Novel Therapies Shaking Up the Renal Cell Carcinoma Landscape

Published: Wednesday, Apr 13, 2016
Robert A. Figlin, MD

Robert A. Figlin, MD

Although therapeutic options for renal cell carcinoma (RCC) have expanded dramatically during the past decade, oncologists are faced with considerable complexity in selecting the right course of treatment for the individual patient, according to experts who participated in a recent OncLive Peer Exchange® roundtable. Indeed, decisions as to which drugs to administer first to an individual patient and, if necessary, the sequence of drugs or combinations for recurrent disease remain both controversial and challenging, the researchers said during a wide-ranging panel discussion entitled “Treating Advanced Renal Cell Carcinoma.”

When to Initiate Targeted Therapy

Panel members were in agreement that it is not necessary to start therapy right away for many patients with metastatic disease. Sandy Srinivas, MD, explained that she waits to make sure that there is growing disease before commencing therapy. In contrast, she offers therapy immediately to symptomatic patients with bulky disease.

Elaborating on this approach, Nizar M. Tannir, MD, FACP, pointed out that a patient presenting with advanced, primary in situ disease requires a different approach than a patient who had nephrectomy with a curative intent a few years earlier and now has recurrent disease. Since advanced disease suggests an aggressive cancer, patients in this category should receive therapy, said Tannir. In addition, surgery plays an important role in the decision-making process, in that there are patients with low-volume disease in a single organ who can be managed with surgery and not immediately started on systemic therapies, which are both costly and toxic.

Selecting an initial therapy is challenging, as there are no validated, established factors that predict with certainty that one agent is superior to any other in this context, noted Martin H. Voss, MD. He has not yet found tissue-based predictive factors to help him decide among FDA-approved options.

With each individual patient, his decision is based primarily on the person’s performance status and comorbidities. Thus, the patient who is very compromised at baseline is unlikely to be a good candidate for aggressive treatment, for example, with high-dose interleukin-2 (IL-2). Citing additional examples, Voss said a patient with significant cardiac disease would not be the best candidate for a VEGF tyrosine kinase inhibitor (TKI) and a patient with poorly controlled diabetes might not be the most appropriate candidate for an mTOR inhibitor.

Choosing a Frontline TKI Pazopanib Versus Sunitinib

Both pazopanib (Votrient) and sunitinib (Sutent) are first-line treatment options for patients with advanced RCC. In choosing between the two drugs, the findings of the COMPARZ phase III trial1 are helpful, said Tannir. In this large randomized trial involving 1110 patients, pazopanib was noninferior to sunitinib regarding progression-free survival (PFS).

Further, pazopanib was found to be superior to sunitinib in 11 out of 14 health-related quality-of-life domains and demonstrated superiority in relation to such adverse events as fatigue, stomatitis, and hand–foot skin reaction. In the subsequent phase II, double blind PISCES trial,2 patients picked pazopanib as the preferred agent by a 70% to 22% margin, mostly due to the perception that it caused less fatigue and offers a better overall quality of lide. Looking at these two trials in aggregate, pazopanib is certainly the preferred agent, said Tannir, adding the caveat that sunitinib was administered at a schedule that is now questioned.

Dosing Strategies

A criticism of the COMPARZ trial has been that some of the quality-of-life endpoints and the adverse event assessments were conducted precisely when sunitinib toxicity peaks at the 4-week mark, Voss pointed out. He and many other oncologists no longer make use of the schedule that the FDA approved years ago, which calls for 4 weeks on treatment followed by 2 weeks off.

Instead, Voss favors a 2-week on, 1-week off schedule. He said several retrospective studies have shown that the modified sunitinib schedule appears to yield essentially equivalent efficacy accompanied by moderated toxicities. Voss continues to use sunitinib with a considerable number of patients, and he points out there are more data with sunitinib than with any other TKI for patients with nonclear-cell RCC. These data show that sunitinib can be a very active agent for these patients; thus, for untreated patients with nonclear-cell RCC, sunitinib is his agent of choice outside of clinical trials. In contrast, for patients with clear-cell RCC in the frontline setting, he prefers pazopanib.

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