The Therapeutic Landscape of Metastatic Renal Cell Carcinoma in 2012

In the last seven years, remarkable progress has transpired in the treatment of metastatic renal cell carcinoma (mRCC). Prior to 2005, therapy for advanced disease was limited to surgical resection and immunotherapy. Immunotherapy generally consisted of interferon-α, which induced short-lived responses and a median overall survival (OS) of 13 months.¹ The introduction of the targeted therapies (TT) has transformed the therapeutic landscape for mRCC. These agents inhibit the hypoxia-inducible factor (HIF) axis either through the vascular endothelial growth factor (VEGF) pathway, which regulates tumor angiogenesis, or via the mammalian target of rapamycin (mTOR), a protein important in cell growth, survival, and response to hypoxia. There are now seven FDA-approved TT including the multi-tyrosine kinase receptor inhibitors (TKIs: sunitinib, pazopanib, axitinib, sorafenib), an antibody to the VEGF-A ligand (bevacizumab), and the mTOR inhibitors (temsirolimus, everolimus). In treatment-naïve patients, four regimens have been approved based on level 1 evidence from randomized controlled trials: sunitinib, bevacizumab + interferon-α in combination, pazopanib, and temsirolimus^2-5 (Table 1).

Given the absence of clinical biomarkers to direct selection, consideration of the trial design and patient populations in which the TT was proven effective can direct choice. Histology (clear cell vs non-clear cell), the type of prior therapies, and the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic stratification (good/intermediate vs poor)⁶ should be taken into account when selecting a particular therapy. While the phase III registration trials have not shown a statistically significant increase in survival with the exception of temsirolimus in poor risk patients, patients are clearly living longer with TT treatment compared with the immunotherapy era.^1-5 Median OS is now >2 years with these agents, which represents a significant advance compared with a median 10 to 13 months in the immunotherapy era.^6,7

The approved first-line VEGF inhibitors include the TKIs sunitinib and pazopanib as well as bevacizumab plus interferon-α. They achieve objective response rates (ORR) of more than 30% and median progression-free survivals (PFS) of 9 to 11 months in the treatment-naïve setting.^4,5,8 Another investigational TKI, tivozanib, has shown promise. In a phase III comparator trial against sorafenib, tivozanib demonstrated a statistically significant improvement in median PFS of 11.9 months compared with 9.1 months (P = .042).⁹

Second-line TKIs include sorafenib and axitinib (Table 1). Sorafenib was the first TT to be approved in 2005. While its initial efficacy was not encouraging in the cytokine-naïve setting, it achieved approval given a median PFS of 5.5 months compared with placebo in a population of cytokine pre-treated patients.¹⁰ However, more recent phase III studies have used sorafenib as the comparator arm in the first- and second-line settings with greater than expected PFS results. This improvement suggests we understand better how to manage its toxicities after many years of experience. The potent selective VEGFR1-3 inhibitor, axitinib, has been approved in the second-line setting after demonstrating superiority over sorafenib with a median PFS of 6.7 months compared with 4.7 months in patients who had predominantly received one cytokine or sunitinib.¹¹ Ongoing studies of axitinib in the treatment-naïve setting are of major interest.

The mTOR inhibitors temsirolimus and everolimus are sirolimus analogues, which inhibit mTOR by binding to FkBP-12. While assumed to have similar mechanistic actions, the two drugs have been studied in very different patient populations (Table 1). The phase III trial of temsirolimus required poor-risk, treatment-naïve patients and demonstrated a statistically significantly superior OS of 7.3 months compared with interferon-α.^3,12 Everolimus was evaluated in VEGF inhibitor-refractory patients.¹³ Median PFS was superior at 4.9 months compared with placebo. It did not show an OS benefit, likely reflecting the crossover effect of control patients receiving everolimus upon progression.¹⁴ Ongoing studies should elucidate the clinical benefit of the mTOR inhibitors in the treatment-naïve and favorable disease settings. Outstanding questions include whether mTOR inhibitors achieve their primary effect through mTOR, HIF axis inhibition, or both, and whether oral and intravenous administration is equivalent and thus, the agents interchangeable.

Table 1. Phase III Targeted Therapy Trials in mRCC^a,b

Trial^c

N

Line

PFS (mo)

ORR (%)

OS (mo)

Sunitinib vs IFN-α^4,25

750

1

11 vs 5

47 vs 12

26.4 vs 21.8

Pazopanib vs BSC⁸

435

1/2

9.2 vs 4.2

11.1 vs 2.8 (untreated)

30 vs 3

22.9 vs 20.5

Bevacizumab+IFN-α vs IFN-α/Placebo^2,26

649

1

10.2 vs 5.4

31 vs 13

23.3 vs 21.3

Bevacizumab +IFN-α vs IFN-α^5,27

732

1

8.5 vs 5.2

26 vs 13

18.3 vs 17.4

Temsirolimus vs IFN-α³

626

1

3.8 vs 1.9

9 vs 5

10.9 vs 7.3

Sorafenib vs Placebo^10,28

903

2

5.5 vs 2.8

10 vs 2

17.8 vs 15.2

Everolimus + BSC vs Placebo + BSC^13,14

416

2+

4.9 vs 1.9

2 vs 0

14.8 vs 14.4

Axitinib vs Sorafenib¹¹

723

2

6.7 vs 4.7

4.8 vs 3.4 (sunitinib-pretreated)

12.1 vs 6.5 (cytokine-refractory)

19 vs 9

NR

BSC indicates best supportive care; mo, months; NR, no response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

^aStatistically significant results are in bold.

^bRisk groups refers to the Memorial Sloan-Kettering Cancer Center Criteria.⁶

^cAll trials required clear cell renal cell carcinoma with the exception of the temsirolimus trial, which permitted non-clear cell histologies.

With seven choices of similar mechanism agents, drug selection is often based on the eligibility criteria or line of therapy in which it was proven effective by level I evidence, toxicity profile, histology, and patient comorbidities (Table 2). Costs and availability are also important considerations. Further, while 80% of patients will achieve clinical benefit with the available TT, 10% to 20% have primary treatment refractory disease, and overall few cures are achieved. Disappointingly, ideal patient selection for the only curative agent, high dose IL-2, remains unclear. Novel approaches are clearly needed.

Several emerging agents with intriguing preliminary efficacy target possible resistance pathways including programmed death-1 (PD-1) and c-Met. BMS-936558 is a fully humanized monoclonal antibody against PD-1, a T cell receptor involved in immune tolerance.¹⁵ In 34 heavily pre-treated mRCC patients, BMS-936558 elicited a 27% ORR and 54% of patients were progression-free at 6 months.¹⁶ Activated c-Met promotes tumor growth, invasion, and metastasis, and c-Met has been implicated in acquired resistance to VEGF TT.¹⁷ Cabozantinib is an oral drug that inhibits both VEGFR and c-Met. In a small study of 25 mostly heavily pre-treated patients, median PFS was 14.7 months and 28% achieved a confirmed partial response.¹⁸

Table 2. Guide to Therapy Selection

VEGF Inhibitors

mTOR Inhibitor

Ideal Patient Population

• Favorable risk disease
• Good performance status
• Need for rapid response Symptomatic Presurgical
• Clear cell histology
• Co-morbidities: Refractory diabetes Poorly controlled dyslipidemia
• Prior VEGF inhibitor

• Poorer risk disease
• Poor performance status
• No need for tumor burden shrinkage
• Non-clear cell histologies
• Co-morbidities: Refractory hypertension Congestive heart failure Refractory thyroid disease
• Prior VEGF inhibitor

Notable Toxicities^{3,8,10,11,13,25-27,29}

• Fatigue
• Hypertension
• Rash
• Mucositis
• Proteinuria
• Myelosuppression
• Diarrhea
• Anorexia, taste changes
• Bleeding, epistaxis
• Thyroid dysfunction
• Rare but clinically significant: Congestive heart failure Thromboembolic events

• Fatigue
• Mucositis
• Acneiform rash
• Anorexia
• Nausea, vomiting
• Diarrhea
• Myelosuppression
• Pneumonitis
• Laboratory abnormalities Dyslipidemia Hyperglycemia

Finally, as germane to the practicing urologist, the question of the efficacy, safety, and optimal timing of cytoreductive nephrectomy (CRN) remains an area of active investigation with the targeted agents. In the absence of a prospective study, many physicans extrapolate from the SWOG 8949 and EORTC 30947 data demonstrating that CRN followed by interferon-α achieved a median 5.8 month survival benefit compared with interferon alone.¹⁹ In the TT era, some large retrospective studies have observed benefit from CRN and relative safety while others have found that activity can be associated with increased wound healing complications.^20,21 In addition, several small prospective studies have demonstrated the relative safety of preoperative VEGF inhibitors.^22,24 Two ongoing prospective European studies will answer the question of efficacy and safety of perioperative sunitinib. The CARMENA trial (NCT00930033) will answer the question of whether CRN followed by sunitinib has a survival benefit over sunitinib monotherapy. The SURTIME (EORTC30073) trial will investigate the optimal sequencing of the two interventions. Patients will be randomized to sunitinib followed by nephrectomy versus nephrectomy followed by sunitinib with a primary endpoint of PFS.

In conclusion, the treatment landscape for mRCC has dramatically improved due to more effective agents and better supportive care. Gone are the days of dismal outcomes with significant toxicity. Yet, progress is needed as we strive to identify curative agents, optimally integrate CRN, and best utilize available therapies by identification of predictive efficacy markers.

Author Affiliations:

¹Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA.

²Dana-Farber Cancer Institute, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.

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