Targeted Therapy and Renal Cell Carcinoma: Are We Making Progress?

Targeted Therapy and Renal Cell Carcinoma: Are We Making Progress?

A Report from the 2007 Annual Meeting of the American Society of Clinical Oncology

Introduction

The incident of renal cell carcinoma (RCC) is rising throughout the world. An estimated 51,190 individuals (31,590 men and 19,600 women) will be diagnosed with this disease and 12,890 individuals will die of it in 2007.[1] Although surgery is a potential cure for patients with early stage disease, many patients experience recurrence after surgery or have metastatic disease at the time of initial diagnosis.

Until recently, the only effective therapies for metastatic RCC have been high-dose Interleukin-2 (IL-2) and Interferon-alpha (IFN-?) with response rates (RR) in the range of 15% and little if any effect on patient survival. However, advances in understanding of the biology of RCC have generated a new rationale for treating this disease, resulting in the introduction of several new agents that have substantially improved therapy.

Targeted Therapy in RCC

RCC arises from the cells of proximal tubules and histologically 85% are the clear cell type. It has been established that loss of function of the von Hippel-Lindau (VHL) gene on chromosome 3p is an early event in the development of clear cell RCC, defects in VHL gene are the most common cause of inherited clear cell RCC, and its loss contributes to the pathogenesis of RCC in 75% of patients with sporadic clear cell RCC. The downstream molecular effects of this defect include the accumulation of angiogenic growth factors, vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and transforming growth factor (TGF), and the increased angiogenesis and blood vessel density characteristic of RCC. Thus, loss of VHL gene function correlates with activation of hypoxia inducible factor (HIF-1?) and a variety of genes important in tumor progression that include VEGF, PDGF, and TGF (Figure 1). Therefore, agents targeting VHL-related growth factors have strong biologic rationale as therapy for metastatic RCC.

Figure 1. Molecular Pathways and Targeted Therapies in Renal-Cell Carcinoma

Figure 1 Abreviations. VHL denotes von Hippel-Lindau protein, HIF hypoxia-inducible factor, TGF-{alpha} transforming growth factor {alpha}, VEGF vascular endothelial growth factor A, PDGFbeta platelet-derived growth factor beta, EGFR epidermal growth factor receptor, VEGFR2 VEGF receptor 2, PDGFRbeta PDGF receptor beta, PTEN phosphatase and tensin homologue, TSC1 and TSC2 tuberous sclerosis complex 1 and 2, FKBP12 FK506-binding protein 12 kD, mTOR mammalian target of rapamycin complex 1 kinase, eIF4E eukaryotic translation initiation factor 4E, and S6K S6 kinase.

Used with permission from Brugarolas J. N Engl J Med 2007;356:185-187

mTOR, the mammalian target of rapamycin, is an intracellular kinase that regulates cellular responses to nutrients, energy and exogenous growth factors. When energy and nutrient resources are replete, or growth factors are stimulating the cells, or when defects in the cells upstream of mTOR provide aberrant stimulation of its activity, mTOR turns on the translation of proteins that drive cell growth, cell proliferation and production of angiogenic growth factors (HIF-1, VEGF, PDGF). Inhibiting mTOR blocks cell cycling at the G1-S interface, inhibits cell growth and inhibits angiogenesis.

With the identification of multiple targeted agents that have demonstrated activity for RCC we will review results from trials presented at the 2007 Annual Meeting of the American Society of Clinical Oncology (ASCO).

Targeting the VEGF Pathway

Anti-VEGF Antibody

Bevacizumab

Bevacizumab is a monoclonal antibody that inhibits tumor angiogenesis by targeting VEGF. In a landmark study by Yang, et al. bevacizumab was well tolerated and significantly increased time-to-progression (TTP) compared with placebo, 2.5 versus 4.8 months.[2] In a multicenter Phase III trial, efficacy and safety of bevacizumab in combination with IFN-?-2a versus IFN-?-2a and placebo as first-line treatment administered to nephrectomized patients with metastatic clear cell RCC were evaluated.[3] Dr. Escudier reported that bevacizumab in combination with IFN-?-2a was well-tolerated and significantly improved both the objective response rate (31% versus 13%, p< 0.001) and progression-free survival (PFS) (10.2 versus 5.4 months, p < 0.001). Furthermore, dividing patients into favorable and intermediate prognostic categories demonstrated a significant PFS.

Researchers also evaluated a regimen of low-dose IL-2 plus bevacizumab. This regimen was associated with modest toxicity with demonstrable antitumor activity. [4] Laboratory studies demonstrated an inhibition of VEGF and an increase in regulatory T cells with no effect on dendritic cell activation.

Multitargeted Kinase Inhibitors

Sunitinib

A Phase III randomized trial that evaluated sunitinib as first-line therapy versus IFN-? was also presented at ASCO 2007.[5] These investigators reported that sunitinib resulted in an overall response rate of 44% versus 11% associated with IFN-?. In patients with favorable to intermediate risk, the median PFS was 11 months for sunitinib versus 4 months for IFN-? (p < 0.000001). The benefit with sunitinib was apparent across all prognostic subgroups studied. Sunitinib had an acceptable safety profile.

Additional trials presented at ASCO supported the use of sunitinib in metastatic RCC. Rosenberg et al. updated the results of the two Phase II trials of sunitinib as second-line therapy in metastatic RCC patients.[6] A significant finding was that the median survival was approximately 2 years, which compared favorably to historical experiences of 12.7 months in second-line therapy studied with other agents.

Another study presented was a multi-institutional study investigating continuous daily administration of sunitinib in patients who were cytokine-refractory RCC utilizing an alternative dose of 37.5 mg daily, with continuous exposure either delivered in the morning or evening.[7] Srivanas et al. reported no significant difference of safety between the morning or evening schedule. Clinical benefit was demonstrated with a median PFS of 8.3 months. Objective RR was inferior compared with reports of 50 mg 4 weeks on, 2 weeks off.

Another study exploring the potential of sunitinib in bevacizumab-refractory metastatic RCC patients was presented at ASCO 2007.[8] The researchers indicated that sunitinib demonstrated antitumor activity with an objective RR of 23% and PFS of 7.5 months. This data clearly suggested the absence of cross-resistance between a VEGF monoclonal antibody (bevacizumab) and a multitargeted agent (sunitinib).

Sorafenib

An update of results was presented from the Phase III trial of sorafenib in advanced renal cell carcinoma.[9]Sorafenib significantly prolonged PFS, 5.5 months compared to 2.8 months following placebo. A persistent overall survival (OS) benefit with sorafenib was noted even after crossover with OS improving by 30%. However, final OS analysis demonstrated an improvement of 13.5% for sorafenib (median 17.8 months) versus placebo (median 15.2 months) and was not statistically significant. A secondary analysis of data demonstrated a significant OS benefit for sorafenib; thus, suggesting the crossover of approximately 50% of the placebo patients confounded the OS analysis.

A randomized Phase II trial of sorafenib versus IFN as first-line treatment in patients with metastatic RCC was presented by Szczylik et al.[10] Two parts of this trial were presented. The first part being a randomization to sorafenib 400 mg twice a day or IFN 9 million units a week, with part 2 consisting of an option of dose escalation to sorafenib 600 mg twice a day or crossover from IFN to sorafenib 400 mg twice a day upon tumor progression. With the PFS being the primary endpoint, the median for the sorafenib arm was 5.7 months versus 5.6 months for IFN. Thus, there is no significant difference. Both agents were well tolerated with the expected adverse events reported. Part 2 data supports the activity of sorafenib in IFN failures and demonstrated that increasing the dose of sorafenib stabilized tumor progression. The second analysis showed a median PFS of 5.3 months for patients who progressed on IFN and went on to receive sorafenib. In addition, a median PFS of 3.6 months was reported for patients who underwent dose escalation on sorafenib to 600 mg twice a day.

Studies combining IFN with sorafenib were also reported at ASCO 2007. The hypothesis here is that the molecular targeting of various pathways by sorafenib may enhance the anti-proliferative effects of IFN. In the study presented by Jonasch et al., the primary endpoint was PFS. The data suggested that there was no difference between low-dose IFN therapy alone or IFN plus sorafenib. Progression-free survival was 9.3 months in both arms.[11] However, Bracarda et al, investigating two schedules utilizing the standard dose of sorafenib with either IFN at 9 million units 3 times a week or 3 million units 5 times a week initiated 7 days prior to sorafenib, demonstrated an overall RR of the two groups to be 25% with an additional 40% of patients stable.[12] The regimen was well tolerated with common side effects being fatigue, skin rash and hand/foot syndrome. These researchers concluded that sorafenib plus IFN was a promising regimen for RCC with further research needed on dose and scheduling.

At this point we have discussed utilizing sorafenib at a standard FDA approved dose of 400 mg twice a day. An abstract presented by the Genitourinary Oncology Program at the Methodist Hospital Research Institute explored an opportunity of a more intensive drug administration.[13] This study allowed individual patient titration and was designed to evaluate the ability for individual dose-escalation, in addition to evaluating RR and PFS. The dose-escalation scheme was as follows: 400 mg b.i.d. days 1-28, 600 mg b.i.d. days 29-56 and 800 mg b.i.d. day 57 throughout. Overall response was 55% (16% CR, 39% PR) and an additional 20% of patients were stable 6 months or more. Dose-escalation was achieved in 93% of patients to the 1200 or 1600 mg per day dose. The dose-escalation of sorafenib was well tolerated with the expected side effects being dermatitis, hand/foot syndrome and diarrhea. The high level of antitumor activity demonstrated by the 55% CR and PR rate in addition to the prolonged median TTP of 8.4+ months requires confirmation of the present data and a pharmacologic evaluation to understand dose escalation of sorafenib.

PTEN/AKT Pathway: Mammalian Target of Rapamycin (mTOR) Inhibitors

Temsirolimus

Temsirolimus is a rapamycin derivative and cell-death cycle inhibitor. In a phase III randomized trial,treatment naïve metastatic RCC patients were randomly assigned to receive temsirolimus alone, IFN-? alone, or both.[14] Overall survival was significantly better in the group that received temsirolimus alone (10.9 monts) than in the groups that received the combination (7.3 months) or IFN-? alone (8.4 months). A breakdown of patients based on tumor histology, age and prognostic risk factors was presented. Single agent temsirolimus was associated with a statistically significant improvement in OS when compared to IFN in not only the clear cell population but in addition to other histologies. Furthermore, age did not influence outcome and there was activity demonstrated in the various prognostic groups. A second abstract presented by Parasuraman et al. clearly demonstrated that temsirolimus has a significantly greater quality-adjusted survival (time without symptoms and toxicity) compared to IFN alone. [15]

Temsirolimus was recently approved by the FDA for treatment of patients with advanced RCC.

RAD001 (Everolimus)

Everolimus is an oral derivative of rapamycin with activity in metastatic RCC demonstrated in Phase I studies. The pharmacodynamics of everolimus have been studied using both weekly and daily dosing regimens. Findings from preclinical-clinical modeling studies and clinical pharmacodynamic studies have demonstrated that daily dosing with 10 mg achieves consistent inhibition of mTOR signaling, while weekly dosing with 70 mg per week does not achieve the same consistent target inhibition. A Phase II study reported by Jac et al. reviewing the efficacy of daily oral everolimus in patients with advanced clear cell RCC demonstrated promising antitumor activity, a 33% RR with a median PFS of 11+ months.[16] A breakdown for the partial responders demonstrated a median PFS of 23.7+ months. Everolimus was well tolerated with the typical mTOR side-effects being mucositis, skin rash, hyperglycemia, hypertriglyceridemia, hypercholesterolemia and less than 20% reported incidents of pneumonitis.

Prognostic Factors

A number of retrospective analyses of prognostic factors for survival in patients with metastatic RCC have been reported in the literature. Efforts to refine these factors are currently underway. Three studies highlighted this point. First, a collaborative evaluation reported the use of carbonic anhydrase IX (CAIX) expression and VHL gene mutation prediction for survival in RCC patients. [17] The authors concluded low CAIX expression in association with the absence of VHL mutation predicts for a poor prognosis in patients with clear cell RCC. A multicenter review confirming the prognostic value of interleukin-6 (IL-6) and VEGF, and testing the role of macrophage colony-stimulating factor (M-CSF) and macrophage inflammatory protein 3-alpha (MIP-3a) to survival in MRCC patients of good and intermediate risk prognostic groups was reported.[18] OS was highly correlated with IL-6, VEGF and M-CSF but not with MIP-3a in a univariate analysis. However, only VEGF remained independently prognostic for OS in a multivariate analysis. This further supported the therapeutic interest and strategies targeting the VEGF receptor.

Finally, the abstract reported by Choueiri et al. is a multicenter experience of the VHL mutation predicting for an objective response to VEGF targeted therapy.[19] Baseline frozen or paraffin embedded tumor samples were received for patients who received VEGF targeted therapy. VHL gene status was reported and correlated to RR. The presence of VHL mutation was demonstrated as a prognostic factor associated with an improvement in RR.

Future directions of Antiangiogenic Therapy in RCC

Sequencing

One of the questions emerging with the development of targeted therapies is whether combinations of agents can improve outcomes while maintaining acceptable side-effect profiles. Several trials, not yet mature, but providing hypothesis and rationale for various concurrent regimens are an important focus. These include: Phase I study of sunitinib and IFN; Phase I and II study of temsirolimus and bevacizumab; Phase I and II of sunitinib plus gefitinib; and Phase I of bevacizumab plus sunitinib.

Antiangiogenic Combinations

A dose and safety trial for sunitinib combined with IFN was reported at ASCO.[20] The authors concluded that the safety and efficacy of 37.5 mg of sunitinib, 4 weeks on with a 2 week break with continuous IFN at 3 million units, 3 times a week, needs to be further explored. Although a small number of patients were necessary to complete this Phase I trial, antitumor activity was observed and the adverse events seen were similar to previous reports of sunitinib, the single agent, neutropenia and fatigue being the predominant. Another study exploring the combination of VEGF inhibition signaling, a Phase I study to determine the maximum tolerated dose (MTD) of bevacizumab plus sunitinib.[21] Antitumor activity was observed. Hypertension was the most significant toxicity, the MTD being reported was sunitinib at 37.5 mg 4 weeks, 2 week off and bevacizumab at 10 mg per kilogram every 2 weeks.

The Phase I safety results using the mTOR inhibitor temsirolimus and the VEGF monoclonal antibody bevacizumab were reported. [22] The dose of 25 mg per week of temsirolimus with bevacizumab at 10 mg/kilogram dose every other week was the recommended dose for the Phase II study. The dose limiting toxicity was hypertriglyceridemia and mucositis. Antitumor activity was reported and thus a Phase II trial is underway.

Sunitinib plus gefitinib was reported to establish dose and feasibility of this combination.[23] The most common adverse events reported were gastrointestinal (diarrhea, nausea and hemorrhage). Antitumor activity was observed both in the form of partial response and stable disease, however, similar to that of sunitinib alone.

Conclusion

Based on the data, for first-line favorable- and intermediate-risk patients sunitinib has become the first choice. In the immediate future an additional option may be approved, bevacizumab plus IFN. For poor-risk patients, temsirolimus established itself as first-line therapy. However, for a selected group of patients, high-dose IL-2 remains an option. For second-line therapy, especially for cytokine failures, sorafenib is an appropriate choice.

Several key trials are emerging. First with confirmation of the intra-patient dose escalated sorafenib data, this would lead to a Phase III study comparing escalation of sorafenib to sunitinib. Second, with the maturity of the everolimus data presented this has led to an already accruing Phase III study for sunitinib and sorafenib failures. If positive results emerge from these two trials, this may impact the current treatment algorithm.

There are many questions that still need to be addressed, among them are defining strategies for optimal treatment selection and defining optimal combination therapy. The agent selection of therapy based on clinical features is helpful but is not ideal. The goal is to be able to select patients on the basis of molecular markers. For example, VHL mutation, and expression of CAIX, may predict for the activity with tyrosine kinase inhibitors. Emerging data evaluating the potential role of pS6 or pAKT expression in predicting activity with mTOR inhibitors will also be of great clinical interest.

Exploring combinations of targeted therapies is essential, but these explorations need to be based on an understanding of relevant pathways and mechanisms of resistance and escape. Combinations may involve vertical blockade, such as blocking the VEGF pathway at multiple points (e.g. sunitinib with bevacizumab or sorafenib with bevacizumab) or horizontal blockade that blocks multiple different pathways (e.g. an mTOR inhibitor – such as temsirolimus or everolimus — with a VEGF inhibitor).

While questions remain, given the availability of multiple treatment options, progress will continue to be made as we further develop these agents.

References:

[1] American Cancer Society. Cancer Facts & Figures. 2007. Atlanta: American Cancer Society; 2007.

[2] Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. New Journal of Medicine. 2003; 349(5):427-34.

[3] B. Escudier, P. Koralewski, A. Pluzanska, et al. A randomized, controlled, double-blind phase III study (AVOREN) of bevacizumab/interferon-?2a vs placebo/interferon- ?2a as first-line therapy in metastatic renal cell carcinoma. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 3.

[4] J. A. Garcia, B. I. Rini, T. Mekhail, et al. A Phase II trial of low-dose interleukin-2 (IL-2) and bevacizumab in patients with metastatic renal cell carcinoma (mRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5103.

[5] R. J. Motzer, R. A. Figlin, T. E. Hutson, et al. Sunitinib versus interferon-alfa (IFN-?) as first-line treatment of metastatic renal cell carcinoma (mRCC): Updated results and analysis of prognostic factors. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5024.

[6] J. E. Rosenberg, R. J. Motzer, M. D. Michaelson, et al. Sunitinib therapy for patients (pts) with metastatic renal cell carcinoma (mRCC): Updated results of two phase II trials and prognostic factor analysis for survival. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5095.

[7] S. Srinivas, J. Roigas, S. Gillessen, et al. Continuous daily administration of sunitinib in patients (pts) with cytokine-refractory metastatic renal cell carcinoma (mRCC): Updated results. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5040.

[8] George DJ, Michaelson M, Rosenberg J, et al. Phase II trial of sunitinib in bevacizumab-refractory metastatic renal cell carcinoma (mRCC): Updated results and analysis of circulating biomarkers. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5035.

[9] R. M. Bukowski, T. Eisen, C. Szczylik, et al. Final results of the randomized phase III trial of sorafenib in advanced renal cell carcinoma: Survival and biomarker analysis. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5023.

[10] C. Szczylik, T. Demkow, M. Staehler, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon in patients with advanced renal cell carcinoma: Final results. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5025.

[11] E. Jonasch, P. Corn, R. G. Ashe, K. Do, N. M. Tannir, Randomized phase II study of sorafenib with or without low-dose IFN in patients with metastatic renal cell carcinoma. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5104.

[12] S. Bracarda, C. Porta, C. Boni, et al. Randomized prospective phase II trial of two schedules of sorafenib daily and interferon-?2a (IFN) in metastatic renal cell carcinoma (RAPSODY): GOIRC Study 0681. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5100.

[13] Amato RJ, Harris P, Dalton M, et al. A phase II trial of intra-patient dose-escalated sorafenib in patients (pts) with metastatic renal cell cancer (MRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5026.

[14] J. P. Dutcher, C. Szczylik, N. Tannir, et al. Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5033.

[15] S. Parasuraman, G. Hudes, D. Levy, et al. Comparison of quality-adjusted survival in patients with advanced renal cell carcinoma receiving first-line treatment with temsirolimus (TEMSR) or interferon-? (IFN) or the combination of IFN+TEMSR. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5049.

[16]. Jac, S. Giessinger, M. Khan, J. Willis, S. Chiang, R. Amato. A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5107.

[17] A. J. Pantuck, Q. Trinh, P. I. Karakiewicz, et al. Use of carbonic anhydrase IX (CAIX) expression and Von Hippel Lindau (VHL) gene mutation status to predict survival in renal cell carcinoma. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5042.

[18] S. Negrier, S. Chabaud, B. Escudier, et al. Serum level of vascular endothelial growth factor (VEGF) as an independent prognostic factor in metastatic renal cell carcinoma (MRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5044.

[19] T. K. Choueiri, S. A. Vaziri, B. I. Rini, et al. Use of Von-Hippel Lindau (VHL) mutation status to predict objective response to vascular endothelial growth factor (VEGF) -targeted therapy in metastatic renal cell carcinoma (RCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5012.

[20] Kondagunta GV, Hudes G, Figlin R, et al. Sunitinib malate (SU) plus interferon (IFN) in first line metastatic renal cell cancer (mRCC): Results of a dose-finding study. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5101.

[21] Feldman DR, Kondagunta GV, Ronnen EV, et al. Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5099.

[22] J. R. Merchan, G. Liu, T. Fitch, et al. Phase I/II trial of CCI-779 and bevacizumab in stage IV renal cell carcinoma: Phase I safety and activity results. Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5034.

[23] Patel P, Kondagunta G, Redman B, et al. Phase I/II study of sunitinib malate in combination with gefitinib in patients (pts) with metastatic renal cell carcinoma (mRCC). Proceedings from the American Society of Clinical Oncology Conference. 2007. Chicago, IL. Abstract # 5097.

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