Improving Outcomes for Renal Cell Carcinoma through Clinical Trials

By Robert J. Motzer, MD,

Thursday, February 19, 2015

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Over the past decade, the availability of targeted therapy has radically improved both the number of therapeutic options and the outcomes for patients with metastatic ccRCC.

This cancer had previously been shown to be highly resistant to chemotherapy, and it responded only modestly to cytokine therapy. Interferon-alfa and high-dose interleukin 2 (IL-2) comprised the mainstay of therapy, with response rates of 10 to 15 percent and average patient survival of approximately one year.

Improved understanding of the genetics and molecular biology of ccRCC led to the identification of new targets for drug development. Of particular importance was the cloning of the von Hippel-Lindau tumor suppressor gene and the elucidation of its role in upregulating growth factors associated with angiogenesis.

Since 2005, US and European regulatory authorities have approved seven targeted agents for the treatment of metastatic RCC in various settings: sunitinib (Sutent®), everolimus (Afinitor®), axitinib (Inlyta®), sorafenib (Nexavar®), bevacizumab (Avastin®) plus interferon, pazopanib (Votrient®), and temsirolimus (Torisel®). Among these are anti-angiogenesis agents targeting vascular endothelial growth factor (VEGF) or the VEGF receptor, as well as inhibitors of mammalian target of rapamycin (mTOR).

In demonstrating efficacy in phase III trials for patients with advanced RCC, these agents changed the treatment paradigm, increased treatment options, and improved patient prognoses.

Table 1. Treatment Guidelines for Targeted Agents in Patients with Metastatic Renal Cell Carcinoma (based on Phase III trial results)
Patients Treatment

First-line: Favorable or Intermediate Risk



Bevacizumab + IFN

First-line: Poor Risk




Previously Treated



Prior Cytokine Therapy




Pivotal Phase III Trials

A risk model based on prognostic factors was developed at MSK and used in the design and interpretation of these phase III trials — and continues to be used for disease management today. (1) Five risk factors for short survival are based on pretreatment features (Table 2). Based on these, patients are assigned to three groups: favorable risk (zero factors), intermediate risk (one or two factors), or poor risk (three or more factors).

Table 2. MSKCC 2002 Risk Model Criteria
Risk Factors Criteria

KPS, %


Time from diagnosis to treatment with systemic therapy, months



< lower limit of laboratory’s reference range

Lactate dehydrogenase (LDH)

>1.5 x upper limit of laboratory’s reference range

Corrected serum calcium, mg/dL


Abbreviations: MSKCC, Memorial Sloan Kettering Cancer Center; KPS, Karnofsky performance status
NOTE: Risk groups defined as: 0 risk factors=favorable; 1-2 risk factors=intermediate; ≥ 3 risk factors= poor.

MSK provided leadership in early-stage trials of several of these drugs, including sunitinib and temsirolimus. (2) (3) (4) Our leadership in the design, conduct, and analysis of phase III trials contributed to regulatory approval in the United States and Europe for five of the seven approved targeted agents (Table 3). (5) (6) (7) (8) (9)

Table 3. Phase III Studies of Targeted Therapy for Renal Cell Carcinoma at MSKCC
Study Drug Comparator N Setting Endpoint (Reached Y/N) Conclusion

Sunitinib (4)

Interferon 750 First line PFS (Y) Sunitinib superior

Temsirolimus (5)

Interferon 626 First line, Poor Risk OS (Y) Temsirolimus superior
Everolimus (6) Placebo 410 TKI-refractory PFS (Y) Everolimus superior
Axitinib (7) Sorafenib 723 Second line PFS (Y) Axitinib superior
Temsirolimus (8) Sorafenib 512 Second line PFS (N), OS (N) Sorafenib superior OS
Pazopanib (9) Sunitinib 1100 First line PFS (Y) Pazopanib non-inferior to sunitinib
Tivozanib (10) Sorafenib 517 First line PFS (Y), OS (N) Tivozanib superior for PFS but not OS
Dovitinib (11) Sorafenib 570 Third line PFS (N) Sorafenib and dovitinib have similar efficacy
Sunitinib Placebo 600* Adjuvant PFS (accrual completed) Too early
Pazopani> Placebo 1500* Adjuvant PFS (accrual completed) Too early
Nivolumab Everolimus 850* Second and third line OS (accrual completed) Too early
Cabozantinib Everolimus 650* Second and third line PFS (accruing) Too early
Nivolumab + Ipilumumab Sunitinib 1200* First line PFS, OS (accruing) Too early
* Planned accrual
Abbreviations: OS= overall survival; PFS = progression-free survival; TKI=tyrosine kinase inhibitor

MSK also led pivotal phase III trials in the study of two experimental anti-angiogenic tyrosine kinase inhibitors (TKIs) — tivozanib and dovitinib — as well as other new agents (see below). (10) (11)

Some notable aspects of these trials include:

  1. The sunitinib phase III trial changed the paradigm of first-line therapy from cytokine treatment to anti-angiogenic therapy.

  2. The temsirolimus phase III trial demonstrated improved survival in the group of RCC patients most difficult to treat, the poor-risk group.

  3. The phase III everolimus trial was the first to show the benefit of sequencing targeted agents — now standard practice.

  4. The COMPARZ trial, which compared pazopanib to sunitinib as first-line therapy, was the largest trial ever conducted of an approved treatment for metastatic RCC and resulted in full approval for pazopanib in Europe. The median overall survival of three and one-half years is a landmark and highlights the better prognosis for patients in the era of targeted therapy.

  5. The COMPARZ trial also demonstrated the importance of considering safety profile and quality-of-life outcomes in choosing pazopanib over sunitinib, since both drugs have similar efficacy.

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Current Efforts to Improve Outcomes

Our phase III trial efforts continue. To date, no systemic therapy has proven beneficial as adjuvant treatment following nephrectomy for locally advanced RCC. The standard of care is active surveillance, and therefore the comparator arm for these phase III trials is placebo.

Success in treating patients with metastases led to the study of VEGF-targeted agents in the adjuvant setting. MSK is the lead center for the PROTECT trial, a 1,500-patient trial that compares pazopanib with placebo in patients with locally advanced RCC treated by nephrectomy. MSK also is the lead accruing site for the S-TRAC randomized phase III clinical trial. This 600-patient study is comparing sunitinib with placebo in patients with a high risk of recurrent RCC after nephrectomy.

Both studies have completed accrual and are projected to be completed in 2016. If the results of these trials are positive, these drugs will be the first to demonstrate benefit for RCC in the adjuvant setting.

The study of novel agents in phase III trials is a priority at MSK, which is a co-lead center in a phase III trial comparing cabozantinib with everolimus in metastatic RCC for patients whose cancer progressed on anti-VEGF therapy. Cabozantinib is a dual inhibitor of VEGF and c-MET, which is hypothesized to be a possible resistance mechanism for VEGF receptor–targeted therapy. This trial had a planned accrual of nearly 700 patients.

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The Promise of Immunotherapy

There is great interest in revisiting the role of immunotherapy in RCC with the development of next-generation targeted immunotherapy. A promising class of immunotherapy agents is checkpoint inhibitors, which act against mechanisms that slow or halt immune response. A randomized phase III trial comparing the anti-PD-1 agent nivolumab with everolimus for patients whose cancer progressed on first- or second-line VEGF-directed therapy completed enrollment of over 800 patients and will be analyzed based on overall survival.

Promising activity for the combination of checkpoint inhibitors nivolumab and ipilumumab was recently reported in a phase I trial for patients with renal cell carcinoma. A randomized phase III trial comparing this combination with sunitinib as first-line therapy for RCC is planned. These studies will help determine whether targeted immunotherapy with checkpoint inhibitors will result in another paradigm shift in the treatment of RCC.

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