Confirming the Role of mtors in Oncology: Treatment of Renal Cell Carcinoma

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1 Confirming the Role of mtors in Oncology: Treatment of Renal Cell Carcinoma Program Director Jose Baselga, MD Chief, Medical Oncology Service Vall d Hebron University Hospital Barcelona, Spain Faculty Robert A. Figlin, MD, FACP Associate Director for Clinical Research, Comprehensive Cancer Center Chair, Division of Medical Oncology & Therapeutics Research Arthur and Rosalie Kaplan Professor of Medical Oncology City of Hope Comprehensive Cancer Center Los Angeles, California Staff Charles A. Meyer Managing Editor, Hematology/Oncology Clinical Care Options, LLC Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC This activity is supported by educational grants from: Copyright 2008 Clinical Care Options, LLC. All rights reserved. 1

2 Edward King, MA Vice President, Editorial Clinical Care Options, LLC Andrew D. Bowser Editorial Director, Hematology/Oncology Clinical Care Options, LLC Jim Mortimer Product Director, Hematology/Oncology Clinical Care Options, LLC Shannon B. Halloway, MHS, PA-C Contributing Writer Disclosures Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty and CCO staff reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity. Jose Baselga, MD, has disclosed that he has received consulting fees from Novartis Robert A. Figlin, MD, FACP, has disclosed that he has received consulting fees from Novartis, Pfizer, and Wyeth and contracted research support from Amgen, Novartis, Pfizer, and Wyeth. Charles A. Meyer has no significant financial relationships to disclose. Edward King, MA, has no significant financial relationships to disclose. Andrew D. Bowser has no significant financial relationships to disclose. Jim Mortimer has no significant financial relationships to disclose. Shannon B. Holloway, MHS, PA-C, has no significant financial relationships to disclose. The content of this activity has been reviewed by an independent peer reviewer to ensure that it is balanced, objective, and free from any commercial bias. The peer reviewer has disclosed no financial relationships relevant to the content of this activity. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 2

3 The following PIM clinical content reviewers, Linda Graham, RN; Jan Hixon, RN; and Trace Hutchison, PharmD, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interests related to the content of this CME activity of any amount during the past 12 months. Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute of Medicine (PIM) and Clinical Care Options, LLC do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM and Clinical Care Options, LLC. Please refer to the official prescribing information for each product for discussion of approved indication, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. Target Audience This activity is intended for physicians, registered nurses, and other healthcare providers involved in the care of patients with cancer. Purpose The purpose of this activity is to enhance the quality of care provided by healthcare professionals involved in the management of patients with cancer by providing them with information on recent developments with mammalian target of rapamycin (mtor) inhibitors in multiple tumor types. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 3

4 Learning Objectives Explain the relationship between mtor and the pathogenesis of renal cell carcinoma (RCC) Discuss the role of PTEN in the development of RCC Cite current data from clinical trials evaluating temsirolimus and everolimus for treating patients with RCC Describe current therapies recommendations for systemic treatment of advanced RCC Physician Continuing Medical Education Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine and Clinical Care Options, LLC. Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Postgraduate Institute for Medicine designates this educational activity for a maximum of 0.75 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Nursing Continuing Education Accreditation Statement CNA/ANCC This educational activity for 0.9 contact hour(s) is provided by Postgraduate Institute for Medicine (PIM). PIM is an approved provider of continuing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center s Commission on Accreditation. Instructions for Credit Participation in this self-study activity should be completed in approximately 45 minutes. To successfully complete this activity and receive credit, participants must follow these steps during the period from May 30, 2008 through May 29, 2009: Register online at Read the target audience, learning objectives, and faculty disclosures. Study the educational activity online or printed out. Submit answers to the posttest questions and evaluation questions online. You must receive a test score of at least 70% and respond to all evaluation questions to receive a certificate. After submitting the evaluation, you may access your online certificate by selecting the certificate link on the posttest confirmation page. Records of all CME activities completed can be found on the "My CME" page. There are no costs/fees for this activity. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 4

5 Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the reviewers or authors of the CCO material, not those of Clinical Care Options, LLC, the CME provider, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 5

6 mtor Inhibitors and Renal Cell Carcinoma Contents Introduction... 7 mtor and Its Inhibition in RCC: Experimental Data... 7 Clinical Trials in RCC: Temsirolimus... 9 Clinical Trials in RCC: Everolimus mtor inhibitors and Current Treatment Recommendations Ongoing Investigations and Continuing Questions References Copyright 2008 Clinical Care Options, LLC. All rights reserved. 6

7 Introduction In 2008, approximately 54,390 people in the United States will be diagnosed with renal cell carcinoma (RCC), and 13,000 will die of the disease. [1] Renal cell carcinoma, which accounts for approximately 4% of all malignancies, most commonly occurs in men older than 60 years of age. The incidence of RCC has risen consistently over the past 30 years, but the reason for this is unknown. [2] Approximately 90% of renal tumors are RCC, and of these, 85% are of the clear-cell histological type. [3] Much is known about the pathogenesis of RCC because of studies examining its close relationship with dysfunction of the von Hippel-Lindau (VHL) gene. VHL regulates hypoxiainducible factor (HIF), a transcription factor that controls cellular responses to hypoxia in the blood or tissue. [4] In the presence of oxygen, the VHL gene product pvhl forms a complex with other proteins and targets HIF for degradation. In response to hypoxia, HIF activity increases and induces the expression of a number of proteins that help cells adapt to low levels of oxygen. Loss of pvhl function leads to a stable accumulation of HIF and a corresponding overproduction of the hypoxia-induced proteins that ultimately contribute to tumor formation and growth through angiogenesis and unregulated cell growth. Renal cell carcinoma is among the most resistant of tumors to therapy. Until 2005, only a single agent, high-dose interleukin-2, was approved by the US Food and Drug Administration (FDA) for the treatment of this disease, [5] although other agents were used. In late 2005 and early 2006, however, 2 multikinase inhibitors sorafenib and sutininib were approved by FDA for treatment of RCC. More recently, inhibition of mammalian target of rapamycin (mtor) has emerged as a treatment approach. One mtor inhibitor, temsirolimus (CCI-779), was approved by FDA in 2007 for advanced RCC. A second agent, everolimus (RAD001), has undergone a phase III placebo-controlled trial, which was stopped after an interim analysis showed that everolimus had met the study s primary endpoint of progression-free survival (PFS). [6] This module examines preclinical data providing a basis for mtor inhibitor use in RCC and clinical trial results to date demonstrating the utility mtor inhibitors in the disease. Also reviewed is the role of mtor inhibitors as described in current treatment guidelines. mtor and Its Inhibition in RCC: Experimental Data mtor regulates nutritional needs, cell growth, and angiogenesis in cells by downregulating or upregulating a variety of proteins, including HIF. [7] Preclinical studies position mtor as an upstream activator of HIF-1 function in cancer cells and suggest that the antitumor activity of rapamycin is partly mediated through the inhibition of cellular responses to hypoxic stress. [8] Other studies confirm the role of mtor as a positive regulator of HIF-1 dependent gene transcription in cells exposed to hypoxia or hypoxia-mimetic agents, suggesting that the particular demands placed on nutrient-deprived cells sequestered in bodily tissues may have provided the evolutionary driving force for the insertion of mtor into the hypoxia response pathway in metazoan organisms. [8] The observed clinical efficacy of mtor inhibitors in patients with RCC, therefore, may be mediated in part by the dependence of efficient HIF translation on the mtor pathway, which is known to increase HIF expression. [9] The use of mtor inhibitors would decrease accumulation of HIF, interfering with tumorigenesis. For example, when tested in preclinical Copyright 2008 Clinical Care Options, LLC. All rights reserved. 7

8 models, temsirolimus, a rapamycin analogue, inhibited vascular endothelial growth factor (VEGF) production through inhibition of HIF-1α expression and transcriptional activation. [10] By countering the mtor-driven accumulation of HIF, mtor inhibitors could interfere with a crucial step of cell proliferation. Another crucial factor in the development of RCC, PTEN is a tumor-suppressor gene that can dephosphorylate phosphatidylinositol 3,4,5-trisphosphate, the product of phosphatidylinositol 3-kinase. Many of the mutations that occur in cancer cells have been mapped to the phosphatase catalytic domain of PTEN. Data suggest that the phosphatase activity of PTEN is essential for its function as a tumor suppressor. [11] Loss of PTEN function leads to activation of phosphoinositide 3-kinase signaling and Akt. [12] Preclinical testing has focused on whether mtor inhibition is useful in treating PTEN-null cancers. Results from murine models demonstrate that mtor inhibition induces apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. In vitro data demonstrate that cell lines that lack PTEN are extremely sensitive to mtor inhibitors. [13] Several PTEN-deficient multiple myeloma lines were challenged with the mtor inhibitor temsirolimus. [14] Three of 4 PTEN-deficient cell lines with constitutively active AKT were remarkably sensitive to cytoreduction and underwent G(1) cell cycle arrest. PTENdeficient prostate cancer cells treated with everolimus exhibited increased rates of apoptosis after exposure to radiation than with radiation alone. [15] These results are consistent with earlier findings that PTEN-deficient cells are remarkably sensitive to mtor inhibition. The results of these studies suggest that the status of PTEN and AKT function is a good predictive marker of sensitivity to this class of drug. PTEN gene expression has been shown to be reduced in RCCs, [16,17] with levels of PTEN protein reduced on average to 10% of normal. [16] Lack of PTEN expression has been shown to be an independent negative prognostic factor for disease-specific survival in patients with metastatic RCC. [18] Moreover, mtor inhibitors have demonstrated antiangiogenic activity in preclinical models. Data from translational research indicate that temsirolimus may potently inhibit angiogenesis by multiple mechanisms, either indirectly, through transcriptional inhibition of hypoxiastimulated, HIF-1 dependent VEGF production, or directly, through inhibition of endothelial cell functions involved in neoangiogenesis, such as growth factor stimulated proliferation and morphogenesis. [10] In addition, data strongly suggest that the antiangiogenic properties of temsirolimus may importantly contribute to the antitumor activity observed with this compound in preclinical models in breast cancer. [10,19] The significant associations between the expression of HIF-α subunits and that of VEGF mrna/protein suggest a functional role for HIF in enhancing expression of VEGF and ultimately angiogenesis. [20] This further supports the rationale that mtor inhibitors may yield therapeutic benefit both by direct tumor cell killing and by inhibiting the development of lesions through impairment of VEGF production. [21] Furthermore, the effect of mtor inhibition on angiogenesis may not be limited to reduction of VEGF by cancer cells: Experiments in human umbilical vein endothelial cells suggested that everolimus had a downstream, direct inhibitory effect on endothelial cell proliferation. [22] In a murine renal cancer xenograft model, inhibition of mtor has induced tumor shrinkage in association with reduced vascularization. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 8

9 Clinical Trials in RCC: Temsirolimus Based on the postulated role of mtor in RCC and on the preclinical activity of temsirolimus, several phase II clinical trials were conducted. In a study conducted by Atkins and colleagues, [23] 111 patients with advanced refractory RCC were randomly assigned to receive 25 mg, 75 mg, or 225 mg of temsirolimus every week as a 30-minute infusion. The objective response rate was 7%, which included 1 complete response and 7 partial responses, with 26% minor response rates also reported. The median time to tumor progression was 5.8 months, and median survival was 15.0 months. Stratified by risk, patients in intermediateprognosis and poor-prognosis subgroups had median survivals 1.6-fold to 1.7-fold longer than those of similarly defined groups in a previous study of interferon alfa (Figure 1). [24] Temsirolimus was generally well tolerated at all dose levels, with hyperglycemia (17%) and hypophosphatemia (13%) the most frequently occurring grade 3 or 4 adverse events. Figure 1. Overall survival by risk strata in patients with advanced refractory RCC treated with temsirolimus, compared with historical group of patients treated with interferon alfa. [23,24] In another phase I/II trial, 71 patients with advanced RCC were given weekly ascending doses (5, 10, 15, 20, and 25 mg) of intravenous temsirolimus combined with interferon alfa (6 or 9 million units) administered subcutaneously 3 times weekly. [24] Based on the dose-limiting toxicities of stomatitis, fatigue, and nausea and vomiting, a maximum tolerated dose of 15 mg was established for temsirolimus. Of the 39 patients who received the 15-mg dose, 8% achieved a partial response and 36% had stable disease for at least 6 months. Median PFS was 9.1 months for all patients in the study. The most common grade 3 or 4 toxicities in this group were leucopenia and hypophosphatemia. The phase III Global Advanced Renal-Cell Carcinoma (ARCC) trial randomized 626 patients with previously untreated, poor-prognosis RCC to temsirolimus, interferon alfa, or both. [25] Poor prognosis was defined as having at least 3 of 6 predictors of short survival: serum lactate dehydrogenase level > 1.5 times the upper limit of the normal range, hemoglobin level Copyright 2008 Clinical Care Options, LLC. All rights reserved. 9

10 below the lower limit of the normal range, corrected serum calcium level > 10 mg per deciliter, time from initial diagnosis of RCC to randomization < 1 year, Karnofsky performance score of 60 or 70, or metastases in multiple organs. Patients received intravenous temsirolimus 25 mg weekly, 3 million U of subcutaneous interferon alfa (with an increase to 18 million U) 3 times weekly, or combination therapy with temsirolimus 15 mg weekly plus 6 million U of interferon alfa 3 times weekly. The primary endpoint was overall survival of the temsirolimus group and the combination-therapy group compared with the interferon group. Patients who received temsirolimus alone had superior overall survival (hazard ratio [HR]: 0.73; 95% confidence interval [CI]: ; P =.008) and PFS (P <.001) compared with patients who received interferon alone (Figure 2). [25] Overall survival in the combination therapy group did not differ significantly from that in the interferon group (HR: 0.96; 95% CI: ; P =.70). Median overall survival was 7.3 months, 10.9 months, and 8.4 months in the interferon, temsirolimus, and combination therapy groups, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P =.02). Investigators attributed to the high rate of serious adverse events to the reduced overall survival in the combination group. The data from this pivotal trial were the basis for May 2007 FDA approval of temsirolimus for advanced RCC. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 10

11 Figure 2. Kaplan-Meier estimates of overall survival (panel A) and PFS (panel B) in patients treated with temsirolimus, interferon alfa, or both in the Global ARCC trial. [25] Copyright 2008 Clinical Care Options, LLC. All rights reserved. 11

12 A recently reported analysis of outcomes in patients with advanced RCC treated with temsirolimus (n = 121) or interferon alfa (n = 118) explored the association between baseline PTEN and HIF-1α protein levels (measured by immunohistochemistry) and overall and progression-free survival. [26] No evidence was seen of statistical interaction between treatment and baseline PTEN or HIF-1α status for either endpoint (Table). Furthermore, prospective clinical investigation is needed to elucidate the influence of these biomarkers on the efficacy of temisirolimus. Table. PTEN and HIF-1α Status: Overall Survival and PFS in Patients Treated With Temsirolimus (n = 121) or Interferon alfa (n = 118) [26] Clinical Trials in RCC: Everolimus Everolimus (RAD-001), an orally administered mtor inhibitor that has been used to prevent organ transplantation rejection, has been evaluated in RCC in phase II and III clinical trials. Amato and colleagues [27] conducted a phase II trial that included 28 patients with predominant clear-cell elements with progressive metastatic RCC. Everolimus was administered orally at a dose of 10 mg daily without interruption for a 28-day cycle, with dose modifications for toxicity. Twenty patients had previously received systemic therapy (with 2 exhibiting complete or partial response), 10 had received radiation, and all but 1 had undergone nephrectomy. Of the 25 evaluable patients, partial response was reported in 9 patients, and 11 patients had stable disease for more than 3 months (Figure 3). Median duration of therapy was approximately 7 months (range: 1-9 months). Treatment-related grade 2 adverse events (the highest reported) included mucositis and skin rash with an incidence no higher than 30% and Copyright 2008 Clinical Care Options, LLC. All rights reserved. 12

13 gastrointestinal adverse effects with an incidence no higher than 20%. Laboratory abnormalities included pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia, and elevated liver function tests, but no abnormality reached grade 3 in more than 20% of patients. Figure 3. Best response by response evaluation criteria in solid tumors in everolimus phase II study. [27] Jac and colleagues [28] reported a phase II trial that enrolled 41 patients with metastatic RCC who had received limited previous treatment. Everolimus was administered orally at a dose of 10 mg daily without interruption for a 28-day cycle, with dose modifications for toxicity. Thirtyseven patients were evaluable for response and toxicity. The median age was 60 years, and 31 patients had received previous therapy. Partial response was observed in 12 patients, and 19 patients had stable disease for at least 3 months. Median duration of therapy was 8 months (range: 1-20 months), and median overall survival was 11.5 months (range: 1-20 months). Treatment-related adverse events included mucositis, skin rash, pneumonitis, and hypophosphatemia. Positron emission scans showed decreased metabolic activity in responding or stable patients. Subsequently, Renal Cell Cancer Treatment With Oral RAD001 Given Daily (RECORD)-1, a multicenter, international phase III trial, evaluated everolimus in 410 patients with advanced RCC previously treated with antiangiogenesis-targeted agents. [29] With stratification based on the Memorial Sloan-Kettering Cancer Center risk criteria, patients were randomly assigned to receive daily everolimus or placebo (Figure 4). Copyright 2008 Clinical Care Options, LLC. All rights reserved. 13

14 Figure 4. RECORD-1 phase III trial of everolimus: study design. [29] Interim analysis found a statistically significant advantage in the everolimus arm for PFS, the primary endpoint, and the trial was halted in early 2008 by the data monitoring committee. [6] The trial randomized 272 patients to everolimus and 138 to placebo. Median PFS, as assessed by independent review, was 4.0 months(95% CI: ) in the everolimus arm, compared with 1.9 ( ) in the placebo arm (hazard ratio: 0.30; 95% CI: ; P <.0001). Significant improvement in PFS in the everolimus arm compared with placebo was observed across MSKC prognostic groups. Most common adverse events (all grades/grade 3/4) were stomatitis (36% in the everolimus arm, with 4% incidence of grade 3/4 vs placebo 7% and 0% with placebo), anemia (28% overall and 7% grade 3/4 for everolimus vs 15% and 5% for placebo), and asthenia (28% overall and 2% grade 3/4 for everolimus vs 20% and 4% for placebo). Among patients randomized to everolimus, 10% exhibited adverse events leading to discontinuation vs 4% with placebo; dose reductions were required by 4% of patients receiving everolimus compared with less than 1% of those receiving placebo. At the interim analysis, 68 deaths had been observed. Study follow-up continues to assess the secondary endpoint of overall survival. mtor inhibitors and Current Treatment Recommendations With the introduction of new options for systemic treatment options in patients with metastatic, recurrent, or unresectable RCC of the clear-cell histology has come the evolution of treatment guidelines. The National Comprehensive Cancer Network (NCCN) categorizes treatment recommendations for advanced RCC based on the level of NCCN consensus and compelling clinical evidence with ranges of 1, 2A, 2B, and 3. [30] Category 1 recommendations come with the highest consensus and supportive evidence. Cytokines represented the standard of care in advanced RCC for approximately 15 years. [30] Despite their toxicity, there remains a role for cytokines in therapy, according to the guidelines, based on evidence of the benefit of high-dose interleukin-2 in select patients with a good performance status score and low-volume or lung-predominant metastatic disease. [31] Copyright 2008 Clinical Care Options, LLC. All rights reserved. 14

15 Recommendations are designated category 2B in both first-line and second-line clear-cell metastatic RCC. [30] Sunitinib is recommended as first-line therapy in patients with advanced clear-cell RCC and good or intermediate prognosis (category 1), based on the results of a large, multinational, phase III trial. [32] In this study, 750 previously untreated, low-risk or intermediate-risk patients were randomly assigned to receive either sunitinib or interferon. RR was 31% and 6% in the sunitinib and interferon arms, respectively, and PFS was 11 months and 5 months, respectively. Sunitinib also is recommended as first-line therapy for patients with nonclear-cell histology (category 2B) as well as second-line therapy for patients with clear-cell type (category 1/2A). mtor inhibitor therapy with temsirolimus is recommended as first-line therapy for patients with clear-cell RCC and poor prognosis (category 1) based on the MSKCC criteria or for patients with poor prognosis (category 1) and with nonclear-cell histology based on the ARCC phase III data. [25,30] Temsirolimus also is recommended as first-line therapy for intermediaterisk or good-risk patients (category 2A with nonclear-cell RCC) and as second-line therapy for those with clear-cell histology types (category 2A/2B). [30] The NCCN guidelines also include sorafenib as an option for first-line therapy (category 2B) for selected patients with relapsed or medically unresectable stage IV disease, with either clear-cell or nonclear-cell histology based on the phase III TARGET study. [33] This trial included 903 previously treated patients with low-risk or intermediate-risk clear-cell histology who were randomly assigned to receive either sorafenib or placebo. [33] Median PFS was 5.5 months and 2.8 months for the sorafenib and placebo arms, respectively, and the objective RR was 10% and 2%, respectively. In addition, sorafenib is recommended for second-line (category 1) treatment in patients with clear-cell RCC. Bevacizumab plus interferon therapy is recommended, with a lesser degree of consensus (category 2B), as first-line and second-line (bevacizumab only, category 2B) treatment for patients with clear-cell histology. [34] This recommendation was made before the publication by Escudier and colleagues in This regimen is based on the results a phase III, multicenter trial (AVOREN) that compared bevacizumab plus interferon therapy with placebo plus interferon regimen in 641 patients. The addition of bevacizumab to interferon significantly increased PFS (10.2 vs 5.4 months in the placebo plus interferon group; HR: 0.63; P <.0001) and objective tumor response rate (30.6% vs 12.4% in the placebo plus interferon group; P <.0001). A trend toward improved overall survival also was observed among patients receiving bevacizumab plus interferon therapy. The role of the combination of bevacizumab plus interferon will be revisited with the next edition of the NCCN guidelines. Outside the United States, the European Association of Urology in 2007 updated its guidelines for treatment of RCC. [35] Based on the ARCC trial results, the guidelines state that temsirolimus should be considered as first-line treatment in poor-risk patients with metastatic disease. The guidelines also recommend that tyrosine kinase inhibitors should be considered as first- or second-line treatment for patients with metastatic RCC. In addition, sunitinib is advised to be first-line therapy in good-risk and intermediate-risk patients. Sorafenib is suggested to be second-line treatment. All of these recommendations are categorized as Copyright 2008 Clinical Care Options, LLC. All rights reserved. 15

16 grade A, meaning they have bases in relevant clinical trials, including at least 1 randomized trial. Ongoing Investigations and Continuing Questions Because of the increasing evidence supporting mtor inhibitors in advanced RCC, more clinical trials are being conducted to assess the efficacy and safety of these agents in combination with other targeted therapies. Merchan and colleagues [36] led a phase I/II trial that evaluated temsirolimus in combination with bevacizumab in patients with clear-cell RCC. Of the 12 patients enrolled in the phase I portion of the trial, partial response was observed in 7 patients, and stable disease was reported in 3 patients. Grade 3 toxicities included hypertriglyceridemia, hypertension, and mucositis. In a phase II study, Chan and colleagues [37] assessed combination everolimus and imatinib therapy in 14 enrolled patients. At 3 months, 3 of the 10 evaluable patients remained progression free. No patient had a complete response or partial response, and 7 patients had stable disease. The most common adverse events were nausea, edema, and elevated creatinine levels. Ongoing trials are evaluating various regimens that include mtor inhibitors as first-line or second-line therapy, such as combinations of everolimus and sunitinib, [38] everolimus and sorafenib, [39] and an oral VEGF receptor inhibitor (AV-951) and temsirolimus. [40] With the growing variety of targeted therapies, approaches to predicting and monitoring response to treatment remain in flux. In patients with clear-cell RCC, a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status. [41] Predictive molecular markers included CA9, PTEN, and p53. As the data evolve, including those from early-stage trials of new mtor inhibitors such as deforolimus (AP23573), [42] our ability to tailor therapies to individual patients promises to improve. Many questions remain regarding the use of mtor inhibition in advanced RCC therapy: How can we optimally sequence the effective agents? Which agents act synergistically to optimize treatment? With which biological markers do we monitor therapeutic progress? In summary, the foundation of experimental and clinical data supporting the use of mtor inhibitors in metastatic RCC has been well established. Ongoing clinical trials will provide continuing guidance in the optimal use of this novel class of agents. With a better understanding of the underlying pathogenesis of RCC, we will be able to track our progress using newer biologic markers in combination with clinical surveillance. This experience promises to be applicable as well in other tumor types in which mtor inhibitors are undergoing study. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 16

17 To receive free CME credit for this article, Please complete the following Posttest online at: Posttest Click on the appropriate response below. 1. Which of the following statements does NOT represent a rationale of use mammalian target of rapamycin (mtor) inhibitors in renal cell carcinoma (RCC)? A. mtor may be involved in the activation of hypoxia-inducible factor (HIF)-1 in cancer cells, and inhibition of mtor may reduce abnormal activity of HIF-1 resulting from the loss of von Hippel-Lindau gene product pvhl function B. mtor inhibition may reduce angiogenesis C. mtor inhibition may enable increased expression of PTEN D. mtor inhibition may induce apoptosis in cancer cells lacking PTEN 2. Which of the following was among the mostly commonly observed adverse events in the phase II trial reported by Atkins and colleagues of temsirolimus in RCC? A. Peripheral neuropathy B. Hypophosphatemia C. Thrombocytopenia D. Hyponatremia 3. Which of the following statements best characterizes the results of the Global Advanced Renal-Cell Carcinoma (ARCC) trial? A. Temsirolimus and interferon alfa combined are more effective than either agent alone, although the combination is more poorly tolerated B. Temsirolimus yields a higher rate of objective response than interferon alfa, but there was no significant difference in progression-free or overall survival C. Temsirolimus prolongs progression-free and overall survival compared with interferon alfa, but only in patients whose tumors lack expression of PTEN D. Temsirolimus prolongs progression-free and overall survival compared with interferon alfa, with no significant additional benefit observed when the 2 agents are combined Copyright 2008 Clinical Care Options, LLC. All rights reserved. 17

18 4. Which of the following statements about the phase II trial reported by Amato and colleagues is NOT true? A. Gastrointestinal adverse events higher than grade 1 in severity were not reported B. Everolimus was administered orally at a dose of 10 mg daily without interruption for a 28-day cycle, with dose modifications for toxicity C. Treatment-related grade 2 adverse events included mucositis, pneumonitis, and skin rash, with an incidence no higher than 30% D. Laboratory abnormalities included hypophosphatemia, hyperglycemia, thrombocytopenia, anemia, and elevated liver function tests 5. Which of the following statements best characterizes the phase III Renal Cell Cancer Treatment With Oral RAD001 Given Daily (RECORD)-1 trial of everolimus? A. The primary endpoint in the trial is overall survival B. Patients who were previously treated with targeted agents were excluded from the trial C. Previous treatment with cetuximab was an inclusion criterion D. The primary endpoint is progression-free survival 6. Which statement about the National Comprehensive Cancer Center guidelines for treatment of advanced RCC is correct? A. mtor inhibitor therapy with temsirolimus is recommended as first-line therapy for patients with clear-cell RCC and poor prognosis B. Cytokine therapy is no longer recommended for use in advanced RCC C. Sunitinib is recommended as first-line therapy only in patients with advanced clear-cell RCC who have a poor prognosis D. All of the above Copyright 2008 Clinical Care Options, LLC. All rights reserved. 18

19 References 1. American Cancer Society. Cancer facts and figures Available at: Accessed March 8, Moore LE, Wilson RT, Campleman SL. Lifestyle factors, exposures, genetic susceptibility, and renal cell cancer risk: a review. Cancer Invest. 2005;23: Karumanchi SA, Merchan J, Sukhatme VP. Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens. 2002;11: Kondo K, Kim WY, Lechpammer M, Kaelin WG. Inhibition of HIF2α is sufficient to suppress pvhl-defective tumor growth. Available at: Accessed April 23, Brugarolas J. Renal-cell carcinoma molecular pathways and therapies. N Engl J Med. 2007;356: Motzer RJ, Escudier B, Oudard S, et al. RAD001 vs placebo in patients with metastatic renal cell carcinoma (RCC) after progression on VEGFr-TKI therapy: Results from a randomized, double-blind, multicenter phase-iii study. Program and abstracts of the 44th Annual Meeting of the American Society of Clinical Oncology; May 30 - June 2, 2008; Chicago, Illinois. Abstract LBA Gibbons JJ, Discafani C, Peterson R. The effect of CCI-779, a novel macrolide antitumor agent, on growth of human tumor cells in vitro and in nude mouse xenografts in vivo. Program and abstracts of the 90th Annual Meeting of the American Association of Cancer Research; April 10-14, 1999; Philadelphia, Pennsylvania. Abstract Hudson CC, Liu M, Chiang GG, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol. 2002;22: Cho D, Signoretti S, Regan M, Mier JW, Atkins MB. The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res. 2007;13(2 pt 2):758s-763s. 10. Del Bufalo D, Ciuffreda L, Trisciuoglio, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res. 2006;66: PTEN pathway. Available at: Resources/Pathway_Slides Charts/PTEN_Pathway.html. Accessed April 22, Copyright 2008 Clinical Care Options, LLC. All rights reserved. 19

20 12. Majumder PK, Febbo PG, Bikoff R, et al. mtor inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med. 2004;10: In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Clinical oncology. 3rd ed. Philadelphia, Pa: Churchill Livingstone; p Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002;62: Cao C, Subhawong T, Albert JM, et al. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 2006;66: Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW. Loss of tumor suppressor protein PTEN during renal arcinogenesis. Int J Cancer. 2002;99: Velickovic M, Delahunt B,McIver B, Grebe SK. Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Mod Pathol. 2002;15: Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict survival of patients with metastatic renal cell carcinoma. J Urol 2005;173: Chan S. Targeting the mammalian target of rapamycin (mtor): a new approach to treating cancer. Br J Cancer. 2004;91: Turner KJ, Moore JW, Jones A, et al. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res. 2002;62: El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ. Loss of Tsc1orTsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Res. 2003;63: Bianco R, Garofalo S, Rosa R, et al. Inhibition of mtor pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti- EGFR drugs. Br J Cancer. 2008;98: Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;5: Motzer RJ, Hudes GR, Curti BD, et al. Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma. J Clin Oncol. 2007;25: Copyright 2008 Clinical Care Options, LLC. All rights reserved. 20

21 25. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356: Figlin RA, De Souza P, McDermott D, et al. Analysis of PTEN and HIF1-α and correlation with efficacy in patients with advanced renal cell carcinoma treated with temsirolimus versus interferon-α. Program and abstracts of the 99th Annual Meeting of the American Association for Cancer Research; April 12-16, 2008; San Diego, California. Abstract Amato RJ, Misellati A, Khan M, Chiang S. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). Program and abstracts of the 42nd Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Georgia. Abstract Jac J, Giessinge S, Khan M, Willis J, Chiang S, Amato R. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). Program and abstracts of the 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, Illinois. Abstract ClinicalTrials.gov. Everolimus plus best supportive care (BSC) versus BSC plus placebo in patients with metastatic carcinoma of the kidney which has progressed after treatment with sorafenib and/or sunitinib. Available at: Accessed April 23, National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. Available at: Accessed April 22, Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and lowdose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21: Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356: Escudier B, Eisen T, Stadler WM, et al, for the TARGET Study Group. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356: Escudier B, Koralewski P, Pluzabska A, et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-α2a vs placebo/interferon-α2a as first-line therapy in metastatic renal cell carcinoma. Program and abstracts of the 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, Illinois. Abstract 3. Copyright 2008 Clinical Care Options, LLC. All rights reserved. 21

22 35. Ljungberg B, Hanbury DC, Kuczyk MA. Guidelines on renal cell carcinoma. Available at: Accessed April 22, Merchan JR, Liu G, Fitch T, et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: phase I safety and activity results. Program and abstracts of the 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, Illinois. Abstract Chan JS, Vuky J, Besaw LA, Beer TM, Ryan CW. A phase II study of mammalian target of rapamycin (mtor) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC). Program and abstracts of the 43rd Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2007; Chicago, Illinois. Abstract ClinicalTrials.gov. A study of RAD001 and sunitinib in metastatic renal cell carcinoma. Available at: Accessed March 12, ClinicalTrials.gov. Sorafenib and RAD001 renal cell carcinoma. Available at: noma&rank=2. Accessed March 12, ClinicalTrials.gov. A phase 1 study of an oral VEGFR inhibitor (AV0951) in combination with Torisel in renal cell cancer. Available at: cinoma&rank=1. Accessed March 12, Kim HL, Seligson D, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005;173: Mita MM, Mita AC, Chu QS, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol. 2008;26: Copyright 2008 Clinical Care Options, LLC. All rights reserved. 22