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CPD 4: RENAL CELL CARCINOMA Biography - Dr Ray McDermott commenced his training in Medical Oncology at the Mater Hospital, Dublin during which time he completed an MBA in Health Services Management. He went on to The Institut Curie, Paris (2000-2002) where he completed a PhD in Tumour Immunology. He subsequently completed his clinical training at Fox Chase Cancer Center, Philadelphia (2002-2004), where he furthered an interest in Genito-Urinary Oncology. During this training period, he published over twenty peer reviewed articles and Book Chapters. He took up a post as Consultant Medical Oncologist at the Adelaide Meath & National Childrens Hospital, Tallaght in July 2004. In 2006, Dr McDermott was instrumental in establishing Ireland as a main member of the Eastern Co-Operative Group, the largest clinical trials group in the USA with over 70 active studies. Dr McDermott is the Principal Investigator for Ireland in this initiative and is involved in twice yearly meetings with ECOG to develop this relationship. Dr McDermott is currently Vice-Chair of ICORG, the Irish Clinical Oncology Research Group.

60 Second Summary Renal cell carcinoma is the second most common urological malignancy and accounts for up to 3% of all new cancer diagnoses worldwide. Up to 40% of cases are at an advanced stage at the time of diagnosis. The median age at diagnosis is 66 years, with a male preponderance of two to one. It is estimated that 10% to 40% of RCCs present with one of a wide range of paraneoplastic syndromes. These include constitutional symptoms such as cachexia or pyrexia; specific metabolic and biochemical abnormalities such as hypercalcaemia; hypertension or polycythaemia; or Stauffer's syndrome, a syndrome of nonmetastatic hepatic dysfunction. RCCs are highly resistant to conventional cytotoxic chemotherapy. With early stage disease, radical nephrectomy is the treatment of choice. There is currently no role for adjuvant therapy in resected RCC although studies are ongoing. Pharmacologic intervention is reserved for recurrent or advanced disease, where the aim of treatment is predominantly palliative and non-curative in nature. Axitinib is another anti-VEGF TKI recently licensed for use in the second-line setting based on the Phase III AXIS study. This study randomized 723 previouslytreated patients to receive either axitinib or sorafenib. Axitinib demonstrated superior progression-free survival of 8.3 months compared to 5.7 months for sorafenib. As RCC is a highly vascular malignancy, an anti-angiogenic approach still remains as the most efficacious strategy to date. Other anti-VEGF TKIs in various stages of clinical investigation included dovitinib, tivozanib and nintedanib.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice. 2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area. 3. PLAN - If I have identified a knowledge gap - will this article

satisfy those needs - or will more reading be required? 4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs? 5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings.

Published by HPN, sponsored by Pfizer Healthcare Ireland. Copies can be downloaded from www. irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.

Written by: Dr Min Yuen Teo, Research Registrar, Medical Oncology and Dr Ray McDermott, Medical Oncologist

Management of Advanced Renal Cell Carcinoma INTRODUCTION Renal cell carcinoma is the second most common urological malignancy and accounts for up to 3% of all new cancer diagnoses worldwide1. Up to 40% of cases are at an advanced stage at the time of daiagnosis2. The median age at diagnosis is 66 years, with a male preponderance of two to one3. The Irish National Cancer Registry recorded 405 cases of RCC in 20074 and the incidence of the disease has been gradually increasing over the last three decades. Although some of this increase may be accounted for by earlier detection of asymptomatic tumours through advanced imaging modalities, it would appear that other factors are also implicated5. Traditionally this has been a difficult disease to treat, with many patients diagnosed succumbing to their illness due to a lack of effective therapies. This situation is now changing as we gain understanding of the underlying disease process. CLINICAL PRESENTATION The classic triad of haematuria, flank pain and a palpable mass

occurs in less than 10% of cases6. An increasing percentage of RCCs are now diagnosed at an early-stage, often picked up incidentally during radiological assessment for other reasons5. More advanced cases may present with non-specific constitutional symptoms such as weight loss, or pyrexia of unknown origin7. Other manifestations depend on the sites of metastatic disease. It is estimated that 10% to 40% of RCCs present with one of a wide range of paraneoplastic syndromes. These include constitutional symptoms such as cachexia or pyrexia; specific metabolic and biochemical abnormalities such as hypercalcaemia; hypertension or polycythaemia; or Stauffer’s syndrome, a syndrome of nonmetastatic hepatic dysfunction8 STAGING AND PROGNOSIS RCCs are staged according to the AJCC classification of malignant tumours (TNM)9. Fiveyear survival ranges from 90% in stage I disease (disease confined to kidneys) to 20% in stage IV (metastatic disease) RCCs.4

AJCC TNM-staging, tumour size, nuclear grade and the presence of a sarcomatoid component are significantly associated with poorer outcomes in all renal cancer histologic subtypes. In the metastatic setting, Motzer el al devised a prognostic model based on the presence or absence of certain variables, namely poor performance status, a time from diagnosis to treatment of less than one year, haemoglobin level less than normal, serum lactate dehydrogenase (LDH) over 1.5 times normal, and an elevated serum calcium. Patients were stratified into one of three groups depending on the number of risk factors present. (Good risk – no risk factors; Intermediate risk – one to two risk factors; Poor risk – three or more risk factors). They demonstrated substantial differences in survival between these groups, ranging from five months in the poor risk group to 30 months in the good risk group10. Their findings were subsequently validated by Mekhail et al who added prior nephrectomy and the number of metastatic sites as independent prognostic factors11.

Continuous Professional Development Modules are sponsored by Pfizer Healthcare Ireland Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.


CPD 4: RENAL CELL CARCINOMA

standard of care in metastatic RCC. However, treatment with sunitinib is not without its toxicities. Higher rate of grade 3 or 4 fatigue, diarrhoea, hypertension and hand-foot syndrome have been reported. An expandedaccess study of sunitinib included patients who would otherwise have been excluded from clinical trials and demonstrated similar efficacy in cytokine-treated patients, and patients over 65 years. Less marked benefits were seen in patients with poor performance status, brain metastases and nonclear cell histology.17

PHARMACOLOGIC MANAGEMENT OF ADVANCED RCC – PAST AND PRESENT RCCs are highly resistant to conventional cytotoxic chemotherapy. With early stage disease, radical nephrectomy is the treatment of choice. There is currently no role for adjuvant therapy in resected RCC although studies are ongoing. Pharmacologic intervention is reserved for recurrent or advanced disease, where the aim of treatment is predominantly palliative and non-curative in nature. Historically, immunotherapy has been the mainstay of therapy but it has proven to be beneficial only in a small number of patients. A Cochrane review of immunotherapy in RCC showed an overall response rate of only 12.4% and median survival of 13 months12. Interferon-alfa (IFN-α) offers modestly improved survival of three months over control although the survival benefit may be preferentially imparted to patients without adverse prognostic factors. More importantly, patients treated with IFN-α experience quite significant toxicity, notably flu like symptoms and fatigue.

High-dose interleukin-2 (IL2) has demonstrated a superior response rate of 20% compared to interferon and has been associated with some durable remissions, however, there is substantial treatment-related toxicity, meaning that it can only be administered in selected specialist centres. Until relatively recently, patients who did not have a response or whose disease progressed after first-line cytokine therapy had no other viable options for treatment. Capitalising on the elucidation of molecular pathways important in the pathogenesis of clear cell RCC, a number of targeted agents have been developed. Table 1 outlined the ESMO recommendation for treatment of advanced RCC. ANTI-ANGIOGENIC AGENTS A paradigm-shifting phase III trial was reported in 2006 comparing sunitinib, an orally-administered small-molecule tyrosine-kinase inhitor (TKI) targeting VEGF with IFN-α. The trial recruited 750 patients and demonstrated a significant improvement in progression-free survival of 11 months versus five months, and overall response rate of 40% versus 8%,16 thus firmly establishing sunitinib as the

Pazopanib is another anti-VEGF TKI with significant activity in the first-line setting. In a Phase III study with over 435 patients, pazopanib demonstrated superior progression-free survival compared to placebo in both treatment-naive and cytokinepretreated patients, at 9.2 – 11.1 months. Numerically, these figures were comparable to sunitinib, and this led to the subsequent COMPARZ study. Only recently reported, this study showed that pazopanib was similar to sunitinib in terms of efficacy, with a more tolerable toxicity profile. Sorafenib is also an oral small-molecule TKI but with a different range of targets and toxicity profile. Escudier et al compared sorafenib to bestsupportive care in 904 cytokine pre-treated patients, showing a statistically-significant increment in progression-free surival of 5.5 months versus 2.8 months, albeit with increased toxicity.18 This led to approval of sorafenib as secondline treatment. Benefits again appear limited to the clear cell population. Axitinib is another anti-VEGF TKI recently licensed for use in the second-line setting based on the Phase III AXIS study. This study randomized 723 previously-treated patients to receive either axitinib or sorafenib. Axitinib demonstrated superior progression-free survival of 8.3 months compared to 5.7 months for sorafenib. However, the gain in progression-free survival was more marked in patients who received prior cytokines than patients who received previous anti-VEGF TKI (predominantly sunitinib). This study was notable

for the feasibiliy of up-titrating dosage of axitinib in the absence of toxicity (Reference). Bevacizumab, a monoclonal antibody targeting VEGF is administered intravenously. Two trials with more than 1,300 patients collectively compared the efficacy of interferon-alfa with and without bevacizumab. The results significantly favoured bevacizumab with a median progression-free survival between 8.5 and 10.2 months 20,21 closely resembling that of sunitinib and reaffirming the role of anti-angiogenic agents in the treatment of advanced renal cell cancer. mTOR INHIBITORS Mammalian target of rapamycin (mTOR) kinase is a component of intracellular signalling pathways involved in the growth and proliferation of cells and the response of such cells to hypoxic stress.22 Temsirolimus an inhibitor of mTOR admistered intravenously on a weekly basis. In a phase III trial, Hudes et al divided 626 patients with poor-risk RCC to receive either interferon-alfa alone, temsirolimus alone, or interferon-alfa in combination with temsirolimus. The results demonstrated a statistically significant improvement in progression-free survival at 1.9, 3.9 and 3.9 months respectively, and median survival of 7.3, 10.9 and 8.4 months respectively.22 Furthermore, more than 20% of the patients had non-clear cell histologic subtype. Temsirolimus has thus been recognised as an acceptable first-line option for poor-risk patients and non-clear cell subtypes. Everolimus / RAD001 is an orallyavailable mTOR inhibitor. The phase III RECORD-I trial involving 416 patients compared everolimus to placebo in patients previously treated with a VEGF TKI, and showed progression-free survival of five months compared to less than two months for placebo.23 mTOR inhibitors are generally quite well tolerated, Most commonly reported severe adverse effects are predominantly fatigue, anaemia and hyperglycaemia MANAGEMENT STRATEGIES The availability of such a range of

Continuous Professional Development Modules are sponsored by Pfizer Healthcare Ireland Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.


CPD 4: RENAL CELL CARCINOMA

therapeutic options has translated into better outcomes for patients, although many will still die of their disease. In a recent report by Heng et al on survival in metastatic RCC in the era of targeted therapy, the median overall survival for the good and intermediate risk groups had not yet reached after a median follow-up of 24.5 months, while the median overall surival for the poor risk group remained sub-optimal at 8.8 months.24 Various strategies and approaches have been adopted to improve outcomes of these patients. These include newer and more efficacious agents, combination of currently available agents and optimising sequencing of available therapies. NEW AGENTS As RCC is a highly vascular malignancy, an anti-angiogenic approach still remains as the most efficacious strategy to date. Other anti-VEGF TKIs in various stages of clinical investigation included dovitinib, tivozanib and nintedanib. Interests in immunotherapy were recently reignited following data from early phase trials of nivolumab, a monoclonal antibody against Programmed Death-1 (PD-1), an immune checkpoint protein found on immune cells and tumour cells. In a dosefinding phase I study, 33 of 296 enrolled patients had advanced RCC and were heavily pre-treated. Objective response rates from 24 – 31% were observed, with some patients experiencing prolonged response to treatment. This had led to a phase III study comparing nivolumab to everolimus in the second or third line setting. The study is currently open in a number of Irish centres. COMBINATION The three main classes of drugs used in the management of advanced renal cell carcinoma - immunotherapy, anti-VEGF agents and mTOR inhibitors, have differing modes of action. This knowledge has led to interest in combination therapies, exemplified by recent success of such a strategy in breast cancer13. Attempts at combination of VEGF blockade and mTOR inhibition have met with limited success due to overlap in their toxicity

profiles. The TORAVA study was a three-arm randomized phase 2 study pitting bevacizumab plus temsirolimus against sunitinib or bevacizumab plus interferon. The experimental arm reported inferior progression-free survival. Over 40% of patients stopped treatment secondary to toxicity, with a rate of grade 3 & 4 toxicity in excess of 70%14. During the ESMO Congress 2012, two other combination studies were reported in abstract form. The INTORACT study investigated temsirolimus plus bevacizumab while the RECORD-2 examined everolimus plus bevacizumab. Both studies had interferon plus bevacizumab as the control arm, and neither demonstrated superiority of the novel combinations. SEQUENCING Although new therapeutic options for patients with advanced RCC are in use, and more are likely to become available in the coming years, the optimal way to these agents sequentially remain underinvestigated. Amongst anti-VEGF TKIs, the ideal sequencing of existing agents is not clear. Although the target is the same, these drugs differ in their affinity for this target and also in their promiscuity for other targets. This is manifest in the toxicities associated with each VEGF TKI which vary significantly. In addition to targeting VEGF, Sorafenib also targets RAF kinase which may be important in other cancer types. Retrospective data have indicated that within a sequential regimen, progression-free survival can be improved by using Sorafenib as first-line therapy followed by sunitinib15-17 rather than the other way around. Data is more limited on sequential use of other VEGF TKIs. The AXIS study compared axitinib with sorafenib as second line therapy and recruited over 700 patients. Fifty-four percent of patients on each arm received prior sunitinib and reported progression-free survival of 4.8 and 3.4 months, respectively18, which was comparable to retrospective sorafenib data17, 19, 20. Other anti-VEGF molecules which have shown activity as second-

line therapy included linifanib21 and pazopanib22, the latter is also the subject of an current phase 2 ICORG investigation (NCT01566747). The largest dataset for mTOR inhibitors in sequence comes from the RECORD-1 study23. Preplanned subgroup analysis from the RECORD-1 study showed that everolimus demonstrated activity following either one or two lines of VEGF blockade24 with progression free survival similar to that seen with Axitinib in second line use. More recently, RECORD-3 was reported in abstract form at the 2013 ASCO Annual Meeting. Patients were randomised to either sunitinib or everolimus, with a planned switch to the other agent on disease progression. Everolimus demonstrated significantly shorter progression-free survival in first line treatment. Second-line sunitinib was not able to make up for lost time and although the data was still immature, everolimus as first-line treatment showed a trend towards inferior overall survival. This supports the VEGF-mTOR sequence in clinical practice. For the proportion of patients who retain a good performance status, management upon progression beyond available agents poses a significant challenge. Small retrospective studies suggest that anti-VEGF rechallenge following everolimus resistance may be effective28, 29, however, new agents with alterantive mechanisms of action are required. ADJUNCTIVE THERAPIES Skeletal metastases affect up to one third of all patients with metastatic renal cell carcinoma. In an analysis of over 800 patients, 32% of patients were afflicted with osseous metastasis, half of which were present at diagnosis and the remainder of which developed bony involvement during the course of their illness30. It was estimated that each patient with bone metastasis experienced 2.4 skeletal-related events, most commonly bony pain necessitating radiotherapy (60.9%), fractures (20%) and malignant cord or nerve root compression (11%)30. Indeed, it has been suggested -based on analysis of over 200 cases of

advanced disease- that osseous involvement by metastatic renal cell carcinoma is a poor prognostic indicator, predicting shorter progression-free survival and poorer overall survival31. Bisphophonates such as zoledronic acid have been shown in multiple tumour types to reduce skeletal-related events. In a subset analysis of renal cell cancer cases which constituted 10% of the entire cohort, zoledronic acid reduced the average rate of skeletal-related events and significantly prolonged time to first event32, 33. Keizman and colleagues also reported that biphosphonates in renal cell carcinoma might improve progression-free and overall survival in a retrospective study34. CONCLUSION The landscape of renal cell carcinoma has changed significantly since 2004, with the introduction of several active targeted therapies. As we move beyond the initial phase of familiarising ourselves with these new agents, their cytostatic properties and different sideeffects profiles, larger questions have begun to present themselves. Adjuvant therapy has historically been ineffective in renal cell carcinoma, and the reproducibility of the activity of targeted therapies in the adjuvant setting remains to be elucidated. In the management of metastatic renal cell carcinoma, combination approaches have been confounded by limited efficacy and substantial toxicity. Sequential monotherapy has become the mainstay of day-to-day clinical practice. Primary refractory disease and osseous metastases have been recognised as poor prognostic indicators. The treatment of advanced renal cell carcinoma appears set to become more complex with further anti-VEGF agents at an advanced stage, and new agents with different targets in development. While the goal of cure remains elusive, trials examining optimisation of existing agents and efficacy of new therapies represent a critical step forward.

Continuous Professional Development Modules are sponsored by Pfizer Healthcare Ireland Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.


CPD 4: RENAL CELL CARCINOMA

Histology and Setting

Risk Group

N

Standard

Option

Clear Cell Good or Intermediate Risk Sunitinib 1st Line

Bevacizumab + Interferion

Cytokines (including high-dose IL2) Sorafenib

Pazopanib

Poor Risk

Temsirolimus

Sunitinib

Sorafenib

Sunitinib

Clear Cell Post-cytokines 2nd Line

Sorafenib

Pazopanib

Axitinib

Post-TKIs

Everolimus

Sorafenib

Axitinib

Clear Cell Post-2 TKIs Everolimus 3rd Line Non-Clear Cell

Temsirolimus

Sunitinib

Sorafenib

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11. Mekhail T, Abou-Jawde R, BouMerhi G. … prognostic factors model for survival in patients with previously untreated metastatic renal …. Journal of Clinical Oncology 2005. 12. Coppin C. Immunotherapy for renal cell cancer in the era of targeted therapy. Expert Rev Anticancer Ther 2008;8:907-19. 13. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormonereceptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9. 14. Negrier S, Gravis G, Perol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol 2011;12:673-80. 15. Merseburger AS, Simon A, Waalkes S, Kuczyk MA. Sorafenib reveals efficacy in sequential treatment of metastatic renal cell cancer. Expert Rev Anticancer Ther 2009;9:1429-34. 16. Porta C, Szczylik C, Escudier B. Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: A critical review. Critical reviews in oncology/hematology 2011. 17. Porta C, Tortora G, Linassier C, et al. Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement. Medical Oncology 2011. 18. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011;378:1931-9. 19. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with

sorafenib and sunitinib in renal cell carcinoma. Cancer 2009;115:61-7. 20. Sablin MP, Negrier S, Ravaud A, et al. Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma. The Journal of urology 2009;182:29-34. 21. Tannir N, Wong Y, Kollmannsberger C, et al. Phase II trial of linifanib in patients with advanced renal cell cancer (RCC) after sunitinib failure. . Journal of Clinical Oncology 2010;28, No 15 Suppl (May 20 Supplement), 2010: Abstr 4527. 22. Reeves JA, Spigel D, Daniel DB, Friedman EK, Burris HA, Hainsworth JD. Pazopanib in patients with metastatic renal cell carcinoma previously treated with sunitinib or bevacizumab: A Sarah Cannon Research Institute phase II trial. . Journal of Clinical Oncology 2011;29, No 15 Suppl (May 20 Supplement), 2011: Abstr 4659. 23. Motzer RJ, Escudier B, Oudard Sp, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma. Final results and analysis of prognostic factors 2010;116:4256-65. 24. Calvo E, Escudier B, Motzer RJ, et al. Everolimus in metastatic renal cell carcinoma: Subgroup analysis of patients with 1 or 2 previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies enrolled in the phase III RECORD-1 study. European Journal of Cancer 2012;48:333-9. 25. Gerullis H, Bergmann L, Maute L, et al. Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma. Medical Oncology 2009;27:373-8. 26. Grundbichler M, Mlineritsch B, Ressler S, et al. Efficacy of Temsirolimus after Previous Treatment with Sunitinib, Sorafenib or Everolimus in Advanced Renal Cell Cancer. Oncology 2011;80:34-41.

27. MacKenzie MJ, Rini BI, Elson P, et al. Temsirolimus in VEGF-refractory metastatic renal cell carcinoma. Annals of Oncology 2010;22:145-8. 28. Grünwald V, Seidel C, Fenner M, Ganser A, Busch J, Weikert S. Treatment of everolimusresistant metastatic renal cell carcinoma with VEGF-targeted therapies. British Journal of Cancer 2011;105:1635-9. 29. Zama IN, Hutson TE, Elson P, et al. Sunitinib rechallenge in metastatic renal cell carcinoma patients. Cancer 2010;116:5400-6. 30. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone 2011;48:160-6. 31. Beuselinck B, Oudard S, Rixe O, et al. Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2010. 32. Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma. Cancer 2003;98:962-9. 33. Rosen LS. Zoledronic Acid Versus Placebo in the Treatment of Skeletal Metastases in Patients With Lung Cancer and Other Solid Tumors: A Phase III, Double-Blind, Randomized Trial--The Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. Journal of Clinical Oncology 2003;21:3150-7. 34. Keizman D, Ish-Shalom M, Pili R, et al. Bisphosphonates combined with sunitinib may improve the response rate, progression free survival and overall survival of patients with bone metastases from renal cell carcinoma. European Journal of Cancer 2012.

Continuous Professional Development Modules are sponsored by Pfizer Healthcare Ireland Pfizer Healthcare Ireland has no editorial oversight of the CPD programmes included in these modules.


HPN CONTINUING PROFESSIONAL DEVELOPMENT - 4 - 2013