Promising Results of CheckMate 9ER Could Guide Future Research in RCC

According to Viktor Grünwald, MD, PhD, of Hannover Medical School, survival and responses to treatment in patients with renal cell carcinoma (RCC) have significantly increased over the past few years, especially with immunotherapy (IO) combinations.

Although unmet needs still remain in the space, triplet combinations–like ipilimumab (Yervoy), nivolumab (Opdivo), and cabozantinib (Cabometyx) being evaluated in the CheckMate 9ER study (NCT03141177)–show much promise.

The CheckMate 9ER study found that patients with RCC who were treated with nivolumab plus cabozantinib to have survival benefits and an increased probability of response when compared with those treated with sunitinib (Sutent) alone. While it has proven to demonstrate good activity, further exploration is needed.

Other exciting updates within the RCC space include the many new novel agents to explore which focus on overall survival, as well as the immune stimulatory agents which can help patients obtain long-term responses.

In an interview with Targeted OncologyTM, Grünwald discussed the newest updates and advances in RCC and what the current space looks like.

Can you discuss the current survival and responses being seen with drugs for patients with RCC?

Grünwald: They are better than ever, I would say. We have a very good time where we have a lot of responses at about 60% or 70% at the end of the day when it comes to first time efficacy parameters. Otherwise, expectations look very good and promising for IO combinations.

Which agents appear to be promising to kind of fill some of the gaps we have in the treatment landscape?

That's difficult. I would say that the triplets could improve outcomes, but that's really unknown. The same is true for other combination partners that are immune agents, but we have to see what the data looks like and how promising they are. So far, it has been very tough to generate this second wave of new agents in RCC in general in cancer treatment and there is a lot of disappointment as well in terms of negative data.

[The unmet needs in this space are] the amount of patients with durable responses that translate into cure at the end of the day. I think that that's the missing link and those patients are still too rare in our trials.

Can you talk a little bit about the mechanism of action in cabozantinib and kind of what differentiates it from other TKIs?

In principle, it's a VEGF inhibitor and it also inhibits MET. I think that that's a strong separator from others. Then there is EXEL which is different from other tyrosine kinase inhibitors. I think the clinical relevance of these deviations in the inhibitory profile the they're less clear.

Can you talk about the recent FDA approvals of cabozantinib and some of the research supporting those approvals?

Cabozantinib has been approved for first-line treatment and RCC in combination with nivolumab and I think that is the most recent achievement. The research behind it is the CheckMate 9ER study that has led to the development of cabozantinib as a first time agent for a combination partner. Most studies have been performed in the second-line with cabozantinib and some of the combinations, or if there's more data underway, to explore its potential in the combination with other immuno agents in second-line, or previously treated lines, and also in the first-line as a triplet combination. So even more intensified treatment.

What do you think is next for cabozantinib in kidney cancer?

The combination of ipilimumab, nivolumab, and cabozantinib is possibly a positive study. That would be the next milestone in its clinical development. Whether it is superseding and outstanding, I think that is really determined by the means of the clinical activity parameters. In terms of significance, I think that will be reached in the first line study.

Can you discuss the study of ipilimumab, nivolumab, and cabozantinib?

The study design is first on treatment of advanced or metastatic RCC. It compares to ipilimumab and nivolumab. That is something that I think is unique, and it has not been performed so far. It is restricted to the use of ipilimumab and nivolumab, meaning it's at least 1 risk factor. Intermediate or higher risk patients are being selected on top of ipilimumab and nivolumab, there is cabozantinib that has been placed as a triplet candidate.

What other areas of research and RCC are exciting right now for you?

It's all exciting. There are always novel avenues to explore and I think what we have seen so far is the big wave of novel agents that really hit hard on overall survival. I think it really is a big endeavor to come up with novel ideas. For me, it is the immune stimulatory agents that are the key player here in order to translate or transform more patients into deeper responders, that have deep responses, and long term responses. That is something that I think is most interesting for me. The problem is that it cannot be achieved in all populations, so I think we have to come up with an idea on how to select patients in order to deliver such novel immune combinations.

I think it needs to be tested in smaller subsets. So far, I think it is very sobering, what we've seen in terms of biomarkers and their availability. Something that has looked very promising is the alteration of the microbiome by the ingestion of a living strain. But we'll see, it's only phase 2 data, but it looks good. It has been recently published just a very few weeks ago, and it's a very exciting publication. It was led by folks from MD Anderson, and I like the idea that a simple alteration of the microbiome is really changing, or may lead to a deep response. It is exciting and it means a lot to patients. And it's very simple on top of that.

With phase 2 data, you have to be very cautious. It's good, it has activity, it crosses the threshold to be further explored, and I think that's something that needs to be done. We need to see a larger trial to understand that type of activity and whether the promise is really holding up when you have a larger patient population.

Do you think that end points can be changed depending on what data from trials are showing?

Despite all the effort that you put into it, it is so difficult. We thought it would be a homerun, but it's not. It's more difficult and it needs more work. In order to dissect the right patient population, I think we definitely need a biomarker certification of our patients, and we don't have that in place. I think, is the major hurdle that we have in kidney cancer. The problem is that most of the analyses that we do there are negative, so they don't predict adequately and that is disappointing.

I think I'm going to be able to better understand what makes it. Just quoting a positive study is not enough, you need to better understand what is the net benefit for a patient and when does it come into place. Is it in the first 5 months or is it something that will affect the long term outcome but it just lacks impact in the initial phase of treatment? I think this is important information because that is something that we have to have in place when we select our types of treatments.

So do we have to shift our end points? No. I think they are in place and we just have to use them. We have a lot of tools, we have a lot of end points that we may use in order to better understand what is the net benefit of a given treatment. Looking into landmark analysis for progression-free survival and overall survival is beneficial and the same is true for responses that we already do. All of these tools are being used already.