Motzer Discusses Nivolumab's Survival, QoL Benefits in RCC

Robert J. Motzer, MD

Nivolumab (Opdivo) improved overall survival (OS) compared with standard of care in patients with advanced renal cell carcinoma (RCC), according to results from the phase III CheckMate-025 trial published in the New England Journal of Medicine and conducted by researchers at over 150 locations, including Memorial Sloan Kettering Cancer Center.

In the randomized phase III trial, 821 patients with advanced RCC previously treated with 1 or 2 antiangiogenic therapies received nivolumab intravenously every 2 weeks or a 10-mg tablet of everolimus (Afinitor) once daily. Participants had a median OS rate of approximately 25 months with nivolumab compared with approximately 19 months with everolimus.

Nivolumab also resulted in fewer treatment-related adverse events (AEs) than everolimus, with 19% of patients experiencing AEs in the nivolumab arm versus 37% in the everolimus arm. The most frequent AEs were nausea and fatigue in patients who received nivolumab, and fatigue and stomatitis in those who received everolimus.

Nivolumab received an FDA breakthrough therapy designation for RCC in September 2015.

OncLive: What were the goals of this trial?

To learn more about nivolumab’s impact for RCC treatment, OncLive spoke with lead study author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.Motzer: There remains an unmet need for better treatment for kidney cancer. It has been very difficult for us to establish, within each individual trial, an improvement in OS. The treatment options that we have fall into two types of therapy: VEGF inhibitors or mTOR inhibitors. There have not really been drugs developed with a novel mechanism of action in a long time. The current drugs available have side effects, they must be taken daily, and when a patient progresses on one, they do obtain some benefit from another one. However, very often, the benefit is limited.

There has been a reawakening of interest in immunotherapies and in these new checkpoint inhibitors. They have a novel mechanism of action that is showing favorable outcome results in patients with other tumor types. It was natural to have this sort of therapy studied in patients with kidney cancer.

What are the most significant findings thus far?

We did a large randomized phase II trial that was reported last year at ASCO with 150 patients, which showed about a 25% response rate in patients treated with nivolumab who had progressed on angiogenic drugs. The median OS was in the 20- to 25-month range. It appeared different than what we had obtained with other standard drugs. A commonly used drug in the second-line setting was everolimus, where the average survival by historical control with that drug was about 15 months. We set up this trial that compared nivolumab to everolimus in patients who had progressed on the standard drugs.The primary endpoint was OS, and nivolumab met that goal of showing a benefit in OS at an interim analysis. There was an improvement in median OS from about 19 months with everolimus to 25 months with nivolumab. The trial also showed a relatively high response rate for nivolumab, with a response rate of 25%. Many of the responses were durable and several patients continued to respond for more than 12 months.

Nivolumab also showed a favorable toxicity profile, with fewer grade 3 or 4 adverse events compared to everolimus. One of the previous standouts for everolimus as a popular treatment in kidney cancer was its favorable safety profile, so showing an improvement in the safety profile compared to everolimus is really remarkable.

In the quality-of-life studies that we conducted, the quality of life improved with patients treated with nivolumab. This was not only compared to the baseline, which is where they started, but also compared to everolimus. There was a significant improvement in quality of life in terms of the patient-reported outcomes for nivolumab versus everolimus.

Do you anticipate an FDA approval of nivolumab in RCC in the near future?

If nivolumab gets approved, will there still be a role for everolimus?

Are there other immunotherapies or combinations being investigated in kidney cancer that you see potential for?

The significance of the trial is that it improved OS in this setting, which had not been previously demonstrated. It is the first trial with a checkpoint inhibitor to show benefit in kidney cancer. I think that opens the door for other studies with other related compounds with combinations. It is possible that there could be a whole new generation of investigations with this class of compounds. It was also a proof of principle that this class works in kidney cancer.It should happen. This is a drug that needs to be offered to patients with kidney cancer. There has been a tremendous interest from patients to receive this drug, as well as from doctors. I think it needs to get in the hands of the doctors so they can quickly administer it to their patients.There will still be a role for everolimus in kidney cancer, but I think it is going to be pushed back in the sequence. It has been predominantly a second-line and sometimes third-line therapy and, based on this study, I think it will be pushed back to a third- and fourth-line therapy.There is a combination of nivolumab plus ipilimumab that is being studied in kidney cancer. There is a large first-line study of that combination compared to sunitinib (Sutent), which is a standard first-line drug used worldwide. The trial is completing its accrual of nearly 1200 patients.

There are also some related compounds being investigated. In a large phase III trial, atezolizumab, which is a PD-L1 inhibitor, is being combined with bevacizumab (Avastin) and compared with sunitinib in the first-line setting. There are some other compounds and combinations that are underway. There will be several of these important studies that will either spin off or continue on, based on the positive results of this phase III trial with nivolumab.

Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. doi:10.1056/NEJMoa1510665.