Drake Discusses CARMENA Trial and Emerging Approaches in RCC

Charles Drake, MD, PhD

Sunitinib (Sutent) alone was noninferior for median overall survival (OS) compared with sunitinib plus cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma (mRCC), according to findings from the phase III noninferiority CARMENA trial presented at the 2018 ASCO Annual Meeting.

In CARMENA, the median OS was 18.4 months for patients in the sunitinib arm compared with 13.9 months for the surgery arm (HR, 0.89; 95% CI, 0.71-1.10). The prespecified noninferiority margin was ≤1.20 for the upper bound of the confidence interval.

Sunitinib produced similar median OS results 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 enrollment.

OncLive: What was the rationale for the study?

In an interview with OncLive, Charles G. Drake, MD, PhD, director of Genitourinary Oncology at New York-Presbyterian/Columbia University Medical Center and co-director of Columbia’s Cancer Immunotherapy Programs, discussed the importance of the CARMENA results, the future of cytoreductive nephrectomy, and how the use of immunotherapy could change treatment in this setting.Drake: We really don't know, when a patient presents with metastatic kidney cancer, whether taking out the primary kidney lesion will help them live longer or better. There are a number of retrospective studies, but all of them are subject to bias because the surgeon picks the person who is healthy enough to have their kidney removed.

This was a very good trial. This was a randomized trial where patients with intermediate- and high-risk kidney cancer were randomized to have either surgery followed by standard therapy or to have standard therapy alone.

What were the results?

What is the current role of cytoreductive nephrectomy?

Patients were identified—and, this is important—by urologists. The urologist would say, “This is a pretty good patient. They have metastatic kidney cancer. They're eligible for a trial where they would either have their tumor resected or not resected.”The results were surprising. The patients who had their primary tumor taken out did not live longer. The 2 approaches were statistically equivalent in terms of overall survival.Up until this study, it was reasonably well used. There were 2 older studies that performed the experiment before we had tyrosine kinase inhibitors (TKIs). Those studies compared surgery plus interferon to interferon alone. Those older studies were positive. Based on that, there was widespread use of nephrectomy.

What is the significance of these results as far as the ongoing use of cytoreductive nephrectomy?

Have investigators explored the use of immunotherapy in this setting?

However, there is always the question in the modern era that, when [CARMENA] was started, whether this would look the same with a TKI—sunitinib, actually—and it didn't. The study was not positive; it didn't suggest a benefit from the surgery.It's very interesting. You would think that having a randomized phase III study would change practice worldwide and it will generally reduce the use of cytoreductive nephrectomy. Nevertheless, there is always the question of patient selection, and there are certain to be some individuals who believe they can select patients who would benefit from cytoreductive nephrectomy. It's not going to go away. There will be some cytoreductive nephrectomy performed, probably in healthier patients, which are better surgical candidates. I do think, overall, global use will go down.Sunitinib is a standard first-line treatment for kidney cancer, but it's becoming decreasingly used in the first-line setting. For these intermediate- and high-risk patients, right now, it's probably not the standard of care. The standard of care at Columbia University Medical Center and other medical centers, especially academic centers, is combination immunotherapy with anti—PD-1 and anti–CTLA-4. Whether you would get the same result with moderate immunotherapy or not is a very good question.

Can you expand on immunotherapy in RCC?

There have been preclinical and now clinical studies suggesting that you should give immunotherapy before surgery. There was a recent paper in the New England Journal of Medicine from Johns Hopkins Medicine researchers showing that, in lung cancer, giving immunotherapy before surgery is much more efficacious than giving it after surgery. We don't know if that's the case in kidney cancer or not, but we do know that sunitinib in the adjuvant setting has generally not been helpful. Therefore, the question is, “If we gave immunotherapy before surgery and compared that with immunotherapy alone, what would be the readout?” That is being tested to some degree in an ECOG trial with nivolumab (Opdivo) monotherapy, but it is an important question.In kidney cancer, the therapy is very rapidly evolving. As I mentioned, the current standard of care in the first-line setting for intermediate- and high-risk [patients] is probably considered anti—PD-1 plus anti–CTLA-4. There are 4 ongoing randomized trials looking at combinations in the first-line setting.

How do you see the treatment landscape evolving?

The combinations usually have an anti—PD-1/PD-L1 plus a VEGF TKI. A single arm from 1 of those studies was presented recently. It was a single-arm, nonrandomized, phase II [trial] of pembrolizumab (Keytruda) plus the TKI axitinib (Inlyta). It was stunning. The response rate in that setting was 73%. That is probably the highest single response rate ever seen in kidney cancer. Therefore, if you really wanted to give efficacious therapy, you would think of anti–PD-1 plus anti–CTLA-4, or maybe anti–PD-1 plus a TKI.Until recently, standard first-line therapy was a TKI—pazopanib (Votrient), sunitinib, or potentially, cabozantinib (Cabometyx) more recently. They have various levels of efficacy; cabozantinib is showing quite good efficacy in that kind of setting.

What has happened recently is the FDA approval and the clinical advancement of anti—PD-1 plus anti–CTLA-4; it has a very good response rate, and many of these [responses are] durable. That is a standard of care for patients with high- and intermediate-risk [disease]. But as I mentioned, there are multiple phase III trials; what is really going to happen is that first-line treatment of kidney cancer will be a PD-1 inhibitor “plus something" combination. That is very important because the patients who don't respond to that are very different than the second-line patients we see right now.

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).