Prognostic factors and clinical trials of new agents in patients with metastatic renal cell carcinoma

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1 Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 Prognostic factors and clinical trials of new agents in patients with metastatic renal cell carcinoma Robert J. Motzer a,b, * a Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA b Department of Medicine, Weil Medical College of Cornell University, New York, NY, USA Accepted 5 December 2002 Contents 1. Introduction... S33 2. Prognostic factors... S34 3. MSKCC experience... S34 4. Risk-adapted therapy... S36 5. Clinical trials... S36 6. Summary and directions S37 Reviewers... S37 References... S37 Biography... S39 Abstract Metastatic renal cell carcinoma (RCC) remains a disease highly resistant to systemic therapy. Results of recent reports in the literature on prognostic factors and clinical trials for patients with metastatic RCC were reviewed. Small numbers of patients exhibit complete or partial responses to interferon and/or interleukin-2, but most patients do not respond and there are few long-term survivors. Therefore, the identification of new agents with better antitumor activity against metastases remains the highest priority of clinical investigation in this refractory tumor. Prospective identification of patients more likely to benefit from cytokine therapy could be used as a stratification factor in Phase III trials, and in risk-directed therapy. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Renal cell carcinoma; Prognostic factors; Clinical trials 1. Introduction Prior reviews have shown that renal cell carcinoma (RCC) is resistant to chemotherapy [1]. Immunotherapy * Present address: Memorial Hospital, 1275 York Avenue, New York, NY 10021, USA. Tel.: / ; fax: / address: motzerr@mskcc.org (R.J. Motzer). with interleukin-2 and/or interferon-a achieve responses in between 10 and 20% of patients, some of which are durable [1]. Two randomized trials reported a small but significant (P B/0.05) improvement in survival with interferon-a therapy [2,3]. In one, interferon-a was compared with medroxyprogesterone and resulted in improvement in median survival of 3 months [2]. In the second trial, interferon-a plus vinblastine was compared with vinblastine alone, and the combination showed a /03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi: /s (03)

2 S34 R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 benefit in median survival of 6 months for interferon-a therapy [3]. A randomized trial showed a survival benefit for cytoreductive nephrectomy prior to treatment with interferon-a [4]. Federal Drug Administration approval for high-dose bolus interleukin-2 was based on results of a multicenter series of 255 patients treated with high-dose interleukin- 2 alone [5]. Complete plus partial responses were achieved in 14% of patients, some of whom had bulky metastases, and the median duration of response was 23 months [5]. A long-term survival update showed a subset of these patients had durable responses [6]. Given the formidable toxicity and supportive care requirements associated with the high-dose bolus regimen, lower doses of interleukin-2 have been studied. Response rates appear similar (15 /20%) in patients treated on single arm studies with inpatient high-dose bolus, other inpatient dose or schedule, and low-dose outpatient schedules [7]. The low response rate, toxicity associated with highdose interleukin-2 therapy, and few long-term survivors following treatment with interferon-a or interleukin-2 provide the rationale for clinical trials of novel agents as a priority for management of patients with this disease. The identification of prognostic factors is important in assessing treatment outcome of new therapies studied in phase II and III trials, and in adapting risk-directed therapy to patients with metastatic RCC who are treated with immunotherapy. The early experience showed that patients most likely to respond to interferon-a had prior nephrectomy and small volume lung-only metastasis [8]. In a randomized phase III trial conducted by the Eastern Cooperative Oncology Group, a major response proportion (complete plus partial response) of 30% was reported for patients with these clinical features [9]. Univariate analyses performed on patients treated with immunotherapy showed that longer survival was associated with high performance status, prior nephrectomy, and lung-predominant metastases [10,11]. Prognostic factors for patients with metastatic RCC varied among the studies but consistently included performance status, nephrectomy, and a measure of extent of disease [12/ 17]. These variables were studied in multivariate analyses and models for predicting survival were derived. A summary of multivariate analyses resulting in criteria for risk stratification is shown in Table 1 [12/17]. The first comprehensive analysis was reported by Elson et al. [12]. The patient population was comprised of 610 patients treated with chemotherapy on Phase II trials between 1975 and 1984 [12]. The patient population [12] differs from that of the present era, reflecting improvement in imaging techniques and selection factors used to choose patients with RCC exclusively for Phase II trials of cytotoxic agents. The median survival for all patients treated in that series was 5.6 months [12] compared with 10 months or longer in a more recent series [18]. Recent efforts have led to models for predicting survival following treatment with interferon-a or interleukin-2 [19], and a model for predicting survival in patients with localized and metastatic RCC at initial diagnosis [20]. 2. Prognostic factors 3. MSKCC experience The relationship between pretreatment clinical features and survival was studied in 670 patients with advanced RCC treated in Memorial Sloan-Kettering Cancer Center (MSKCC) clinical trials of immunotherapy (interferon-a, interleukin-2) and chemotherapy between 1975 and 1996 [18]. The median overall survival Table 1 Prognostic factors for survival Author Year Points Treatment Independent pretreatment prognostic factors used in model Elson et al. [12] Chemotherapy Performance Status, Time from initial diagnosis, Number of metastatic sites, prior chemotherapy, and prior weight loss DeForges [13] Chemotherapy and interferon Hepatic metastasis, Lung metastasis, Time from initial diagnosis, Sedimentation rate, Weight loss Palmer et al. [14] Interleukin-2 Performance status, Time from initial diagnosis, Number of metastatic sites Jones et al. [15] Interleukin-2 Performance status, Number of metastatic sites, Time from initial diagnosis Fossa et al. [16] Interferon / chemotherapy Performance status, Sedimentation rate, Weight loss Lopez-Hannineh et al. [17] Interleukin-2 with/without interferon, FU Erythrocyte Sedimentation Rate, Lactate dehydrogenase concentration, Neutrophil count, hemoglobin, extrapulmonary metastases Motzer et al. [18] Interferon, interleukin-2, chemotherapy Nephrectomy, Karnofsky performance status, Hemoglobin, Adjusted calcium, Lactate dehydrogenase Negrier et al. [19] Interferon, interleukin-2 Neutrophil count, Time from initial diagnosis, Number of metastatic sites, Liver metastases Zisman [20] Interleukin-2 or Nephrectomy only Performance status, tumor grade

3 R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 S35 Table 2 Survival according to risk group[18] Number of risk factors Percentage Alive (%) Median survival (95% CI) 1-year survival (%) 3-year survival (%) (17.1, 27.9) or (8.9, 11.4) , 4, or (3.4, 5.0) 12 0 time was 10 months. The proportion of patients surviving at 1 year was 42%; the 2- and 3-year survival proportions were 20 and 11%, respectively. Pretreatment features associated with a shorter survival in the multivariate analysis were low Karnofsky performance status ( B/80%), high lactate dehydrogenase ( /1.5 /upper limit of normal), low hemoglobin ( B/lower limit of normal), high corrected serum calcium ( /10 mg/dl), and absence of nephrectomy. These prognostic factors were used to categorize patients by risk into three different groups (Table 2, Fig. 1). The median time to death in the 25% of patients with zero risk factors (favorable-risk) was 20 months. Fifty-three percent of the patients had one or two of these prognostic features (intermediate-risk) and the median survival in this group was 10 months. Patients with three or more risk factors (poor-risk), comprising 22% of the patients, had a median survival of 4 months. Reducing heterogeneity due to various therapies and assessing the role of nephrectomy as a risk factor in the light of the randomized trial [21] prompted an analysis on prognostic factors for survival following interferon-a therapy for 463 previously untreated patients [22]. The median overall survival time was 13 months (95% CI: 12 /15 months). The proportion of patients surviving at 1 and 3 years was 54 and 19%, respectively. The median time to progression was 4.7 months (95% CI: 4.1/5.3 months) [22]. Five variables were selected by univariate and multivariate analysis as prognostic, and used as risk factors for short survival: low Karnofsky performance status ( B/80%), high lactate dehydrogenase ( /1.5 /upper limit of normal), low serum hemoglobin ( B/lower limit of normal), high corrected serum calcium ( /10 mg/ dl), and time from initial RCC diagnosis to start of interferon-a therapy of less than 1 year [22]. Each patient was assigned to one of three risk groups: those with zero risk factors (favorable risk), those with one or two (intermediate risk), and those with three or more (poor risk). There was a significant difference in survival distributions of the three risk groups (P-valueB/0.0001). The median time to death of patients deemed favorable Fig. 1.

4 S36 R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 risk was 30 months [22]. Median survival in the intermediate-risk group was 14 months [22]. In contrast, the poor-risk group had a median survival of 5 months. The prognostic model is suitable for risk stratification of Phase III trials using interferon-a as the comparative treatment arm. Investigational therapies with immunotherapy, angiogenesis inhibition, or other novel treatment strategies could show an antitumor effect by producing prolonged stabilization of disease or slow tumor regression over many months [23]. Therefore, Phase II and III clinical trials of these agents against RCC may investigate progression-free survival as an endpoint of treatment outcome. The 4- and 5-month progression-free survivals associated with interferon-a therapy were 55 and 42%, respectively [22]. 4. Risk-adapted therapy In the development of the MSKCC model, the relationship of survival to treatment program was studied [18]. Patients were grouped according to whether they had treatment with cytokine therapy or chemotherapy. The program was classified as cytokine therapy when interferon-a and/or interleukin-2 were included in the treatment regimen. Treatment type of chemotherapy was assigned when the program was comprised of cytotoxic therapy or hormonal therapy and no interferon-a or interleukin-2 was given. Patients treated with cytokine therapy had a longer survival compared with patients treated with chemotherapy regardless of the year of treatment or risk category based on pretreatment features. With regard to the latter, the median survivals for favorable-risk, intermediate-risk, and poor-risk patients treated with cytokines were 27, 12, and 6 months, respectively [24]. In comparison, the median survivals for patients treated with chemotherapy were 15, 7, and 3 months for the three risk groups [24]. The magnitude of difference in median survival was greater in the favorable- and intermediate- risk groups [24]. These observations suggest that patients with favorable prognostic features according to the model [18] may derive therapeutic benefit from cytokine therapy. 5. Clinical trials Treatment with gemcitabine plus fluorouracil was associated with stable disease plus infrequent partial response in patients who were cytokine refractory [25]. Studies of combination of gemcitabine plus fluorouracil with interleukin-2 and interferon-a have not shown benefit for these combinations [26]. Clinical trials of gemcitabine plus capecitabine are underway. A randomized trial comparing interferon-a with or without retinoid showed no benefit for the combination [27]. Commercially available interferon-a preparations are characterized by a relatively short plasma half-life and require frequent dosing. Pegylated interferon is being developed and have sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon-a. The pharmacokinetic profile allows weekly dosing. Phase I and II trials have been completed and show similar response proportions compared with interferon-a [28]. A direct comparison of antitumor effect and toxicity for pegylated interferon-a to interferon-a requires a Phase III trial. A new cytokine, interleukin-12, showed antitumor activity in Phase I trials [29,30]. A randomized Phase II/ III trial was stopped early due to a low response proportion of interleukin-12 rate as a single agent [31]. Based on synergy with interleukin-2 in animal models, [32] study of this combination is underway. Given the formidable toxicity and supportive care requirements associated with the high-dose bolus regimen, lower doses of interleukin-2 have been studied. The relative efficacy of three schedules of interleukin-2 is being addressed in a randomized trial at the National Cancer Institute. Initially, this was a two-arm study, and an interim report showed comparable efficacy and less toxicity associated with a low-dose intravenous interleukin-2 schedule compared with the high-dose bolus schedule [33]. A third arm was added, comprised of lowdose subcutaneous interleukin-2, and an update showed improved tolerability and complete and partial responses in 11% of patients, compared with 16% with high-dose bolus therapy [34]. The major benefit cited for treatment with high-dose bolus interleukin-2 in prior studies was durability of response [35], and a comparison of durable responses awaits completion of trial accrual and long-term follow-up [34]. Allogeneic bone marrow transplantation has been reported by Childs et al to achieve complete and partial responses in metastatic RCC as a graft-versus-tumor effect [36]. A study performed at the University of Chicago showed that the approach was feasible and partial responses were observed at the cost of considerable toxicity [37]. However, requirement of a compatible donor, treatment-related morbidity and mortality, and delayed treatment effect are recognized limitations for this approach. The majority of RCC is comprised of clear cell carcinoma, which is characterized by mutation in the VHL gene [38]. Since the VHL protein has been shown to stabilize vascular endothelial growth factor [39], and since RCC is a highly vascular tumor with an angiographic pattern that is considered diagnostic [40], the study of angiogenesis inhibitors appears particularly relevant in RCC. Studies of thalidomide in patients with metastatic RCC refractory to cytokine therapy have

5 R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 S37 shown a low response proportion and stable disease [41 /44]. The potential effect of thalidomide on progression-free and overall survival for patients with advanced RCC is being addressed in the ECOG randomized phase III trial comparing low-dose interferon-a with or without thalidomide. Since one report of the combination of thalidomide plus interleukin-2 showed responses, a phase III trial of interleukin-2 with or without thalidomide is also planned [45]. New immunomodulatory analogs of thalidomide that have shown potentially greater antitumor effects in preclinical models [46] also warrant study in metastatic RCC. A randomized phase II double blind clinical trial to evaluate the activity of a neutralizing antibody to VEGF was performed. Patients were randomized to receive placebo or the antibody at one of two doses. After 110 patients were randomized, the trial was stopped because Bevacizumab showed significant prolongation of time to progression when given at the high dose [47]. A randomized phase III trial is warranted to study effect on survival. Epidermal growth factor expression is common in RCC, and has prompted study of agents that inhibit this pathway. Both Cetuximab (C225) and Iressa (ZD1839) were studied but showed no activity against RCC [48,49]. CCI-779 inhibits mtor kinase activity and causes G1 arrest. A randomized phase II trial in cytokine refractory patients showed the median time to progression and survival for the group was long compared with historical control [50]. Combination studies with interferon-alfa are underway and a randomized phase III trial is being considered. 6. Summary and directions Metastatic RCC remains a disease highly resistant to systemic therapy. Small numbers of patients exhibit complete or partial responses to interferon and/or interleukin-2, but most patients do not respond and there are few long-term survivors. Therefore, the identification of new agents with better antitumor activity against metastases remains the highest priority of clinical investigation in this refractory tumor. Prognostic models based on pretreatment clinical and laboratory variables can help define patients more likely to benefit from standard therapies, as well as assist in the interpretation of drug effectiveness in phase II clinical trials. Investigations into new prognostic factors based on the biology of the cancer and pathology of patient immune response are useful in that they may lead to new therapeutic strategies in the future. Prospective identification of patients more likely to benefit from cytokine therapy could be used in Phase III trials, and in risk-directed therapy. Reviewers Cora N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Pavilion Cesalpini, Circonvallazione Gianicolense 87, I Rome, Italy. Sylvic Negrier, Department of Medical Oncology, Center Léon Bérard, 28, rue Laennec, F Lyon Cedex 8, France. Professor Nicholas J. Vogelzang, Fred C. Buffett Professor of Medicine, Surgery (Urology), Ben May Institute for Cancer Research, University of Chicago Cancer Research Center, 5841 S. Maryland Ave., MC1140, Chicago, IL , USA. Sophie D. Fossa, Clinical Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway. References [1] Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000;163:408/17. [2] Medical Research Council, and Collaborators. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 1999;353:14/7. [3] Pyrhonen S, Salminen E, Lehtonen T, et al. 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Thalidomide treatment of metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 2000;19:352a. [43] Li Z, Amato R, Papandreou C, et al. Phase II study of thalidomide for patients with metastatic renal cell carcinoma progressing after interleukin-2 based therapy. Proc Am Soc Clin Oncol 2001;20:180a. [44] Cho MD, Konishi N, Kitahori Y, et al. Detection of DNA amplification in human renal cell carcinoma cell lines using restriction landmark genomic scanning. Cell Mol Biol 1998;44:913/8. [45] Amato RJ, Breheny S, Tracy E. Phase I/II study of thalidomide plus interleukin-2 for patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 2002;21:190a (abstract 759). [46] Hideschima T, Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human mulitple myeloma cells to conventional therapy. Blood 2000;96:2943/50. [47] Yang JC, Haworth L, Steinberg SM, Rosenberg SA, Novotny W. A randomized double-blind placebo-controlled trial of bevacizumab (anti-vegf antibody) demonstrating a prolongation in time to progression in patients with metastatic renal cancer. Proc Am Soc Clin Oncol 2002;21:5a (abstract 15). [48] Motzer RJ, Amato R, Todd M, Hwu W, Cohen R, Baselga J, Muss H, Cooper M, Yu R, Needle M. Phase II trial of antiepidermal growth factor receptor antibody C225 in patient with advanced renal cell carcinoma, Invest New Drugs 2002, in press.

7 R.J. Motzer / Critical Reviews in Oncology/Hematology 46 (2003) S33/S39 S39 [49] Drucker BJ, Schwartz L, Marion S, Motzer R. Phase II trial of ZD (Iressa), an EGF inhibitor, in patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 2002;21:181a (abstract 720). [50] Atkins MB, Hidalgo M, Stadler W, Logan T, Dutcher JP, Hudes G, Park Y, Marshall B, Boni J, Dukart G. A randomized doubleblind phase 2 study of intravenous CCI-779 administered weekly to patients with advanced renal cell carcinoma. Proc Am Soc Clin Oncol 2002;21:10a (abstract 36). Biography Robert J. Motzer is an attending physician in the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and a Professor of Medicine at Weil Medical College of Cornell University, New York, NY.