Treating Renal Cell Carcinoma in 2013

Sumanta Kumar Pal, MD

Over the past few years, seven new drugs have gained approval from the FDA for the treatment of patients with metastatic renal cell carcinoma (RCC). Primarily these approaches target angiogenesis and mTOR. The advent of these molecularly targeted therapies has significantly improved the standard of care for patients with RCC. Despite this, a clear need still exists to refine these treatments, and to discover novel treatment approaches.JTTsat down with Sumanta Kumar Pal, MD, at the Chemotherapy Foundation Symposium in New York City, to discuss adjuvant therapy, current challenges, and the future of treatments for patients with RCC. Pal is the codirector of the Kidney Cancer Program at City of Hope Medical Center in Duarte, California.

What is the role of adjuvant therapy in RCC?

Dr. Pal:This is a frequent consultation at my clinic from urologists. They’ll oftentimes see a patient with high-risk disease, perhaps pathologic T2 or T3 disease with sarcomatoid features and aggressive tumor grade, and the question will be, “Would you or would you not put this patient immediately on some of the targeted agents that are used in the metastatic setting?” I would argue right now, in 2013, the answer to that question is no.

What are some of the key trials for adjuvant therapy?

First and foremost, I would suggest that, at this point in time, adjuvant therapy is really not a standard of care for localized RCC. However, there are several studies that are potentially going to put these agents into that disease space.

So, for instance, in the category of VEGF-directed therapies, I can think of five trials that have been completed to date that assess targeted therapies directed at VEGF. Just as one example, the ASSURE trial, which was completed about 2 years ago now, compares sunitinib, sorafenib, and placebo in a large pool of patients—close to 2000 patients. That study will hopefully report out within the next 2 or 3 years.

We had a couple of important lessons learned from studies like the ASSURE trial. First and foremost, patients in the adjuvant setting may not tolerate the same doses that they might in the metastatic setting. For instance, in the ASSURE trial, doses had to be reduced with sunitinib and sorafenib. Patients, as opposed to starting out with the standard 50 mg/day of sunitinib or 800 mg total per day of sorafenib, received just 37.5 mg of sunitinib and literally half the dose of sorafenib therapy. So these might be important lessons moving forward.

We do have one trial in the adjuvant setting that looks at mTOR inhibition using the agent everolimus. This is the socalled EVEREST trial, and this trial compares everolimus versus placebo in a total pool of about 1100 patients. That study is about halfway accrued.

The only assessment of a targeted therapy that has been completed to date, that is outside of the VEGF- and mTORdirected categories, is for one of the nontraditional agents called girentuximab. This is an agent that targets CA9. These data were just reported at ASCO this past year, and girentuximab was not noted to have any significant impact on disease-free survival or overall survival—two of the critical endpoints in that study.

In the metastatic setting, is there an optimal treatment sequence?

Sequencing therapies in RCC is an incredibly complex issue. There are relatively firm guidelines set forth by groups like the NCCN that really inform us on how to utilize these agents. For instance, if you run into a patient with what’s categorized as poor-risk disease, you might want to start with the mTOR inhibitor temsirolimus. On the other hand, if you have a patient with good or intermediate-risk disease, I would typically start with a VEGF-directed agent—your options in that category are sunitinib, pazopanib, or bevacizumab. And we actually do have a good level of evidence for all three of those agents in that specific setting. There was a phase III data set pitting sunitinib and pazopanib headto- head against one another, and that data set I thought was somewhat equivocal, so I still tend to use sunitinib as my preferred first-line agent.

What are some of the challenges of treating patients with RCC?

People look at metastatic RCC as a disease in which there’s been massive progress, and I wouldn’t disagree with that. If we look at the trajectory of drug approvals in RCC between 1992 and 2005, they literally had one drug approval and that was for interleukin-2. From that point forward, we’ve actually had seven drug approvals—so incredibly promising for patients and their families.

But having said that, when I look at RCC, I fundamentally think that we have two buckets of targeted therapy. We have our VEGF-directed agents and our mTOR-directed therapies, and what I think the field is really lacking is that there are no novel approaches. So I’m really looking for trials with PD-1 inhibitors, PD-L1 inhibitors, and novel dual-targeting agents such as cabozantinib to really reshape the treatment paradigm for this disease.

Can you talk more about the potential of anti-PD-1 or anti-PD-L1 agents to treat RCC?

PD-1 inhibition refers to a process by which we actually stimulate the anti-tumor immune response. It resembles, at least to some extent, the CTLA-4 blockade that occurs with ipilimumab or tremelimumab, both of which have demonstrated some efficacy in the setting of melanoma. I would say that PD-1 inhibition right now is completely experimental in the domain of RCC, and there are agents outside of simply PD-1 inhibitors that are being assessed. For instance, the agent MPDL3280A is being assessed in the setting of RCC, and that’s a PD-L1 inhibitor. So, as opposed to inhibiting at the program death-1 or PD-1 receptor, it actually inhibits the ligand that binds to it.