Redefining the Role of Cytoreductive Nephrectomy in RCC

Peter E. Clark, MD

The addition of cytoreductive nephrectomy to sunitinib (Sutent) did not provide a survival benefit in patients with metastatic renal cell carcinoma (RCC), according to findings from the phase III CARMENA trial. The issue now, explained Peter E. Clark, MD, is how to integrate these findings into established paradigms.

Results of the study showed that the median overall survival (OS) was 18.4 months for patients who received sunitinib alone compared with 13.9 months for those who received surgery followed by sunitinib (HR, 0.89; 95% CI, 0.71-1.10).

The TKI produced similar median OS outcomes for patients with intermediate (23.4 vs 19.0 months; HR, 0.92; 95% CI, 0.68-1.24) and poor prognosis (13.3 vs 10.2 months; HR, 0.85; 95% CI, 0.62-1.17). Patients with good prognosis were not eligible for trial enrollment.

For patients with RCC, the standard of care has been cytoreductive nephrectomy followed by systemic therapy. Although the data from the phase III trial might not change the treatment approach for good-risk patients, it showed that intermediate- and poor-risk patients can be spared unnecessary surgery and the associated adverse events.

Because cytoreductive nephrectomy still plays a role in the management of some patients, the goal should be to develop an effective biomarker to determine the subset of patients who will derive the most benefit from the procedure.

OncLive: What is the current role of cytoreductive nephrectomy in RCC?

In an interview at the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Clark, chair of urology at Levine Cancer Institute, discussed the role of surgery in the rapidly evolving treatment paradigm for patients with RCC.Clark: Traditionally in RCC, unlike other cancer types, surgery retains an important role in the management of the disease despite the patient having metastases. That is what we refer to as a cytoreductive nephrectomy…That paradigm was developed about 20 years ago with randomized trials using older therapeutic approaches that we do not even use anymore.

The question that has recently been brought up is, “Now that we have systemic therapy using TKIs, does that old paradigm still apply?” There was a clinical trial called CARMENA that tested the notion of whether a cytoreductive nephrectomy added value when it was added to systemic therapy involving a TKI—in this case, sunitinib. The bottom line is that CARMENA showed there really was not a difference. Frankly, this was a shock to most of us. Most of us assumed there would be at least some difference.

The issue now is how to integrate these findings into our old paradigms. How do we readjust the way we thought about cytoreductive nephrectomy in this space? The takeaway message is that it really boils down to patient selection. CARMENA tells us there is not as much advantage to surgery as there was before. You need to be particularly selective in who you choose to do this procedure with. We should not be using it freely and we should not be using it in the highest-risk patients. Do not use it in patients who have unresectable disease.

Is there potentially a biomarker to determine which patients will most benefit from this approach?

Essentially, do not push the envelope. We used to always push the envelope because we thought we were automatically prolonging survival with a nephrectomy.That is the holy grail. It would be extremely useful if we could do a better job of understanding who has rapidly progressive disease and in which patients surgery will not be particularly useful. For those who have indolent disease, we can assume a nephrectomy would be useful and buy them some time. Right now, we mainly use clinical factors to try to determine the natural history of the disease. If we have a biomarker, that would be very helpful.

How has the rise of TKIs changed the treatment landscape for RCC?

Often, we are making a decision for a patient when they first get diagnosed. We do not know much about the disease at this point. We also need biomarkers to try to pick which systemic therapy to use. We need a variety of different techniques.It has completely revolutionized the way we treat kidney cancer. In the old days, we mostly used interferons; this was kind of useless. There was another drug called high-dose interleukin-2, which in a very select group of patients would work well, but it was very toxic. We really had almost no effective treatments.

In the RCC space, what further research is needed?

TKIs have opened the door to a slew of new therapies. We also have checkpoint inhibitors, which have really turned everything on its head. The current menu of drugs is enormous; it is remarkable. We went from basically having nothing on the menu to now having a whole new challenge, which is in sequencing.It would probably be in developing predictive biomarkers to decide which therapy to hit the tumor with first. This would have the most impact. If there is a class of drugs we do not know about yet, obviously that could add value. We have 3 broad classes right now, so if there is a fourth, that would be helpful.

Méjen A, Escudier B, Thezenas S, et al. CARMENA: cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. J Clin Oncol. 2018;36(suppl; abstr LBA3).