Targeted therapy in metastatic renal carcinoma

Cancer Letters 343 (2014) 156–160

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Cancer Letters journal homepage: www.elsevier.com/locate/canlet

Mini-review

Targeted therapy in metastatic renal carcinoma Jane Mattei, Rodrigo Donalisio da Silva, David Sehrt, Wilson R. Molina, Fernando J. Kim ⇑ Chief of Urology, Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204, United States

a r t i c l e

i n f o

Article history: Received 27 August 2013 Received in revised form 23 September 2013 Accepted 26 September 2013

Keywords: Target therapy Renal cell carcinoma Metastatic disease Renal tumor Adjuvant treatment

a b s t r a c t Background: Advanced renal cell carcinoma is one of the most treatment-resistant malignancies to conventional cytotoxic chemotherapy. The development of new targeted therapy was result of understanding biological pathways underlying renal cell carcinoma. Our objective is to provide an overview of current therapies in metastatic renal cell carcinoma. Methods: MEDLINE/PUBMED was queried in December 2012 to identify abstracts, original and review articles. The research was conducted using the following words: ‘‘metastatic renal cell carcinoma’’ and ‘‘target therapy’’. Phase II and Phase III clinical trials were included followed FDA approval. Total of 40 studies were eligible for review. Conclusion: The result of this review shows benefit of these target drugs in tumor burden, increase progression-free and overall survival and improvement the quality of life compared with previous toxic immunotherapy, although complete response remains rare. Published by Elsevier Ireland Ltd.

1. Introduction Metastatic renal cell carcinoma is highly resistant to chemotherapy. Although a higher incidence of small renal masses are being detected, approximately one in three patients still present with metastases disease [1,2]. Immunotherapy including IL-2 and IFN-a had long been the main stay of treatment of advanced renal cell carcinoma (RCC) with responses only in a small subset of patients resulting in a 5-year survival of 6% [3,4]. Significant advances in the understanding of renal cell tumor biology have led to the development of molecular therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways resulting in significant improvement in overall survival and quality of life [1]. This aim of this systematic review is to provide a summary of contemporary and investigational therapies for the treatment of metastatic renal cell carcinoma.

The terms identified included names of following therapies; ‘Sunitinib’, ‘Sorafenif’, ‘Pazopanib’, ‘Axitinib’, ‘Cediranib’, ‘Everolimus’, ‘Temsirolimus’, ‘Bevacizumab’, and ‘Erlotinib’ Study inclusion criteria included contemporary articles published after 2000, were published in English, reported data of the Phase II and III Clinical Trials and of outcomes following FDA approval, one reviewer identified all studies that appeared to fit the inclusion criteria for full review. Total of 40 studies were eligible for review (see Fig. 1). 2.2. Data extraction and analysis Studies relevant to the targeted therapy of metastatic renal cell carcinoma were included. The following variables were extracted from each study: study name, period of the study, molecular targets of the drug, FDA approval status, and indication of treatment, recommended dosage of the drug, safety and efficacy of the drug. Efficacy was evaluated by the Overall survival (OS), progression free survival (PFS), and time to progression (TTP) as defined by the FDA Center for Drug Evaluation and Research. Safety was evaluated by the severity of adverse events defined by the Common Toxicity Criteria (CTC) (see Table 1).

3. Evidence synthesis 2. Methods 2.1. Search strategy and study selection The systemic review of targeted therapies in metastatic RCC was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was aimed at finding relevant studies and clinical trials from PUBMED/MEDLINE (1966–2013). Targeted therapies were identified by researching ‘‘target therapy and ‘‘metastatic renal cell carcinoma’’.

⇑ Corresponding author. Tel.: +1 303 436 6575. E-mail address: [email protected] (F.J. Kim). 0304-3835/$ - see front matter Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.canlet.2013.09.038

3.1. VEGF targeted therapies Renal cell carcinomas are among the most vascularized of all solid tumors and angiogenesis is critical for tumor growth and progression. Vascular endothelial growth factor and its receptorVEGF/VEGFR mediate VEGFR regulation of vessel permeability, endothelial cell activation, survival, proliferation, invasion and migration. Receptors for VEGFR and PDGFR exhibit tyrosine kinase activity and, upon ligand binding, activate downstream signaling pathways as the Raf/MEK/ERK [5]. Raf is a key in regulating endothelial cell survival, during angiogenesis, via effects on

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Fig. 1. Therapeutic biological pathways in renal-cell carcinoma.

intrinsic and extrinsic apoptosis pathways [6–8]. A number of drugs have been developed to target this pathway. 3.2. Sorafenib Sorafenib was the first antiangiogenic multikinase inhibitor for mRCC approved by the FDA (2005). It is an oral multikinase inhibitor with activity against RAS family, VEGFR-1-3 and PDGFR 7. Sorafenib is considered a second line therapy and recommended dose is 400 mg twice a day. The TARGET trial (Phase III) evaluated the efficacy of sorafenib vs. placebo in 903 patients who had failed previous standard therapy. 8 Interim analysis showed a significantly longer PFS with sorafenib compared to placebo (5.5 vs. 2.8 months; p < 0.001). Partial responses were reported in 10% of patients receiving sorafenib and in 2% of those receiving placebo (p < 0.001). The placebo patients were allowed to cross over at that time that sorafenib showed to reduce the risk of death. After 16 months after crossover, the overall survival time in the sorafenib treated cohort was 17.8 months compared with 15.2 months for the placebo group (p < 0.146). After censoring of the crossover patients, the estimated overall survival for the placebo-treated patients was 14.3 months. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity [7–9]. 3.3. Sunitinib Sunitinib soon followed and was approved by the FDA in 2006. Sunitinib also is an inhibitor of VEGFR1-3 and PDGFR. It has also direct antitumor effects on ligands which promotes the proliferation and differentiation of hematopoietic cells as the Fms-like tyrosine kinase 3 (FLT3), stem-cell factor receptor (c-KIT) [10,11]. Sunitinib is considered a primary option for the treatment of

mRCC. It is orally administered with the recommended daily dose of 50 mg/day by a schedule 4/2. The Phase III trial of sunitinib enrolled 750 patients and compared sunitinib to interferon. Sunitinib doubled progressionfree survival (11 months vs. 5 months). The objective response rates were 47% and 12% for sunitinib and interferon-a, respectively (p < 0.001) and the median overall survival was 26.4 months for sunitinib and 21.8 months for interferon-alfa (p = 0.051) [12]. Moreover, a global expanded access Phase III study with 4564 patients was conducted to provide sunitinib on relatively unselected or trial-ineligible patients with brain metastases and with poor ECOG performance status. Results showed a median progression-free survival of 10.9 months and median overall survival of 18.4 months with similar overall survival in patients with and without prior cytokine therapy. Adverse events related with sunitinib included hypertension, fatigue, diarrhea and hand-foot syndrome, but none of these adverse events were graded with high severity. When applied Q-TWiST (quality-adjusted time without symptoms of disease progression or toxicity of treatment) score, sunitinib resulted better clinical efficacy and quality-of-life outcomes compared with IFN-alfa for mRCC patients [13]. 3.4. Pazopanib Pazopanib was approved by the FDA in 2009 and is a second generation of multi-target tyrosine kinase receptor. It is an orallyan orally bioavailable, multi-targeted TKI that inhibits the function of multiple receptor kinases including VEGFR1-3, RET and c-kit [14– 16]. It is recommended as a first-line treatment and an option as a second line in previously cytokine-treated patients [17,18]. The drug is administered orally with 800 mg once daily. The Phase III trial showed a significant improvement in PFS and RR in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC. Of 435 patients enrolled, the

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Table 1 Molecular targeting agent clinical trial outcomes in the treatment of renal cell carcinoma. Mechanism

Therapy

Average Cost of Medication (per month)

Target

Line of therapy

Study

PFS (months)

VEGF inhibitor

Sorafenib

$2831.18

Second linecyto

Sorafenib vs. Placebo

Sunitinib

$3029.50

First line

Sunitinib vs. IFN

5.5 vs. 2.8* 11 vs. 5*

Pazopanib

$4264.42

VEGFR2-3; PDGFR; RAF; cKit VEGFR1-3; PDGFR; KIT; FMS;FLT3 VEGFR1-3; PDGFR, c-kit

First line First line

Pazopanib vs. Sunitinib Pazopanib vs. Placebo

Second line

Pazopanib vs. Placebo

First line

Axitinib vs. Sorafenib

Second linecyto,

Axitinib vs. Sorafenib

Axitinib

$11,339.33

VEGFR1-3; c-Kit; PDGFR– B

vegf, mtor

Cediranibi Bevacizumab-IFN

+

$2743.93

VEGFR1-2; c-Kit

First line

Cediranib vs. Placebo

VEGF

First line

Bevacizumab-IFN vs. IFN Bevacizumab-IFN vs. IFN

mTOR inhibitors

BevacizumabErlotinibi

$4864.58

EGFR tyrosine kinase

First line

Temsirolimus

$4167.95

mTOR; HIF1-2; VEGF

First line

Bevacizumab-Erlontinib vs Bevacizumab Temsirolimus vs. IFN vegf

Everolimus

$4866.67

mTOR; HIF1; VEGF

Second line Second/third linevegf

Temsirolimus vs. Sorafenib Everolimus vs. Placebo

8.4 vs. 9.5 11.1 vs. 2.8* 7.4 vs. 4.2* 10.1 vs. 6.5* 6.7 vs. 4.7* 12.1 vs. 2.8* 8.5 vs. 5.2* 10.2 vs. 5.4* 9.9 vs. 8.5 10.9 vs. 7.3* 4.3 vs. 3.9 4.9 vs. 1.9*

PFS – prgression free survival; i – investigational drug; cyto – Post-cytokine; vegf – Post-VEGF; mtor – Post-mTORi; + excludes cost of IFN; costs are based on our institutional 340b pricing. * Statistically significant.

PFS in the overall study population was a median 9.2 vs. 4.2 months (p < 0.0001); the treatment-naive subpopulation was a median was 11.1 vs. 2.8 months (p < 0.0001) and cytokine-pretreated subpopulation was a median of 7.4 vs. 4.2 months. Treatment-naive pazopanib-treated patients had a RR of 32%, while cytokine-pretreated patients had a RR of 29%. The final OS results showed a median OS of 22.9 vs. 20.5 months, which were not significantly different (p = 0.224). Pazopanib demonstrated acceptable safety and tolerability, even though it has been associated with liver toxicity. Adverse events were hair color changes, nausea, anorexia, vomiting and the Grade 3–4 toxicity were hypertension and diarrhea [19].

3.5. Axitinib In 2012, the FDA approved axitinib and it is another secondgeneration multi-target tyrosine kinase inhibitor, target in VEGFR1–3, c-Kit and PDGFR. Its potency is 50–450 times greater than the first-generation VEGFR inhibitors [20,21]. Axitinib is an option as a second-line therapy option in cytokine-refractory metastatic RCC. The recommended dose schedule of axitinib is 5.0 mg twice daily [22]. A total of 723 patients were enrolled in the Phase III trial comparing the efficacy of axitub to sorafenib. The median PFS was 6.7 months with axitinib compared to 4.7 months with sorafenib (p < 0.0001). In the Phase II trial the OS was 29.9 months and a TTP of 15.7 months. The overall response rate was 22.6%, and the median duration of response was 17.5 months. Axitinib presented adverse events which were similar to sorafenib, including diarrhea, hypertension, fatigue, and dysphonia and hand-foot syndrome23. Toxicities in the Phase II trial were mild to moderate and were manageable. Grade 3–4 adverse events included hand-foot syndrome, fatigue, hypertension, dyspnea, diarrhea, dehydration and hypotension.

3.6. Cediranib Cediranib is an investigational drug under the FDA. It is an ATPcompetitive inhibitor of receptor tyrosine kinases (RTKs) members’ related family of VEGF1-3 in nanomolar concentration [14]. The drug is being evaluated as a first-line therapy. The recommend dose is 45 mg/day A Phase II compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signaling inhibitor 34% patients on Cediranib patients achieved a partial response and 47% experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo with median 12.1 vs. 2.8 months (p = 0.017). In addition, more than half of patients who achieved a partial response with cediranib experienced responses lasting more than a year. The most common adverse events for patients were diarrhea, fatigue, hypertension and dysphonia. These events were manageable by supportive care or dose reductions reductions [23,24].

3.7. Bevacizumab Bevacizumab is a human recombinant IgG monoclonal antibody who target VEGF-2, occurring increase of vascular permeability and reducing proliferation and migration of endothelial cells [14]. FDA approved in 2009 at 10 mg/kg IV every 2 weeks in combination with interferon alfa. A phase III (CALGB 90206) [25] randomized trial of bevacizumab (10 mg/kg each 2 weeks) plus IFN-alfa (9 million U/3 times weekly) vs. IFN-alfa monotherapy was conducted in a 732 metastatic RCC previously untreated. ORR with bevacizumab plus IFN-alfa wasalfa was higher compared to IFN monotherapy (25.5 vs. 13.1% p < 0.0001). The median OS was 18.3 months for bevacizumab plus IFN-alfa and 17.4 months for IFN-alfa monotherapy

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(p = 0 .097). There was significantly more Grade 3–4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFNalfa. Another Phase III trial (AVOREN) with 649 patients previously untreated were randomized to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN-alfa (9 MUI) or placebo and IFN-alfa. Rates of overall response and stable disease in the bevacizumab plus IFN-alfa vs. placebo plus IFN-alfa arms were 31% and 46% vs. 13% and 50%, respectively. Compared to the control group, the median PFS was significantly longer in the bevacizumab and IFN-alfa (10.2 vs. 5.4 months; p < 0.0001). The combination of bevacizumab and interferon resulted a significant improvement in progression-free survival compared with interferon-alfa. Fatigue, asthenia and proteinuria were the most common grade 3 toxicities [26]. 3.8. Erlotinib Erlotinib is an orally available and inhibits the tyrosine kinase domain of epidermal growth factor receptor (EGFR) leading to the inhibition of EGFR autophosphorylation and downstream signaling [27]. Erlotinib is waiting awaiting FDA approval, but the recommend dose is 150 mg/day. Erlotinib demonstrated encouraging activity in renal cell carcinoma when was associated with bevacizumab in a Phase II trial 63 patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg/2 weeks and erlotinib 150 mg/daily. From 59 assessable patients, 25% had objective responses and 61% had a stable disease after 8 weeks and survival at 18 months was 60% [28]. However, a randomized, double-blind, Phase II trial of erlotinib and bevacizumab compared with bevacizumab alone was not superior than to only bevacizumab. The treatment was well tolerated and the most common toxicity was skin rash [29]. Other Phase II evaluated erlotinib combined with sirulimus in metastatic RCC 25 patients previously treated with sunitinib and/ or sorafenib were evaluated. No complete or partial responses were observed, but stable disease was noted in 21.8% of patients in 46 months. The progression-free survival and overall survival were 12 and 40 weeks respectively. This study did not show advantage in a combination of erlotinib and sirolimus over a single-agent as second line therapy [30]. 4. Mammilian target of rapamycin (mTOR) inhibitors Another underlying signaling pathways in RCC is the mammalian target of rapamycin (mTOR) pathway, which has a critical role in the regulation of cell growth, proliferation and angiogenesis and angiogenesis [31]. This pathway is under influence of important ant growth factors as EGF, IGF-1, PDGFR and MAPK pathway. Has been demonstrated that mTOR pathway is more significantly altered in clear-cell RCC, high-grade and tumors with poor prognostic features [32,33]. 4.1. Everolimus Everolimus is a specific mTOR inhibitor, a downstream member of the RAS/PI3K/PKB pathway. It was approved by FDA in 2009 as an option in advanced RCC patients who had failed treatment with VEGF therapy. Usual dose is 10 mg once daily [34]. Phase II trial demonstrated antitumor activity in 41 metastatic RCC who had received at maximum one previous therapy. Everolimus dose was 10 mg daily/28-day cycle. Results showed a median progression-free survival of 11.2 months and the median overall survival of 22.1 months. Partial responses were observed

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in 5 patients, stable disease lasting 3 months was reported in 27 patients and stable disease lasting 6 months was reported in 21 patients. Nausea, diarrhea, stomatitis, pneumonitis and rash were the main Grade 3–4 side effects of everolimus [35]. Antitumoral activity was demonstrated in a Phase II trial at combination of everolimus and bevacizumab. Metastatic renal cell carcinoma patients without previous therapy or who had failure to sunitinib and/or sorafenib were eligible 80 patients, 50 untreated and 30 previously treated, received bevacizumab 10 mg/kg intravenously every 2 weeks and everolimus 10 mg orally daily. The median progression-free survivals in previously untreated were 9.1 months and previously treated were 7.1 months. Proteinuria was the most important adverse event [36]. A Phase III trial, controlled by placebo, with everolimus as a second-line therapy for advanced clear cell carcinoma refractory to sunitinib, sorafenib or both agents 410 patients were randomized to receive everolimus 10 mg or placebo in addition to best supportive care. Patients were stratified according MSKCC (Memorial Sloan-Kettering Cancer Center) prognostics score as favorable, intermediate or poor risk, and whether they had previously received one or two VEGF receptor tyrosine kinase inhibitors. PFS was significantly prolonged for everolimus 4.9 months compared with placebo, 1.87 months [37]. Stomatitis, rash, diarrhea and non-infectious pneumonitis were the most common toxicities.

4.2. Temsirolimus Temsirolimus is another specific mTOR inhibitor and inhibits tumor angiogenesis by reducing synthesis of VEGF 14. Temsirolimus was approved by FDA in 2007 for advanced/metastatic RCC patients with three or more poor prognostic features. The standard dose is 25 mg i.v/weekly. A combination of temsirolimus and interferon-alfa was performed in a Phase I/II trial [38] for advanced RCC in ascending-dose to up 25 mg/once a week combined with IFN-6 or 9 million U three times per week. 71 RCC were eligible and the recommended doses for temsirolimus was 15 mg and for IFN-a 6 million U. Among patients who received the recommended dose, 8% achieved partial response, 36% stable disease for 24 weeks and the median progression-free survival for all patients was 9.1 months. Adverse events were stomatitis, fatigue, nausea/vomiting and grade 3 toxicities included leukopenia and hypophosphatemia. A multicenter Phase III [39] trial enrolled 626 advanced and poor prognosis patients and confirmed that temsirolimus plus interferon did not improve survival. Patients with no previous treatment received 25 mg of intravenous temsirolimus weekly, 3–18 million U of interferon alfa/3x week or a combination of 15 mg of temsirolimus weekly plus 6 million U of interferon alfa/ 3x week. Patients on temsirolimus alone had longer overall survival and progression-free survival (p < 0.001) than patients who received interferon only (p < 0.001). The combination showed increased toxicity with no significant improvement in OS when compared to IFN-alfa alone. Median overall survivals in the interferon, temsirolimus and combination groups were 7.3, 10.9, and 8.4 months, respectively. A OS of temsirolimus monotherapy was longer compared to IFN-a monotherapy (medians, 10.9 vs. 7.3 months) and median PFS time for the temsirolimus was 5.5 months compared with 3.1 months on Interferon-alfa) (p = 0.001). The most common adverse events were rash, peripheral edema, hyperglycemia and hyperlipidemia in the temsirolimus group, whereas asthenia was more significant in the interferon group. Grade 3–4 toxicity occurred in almost 90% of patients in a combination therapy.

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4.3. Cytoreductive nephrectomy in target therapy era Cytoreductive nephrectomy has been shown to extent overall patients survival in the multimodal treatment of metastatic RCC. For targeting agents there is no current knowledge whether cytoreductive surgery is advocated before or after successful medical therapy. In target therapy era it’s likely to remain part of the treatment and it’s recommended when possible. Completed remove of metastasis contributes to improved clinical prognosis and should be considered when feasible [40]. 5. Conclusion In recent years, the clarification of molecular mechanisms of RCC has permitted a tremendous progress in development and approval of multiple targeted agents for treatment of advanced RCC. Therapy targeted at the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways now represents the standard of care in metastatic RCC. The third generation of tyrosine kinases inhibitors appears has similar efficacy or superior than existing agents, but with more acceptable toxicity. However, more studies need to be performed comparing patient populations in both groups. Each of these therapies offers a very evident clinical benefit as reduction in tumor burden, increasing progression-free, overall survival and improves the quality of life compared with previous therapy. On the other hand, complete responses have been only rarely noted, necessitating continual therapy for most patients. Therefore, considerable challenges still face this field and several questions remain to be answered. It is unknown if any clinical benefit is added in initiating a second targeted therapy before patients experience disease progression. Also, is not clear about the most favorable sequencing therapies and whether they have a role in the adjuvant setting. These are important questions for future studies in order to eradicating or increase survival and quality of life of renal cell carcinoma patients. Conflicts of Interest Fernando J. Kim is a principal investigator for Olympus, Covidien, and Healthtronics. Wilson R. Molina has a fellowship grant with Boston Scientific. References [1] Y. Najjar, B. Rini, Novel agents in renal carcinoma: a reality check, Ther. Adv. Med. Oncol. 4 (4) (2012) 183–194. [2] W. Stadler, Targeted agents for the treatment of advanced renal cell carcinoma, Cancer 104 (11) (2005) 2323–2333. [3] W. Berg, C. Divgi, D. Nanus, R. Motzer, Novel investigative approaches for advanced renal cell carcinoma, Semin. Oncol. 27 (2) (2000) 234–239. [4] T. Dorff, A. Goldkorn, D. Quinn, Targeted therapy in renal cancer, Ther. Adv. Med. Oncol. 1 (3) (2009) 183–205. [5] R. Janusz, S. Robert, Rasregulation of vascular endothelial growth factor and angiogenesis, Methods Enzymol. 333 (2001) 267–283. [6] R. Hilger, M. Scheulen, D. Strumberg, The Ras–Raf–MEK–ERK pathway in the treatment of cancer, Onkologie 25 (6) (2002 December) 511–518. [7] Rini B. Sorafenib, Expert. Opin. Pharmacother. 7 (4) (2006) 453–461. [8] B. Escudier, T. Eisen, W.M. Stadler, et al., Sorafenib in advanced clear-cell renalcell carcinoma, New Engl. J. Med. 356 (2) (2007) 125–134. [9] M.J. Ratain, T. Eisen, W.M. Stadler, et al., Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma, J. Clin. Oncol. 24 (16) (2006) 2505–2512. [10] R. Motzer, B. Rini, R. Bukowski, et al., Sunitinib in patients with metastatic renal cell carcinoma, JAMA 295 (21) (2006) 2516–2524. [11] Rini B. Sunitinib, Expert. Opin. Pharmacother. 8 (14) (2007) 2359–2369.

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