In this interview, Matthew Zibelman, MD, Fox Chase Cancer Center, shares the results of his study entitled “A phase I/II study of nivolumab and axitinib in patients with advanced renal cell carcinoma.” The findings were presented at the ASCO Genitourinary Cancers Symposium.

Matthew Zibelman, MD: My name is Matt Zibelman. I am an associate professor of medical oncology at Fox Chase Cancer Center in Philadelphia. I am also a practicing genitourinary (GU) medical oncologist, and I am the director of the clinical research service line for the GU group at Fox Chase.

What key objectives did you aim to achieve with this study?

Dr Zibelman: This study was a phase 1/2 study of nivolumab and axitinib in patients with advanced renal cell carcinoma. It was designed to look at a different combination of an oral VEGFR tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor in these patients. At the time, there was no approved combination. We had data for axitinib with pembrolizumab, and nivolumab was an approved agent, but we did not have data together. The hope was to demonstrate that this combination could be equally as efficacious for untreated patients, as well as have efficacy in patients who had prior treatment, which we lacked data on at that point.

This trial had two arms, and what we're presenting at this conference are the results of the patients who went on the combination on trial after having prior therapy. The goal of this arm was to demonstrate the efficacy of the axitinib and nivolumab combination after prior systemic therapy in patients with metastatic renal cell carcinoma (mRCC).

What were the primary efficacy outcomes observed and how do they compare to existing standards of care?

Dr Zibelman: We don't have a lot of data for this exact population, so it's hard to totally compare the outcomes to the three approved combinations that are used primarily in the first-line setting. In this study, there was an objective response rate of 26.9%, all partial responses. However, many patients achieved some [tumor] shrinkage and ultimately prolonged stable disease with an 84.6 % overall disease control rate, meaning only about 11% of patients had primary progressive disease, which is promising in the patients who had had prior therapy. Almost all of the patients had only prior TKI therapy. Two patients had prior treatment with nivolumab and ipilimumab as their prior combination.

How could the study guide future research on patient stratification for combination therapies in RCC?

Dr Zibelman: It's hard to take the data from this study to make grand statements about further stratifying patients with kidney cancer, given that there are  three combinations already approved that are likely to continue to be the primary combinations used for this disease. What we can see here is that for patients who, for whatever reason, don’t get a combination like this in the first-line setting, it is still a very viable combination in a subsequent line of therapy.

The most important finding from this study is that there was a subset of patients who were able to stop therapy at a certain time point and have prolonged periods of time without systemic therapy or with minimal systemic therapy and were able to have a high quality of life in that setting. All of the other three trials continued to treat patients indefinitely, whereas this trial allowed patients to stop one or both drugs at 2 years, and it's the only study that did that. As a result, we had four patients stop at 2 years, all of whom went on to have a median of 2 years of time off systemic therapy; most of them still remain off of systemic therapy. There were four patients who stopped treatment before two years and were able to have a significant amount of time off of systemic therapy.

The biggest takeaway from this study is not how to stratify patients, but to show that patients who have a great response to a combination such as this may be able to stop one or both drugs and experience prolonged treatment-free interval, which is a good outcome for many patients.

How do you see these findings affecting clinical practice guidelines for advanced RCC management?

I would love to say that this small investigator-initiated study is going make a big dent in how payers paid for this combination. However, that's probably unlikely. It will at least demonstrate the safety and potential efficacy of this combination, but given that this is not a randomized phase 3 study, the three US Food and Drug Administration-approved combinations would still dominate the market.

Based on your experience with this trial, what are the next steps that you believe are in research for combination therapies in RCC?

We've established that these combinations with a checkpoint inhibitor and VEGF-targeted drug are promising and are part of the standard of care. There is also a role for nivolumab and ipilimumab and using an immunotherapy-only combination for these patients. The results from the COSMIC-313 trial using nivolumab, ipilimumab with cabozantinib in the first line have been disappointing. But triplet combinations—even quadruplet combinations—may still have a role in the future.

We look forward to looking at combinations including belzutifan, the HIF-2α inhibitor, along with combinations such as the ones in this study, in the future and whether a quadruple combination could potentially be both safe and efficacious and provide a long-term benefit for some subset of patients.

Are there any other takeaways that you'd like audiences to take away from this study?

I'll harken back to something I said earlier, which is that patients do not have to stay on both of these therapies indefinitely if they are responding well. Also, patients who achieve a very good partial response or a complete response may be able to stop one or both drugs and be observed closely. They may be able to have a prolonged period of time off of systemic therapy, which helps decrease side effects, improve quality of life, decrease time toxicity and financial toxicity potentially, and is really a benefit to our patients.