first-

line treatments that demonstrate activity. 'It is critical to properly manage treatment-associated toxicity to prevent early switching from the most active first-line therapies and fully exploit their potential', explained Professor Negrier.

In therapy sequencing, there is no evidence that a change in mechanism of action following anti-angiogenic targeted agents would result in better outcomes compared with maintaining VEGFR inhibition in the second-line setting. Not only has cross-resistance not been observed with the sequential use of VEGFR inhibitors, but clinical data and meta-analyses indicate that mRCC patients remain sensitive to VEGFR inhibition following first-line anti-angiogenic therapy and toxicity is attenuated.34-39

So far, the only recommended (ESMO/EAU guidelines) second-line treatment option following VEGFR inhibitors is the mTOR inhibitor everolimus. 9,10 However, the VEGFR inhibitor axitinib has recently been shown in the AXIS study 40 to significantly improve PFS in a second-line setting following sunitinib, when compared to sorafenib in patients with treatment-refractory mRCC (n = 723) (Fig. 7).

AXIS is the first head-to-head trial of targeted agents in second-line mRCC and its results support sequencing of TKI to TKI. Axitinib is currently being evaluated by the European Medicines Agency (EMA) as a second-line treatment for mRCC. It is currently considered a

Summary Box 3

• Despite the benefits observed with the currently available first-line agents, resistance to targeted agents eventually develops

• A rational approach to sequencing targeted agents may be used to provide patients with a long-term continuum of care

• Selecting the most appropriate agent to use in a second-line setting should be based on robust clinical evidence

• AXIS, a study that investigates the efficacy of the VEGFR inhibitor axitinib in a second-line setting, is the first head-to-head trial of targeted agents in second-line mRCC

Axitinib significantly improved progression free survival when compared with sorafenib

a/ Axitinib is currently being evaluated by the European Medicines Agency (EMA) as a second-line treatment for mRCC

category 1 recommendation in patients who have failed at least one systemic therapy by the 2012 National Comprehensive Cancer Network (NCCN) Guidelines in the United States. 41

The current availability of multiple efficacious targeted agents means that therapeutic options still exist for patients who have failed first- or second-line therapy. Amongst sequential phase II/III trials that investigated third-line treatment options, RECORD-1 (n = 390) identified everolimus as an active treatment.42-44 Most of the patients in this study (79%) had received two or more prior therapies and almost a third (26%) had previously received two VEGFR inhibitors.44,45 Therefore, these results may provide clinicians with a valid evidence-based option to improve outcomes of mRCC patients in third-line settings.

5. Europe 2012: is kidney cancer management at

Bernard Escudier, Institut Gustave Roussy, Ville-juif, France

Bernard Escudier is the Head of the Im-

munotherapy Unit in the Department of Medical Oncology at the Institut Gustave Roussy in Villejuif. He is the President of 'ARTuR', the French association on renal tumours, and the Head of the French Group of Immunotherapy. His research interests are in the fields of renal carcinoma, melanoma, immunotherapy, as well as the development of new treatment strategies (anti-angiogenic drugs, gene therapy). Professor Escudier is the principal investigator of many clinical trials in renal cell cancer.

A key message emerging from the Pfizer sponsored meeting held at the 7th EIKCS in Vienna this year is

that new targeted treatments and improved survival rates are not only revolutionising mRCC treatment but are also putting forward new questions and challenges to healthcare professionals (HCPs) and kidney cancer patients.

The 'Europe 2012: Is kidney cancer management at a crossroad?' report was developed by an independent expert panel of leading kidney cancer specialists from five European countriesA, following a meeting held in Paris at the end of 2011. The meeting aimed to identify challenges and other critical barriers to optimal mRCC treatment, as well as to propose solutions to improve patient and clinician experience in managing this condition. A number of key issues were identified: guidance to HCPs on new treatment and therapy management strategies; consistent treatment guidelines; equal access to new treatments for patients across Europe and, finally, acknowledgement of the role of patients in optimising therapy outcomes.

5.1. Treatments

The availability of an increasing number of treatment options for kidney cancer means that more guidance is needed for HCPs on how best to optimise treatment through appropriate therapy management. 'mRCC is a relatively rare cancer, and most oncologists outside of expert centres will only see a small number of mRCC patients in a year', said Professor Bernard Escudier. 'There is a need for more HCPs to gain the necessary experience in using the new targeted agents and to address the challenge of educating patients in a new way of treating cancer as a chronic disease that can be controlled by selecting the most appropriate

a crossroad?

A Expert panel:

Bernard Escudier, Head of the Immunotherapy Unit, Institut Gustave Roussy, France

Emilio Esteban Gonzalez, Laboratory of the University Institute of Oncology, Spain

Michael Staehler, Ludwig Maximilians University, Germany

Sergio Bracarda, Ospedale San Donato, Arezzo, Italy

Tom Powles, Consultant Oncologist, Barts and the London, UK

Berit Eberhardt-Wetherington, Das Lebenshaus, Germany

Markus Wartenberg, Das Lebenshaus, Germany

treatment over time', he added. More guidance is therefore needed for HCPs on how to optimise treatment duration and sequencing in order to achieve long-term results for their patients.

5.2. Guidelines and healthcare professional experience

Guidelines play a key role in maintaining high standards of patient care. However, anecdotal evidence has shown that currently available mRCC guidelines are not being widely used by HCPs and tend not to reflect reallife clinical practice. 'It would be expected from academic institutions or drug companies to create widely accepted and comprehensive treatment guidelines, to ensure that the standard of care at non-expert centres is comparable to that at expert institutions', commented Professor Escudier. There is also an urgent need to improve the education of general oncologists, as well as other HCPs involved in oncology (e.g. nurses and radiotherapy specialists). Whereas it will be possible to answer many specific questions with new and improved clinical studies, experience in managing mRCC will be the most important learning tool for HCPs.

5.3. Access to new treatments and patient empowerment

Access to new treatments for mRCC varies considerably throughout Europe compared to the rest of the world. It is imperative that clinicians have access to the most promising new agents to enhance patients' likelihood of survival. For a relatively rare cancer such as kidney cancer, it is currently still being debated whether patients across Europe should be referred only to expert centres or whether high quality clinical experience should be spread to non-expert centres too. Increasing the number of specialised centres across Europe would help to reduce waiting times and the need to travel long distances for treatment. As the prognosis of mRCC patients improves, the number of people living with treatment side effects is increasing, and patients need to be given the right support to help recognise and communicate about their side effects to ensure they achieve optimal efficacy. Patient advocacy groups are vital in supporting the specific needs of mRCC patients, who have access to support groups and online information.

5.4. Conclusions and call to action

Recognising the need to challenge the way clinicians manage mRCC therapy to further improve the outcome for patients, the authors of the report developed a 'Call to Action' that addresses four main areas of unmet needs: • Improve levels of education and disease awareness among all HCPs involved with mRCC management throughout Europe

• Ensure research and development into new targeted therapies and associated biomarkers is prioritised to establish optimal treatment sequencing for mRCC

• Eliminate the disparity in survival rates seen across Europe by ensuring all patients have access to the appropriate mRCC medicines across multiple lines of treatment

• Give more time and emphasis to the management of mRCC as a chronic disease to support people living with side effects as survival rates increase

6. Conclusions

• Efficacy and clinical experience are key drivers of treatment selection in a first-line setting.

• Targeted agents need to be effectively managed to obtain optimal clinical outcomes.

• Clinical biomarkers are under evaluation to understand their potential role in predicting treatment efficacy.

• Temsirolimus is the only agent to date to demonstrate a significant improvement in median overall survival in the poor-risk patient population.

• A rational approach to sequencing targeted agents may be used to provide patients with a long-term continuum of care; robust clinical evidence should guide selection of the most appropriate second-line agents.

7. Acknowledgements

This report contains highlights from presentations delivered by the relevant authors at the Pfizer-sponsored symposium at EIKCS entitled 'Long-term management of mRCC: Recent advances and ongoing debates'. The report includes content based on interviews conducted with the relevant authors at EIKCS. A summary of the 'Europe 2012: is kidney cancer management at a crossroad?' report is also presented and includes content based on an interview conducted with Bernard Escudier, a member of the expert panel responsible for developing the report.

Medical writing support was provided by Silvia Grisendi at Edelman (London, UK) and funded by Pfizer Inc.

8. Conflict of interest statement

Manuela Schmidinger has received honoraria from, and served as a consultant for, Pfizer, Roche, Astellas, GSK and Novartis, and has received research grants from Pfizer and Roche. Martin Gore has served on the speaker bureaus and advisory boards of Roche, GSK, Novartis, Bayer, Pfizer, Schering Plough, Bristol-Myers Squibb, Aveo, AstraZeneca and Astellas. Camillo Porta

has acted as a speaker and/or consultant for Pfizer, Bayer-Schering, Roche, GSK, Novartis, Aveo, Astellas, Boehringer-Ingelheim and Recordati, and has received research funding from Bayer-Schering and Novartis. Sylvie Negrier has received honoraria from Pfizer, GSK and Novartis, and has received research funding from Pfizer, GSK and Novartis. Bernard Escudier has received honoraria from Pfizer, Bayer, GSK, Aveo, Novartis and BMS.

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