Efficacy of Nivolumab Plus Cabozantinib vs Sunitinib as Treatment for Renal Cell Carcinoma

Tom Hutson, DO, PharmD, Texas A&M College of Medicine, discusses his presentation from the 2023 ASCO Genitourinary Symposium, which analyzed the use of nivolumab plus cabozantinib versus sunitinib for treating patients with renal cell carcinoma, providing a follow-up to the CheckMate 9ER trial.

Transcript:

Thomas Hutson, DO, PharmD:  Hi, my name's Tom Hutson. I am a Professor of Medicine at Texas A&M College of Medicine, the Director of the GU Oncology Program for Texas Oncology, Co-Director of the Urologic Cancer Research and Treatment Center with Baylor Scott and White Health, as well as the Phase 1 and Early Development Program Chair for Sarah Cannon Research Institute. I'm based out of Dallas, Texas and I'm happy to be with you today.

Can you give us some background about your study and its findings?

Dr Hutson: So I'm pleased today to present on behalf of my co-authors the nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma, which we all know as the CheckMate 9ER trial, the three-year follow-up that was presented by my co-author Dr Barata at the 2023 ASCO GU Cancer Symposium. This is one of the primary IO/TKI studies that have established themselves as the new standard of care for front-line management of patients with clear cell renal cell carcinoma. As you all may recall, we're in now what I refer to as the second-generation of therapies and combination therapies for the management of this disease. The first-generation standard of care for almost 12 to 14 years was a drug called sunitinib. So that was the reference standard. And this trial took a combination of cabozantinib, which is a newer generation multitargeted tyrosine kinase inhibitor that was already approved for use in the refractory setting for all patients and in the frontline setting in the intermediate poor risk patients based upon the Phase 2 Cabo Sun trial.

And combine that with nivolumab, which is one of the PD-1 therapies that have been approved now for multiple types of tumors. It's an immunomodulatory antibody treatment, and we combined the two together and compared them to sunitinib as initial treatment in a one-to-one fashion. The trial was an international study of 323 patients randomized to the nivo-cabo arm and 328 patients to the sunitinib arm. And the treatment of this trial went on until unacceptable toxicity of disease progression, with the caveat that one could have no more than two years of the nivolumab. Once you reached that point of nivolumab at two years, then that was stopped and patients continued on single agent cabozantinib.

What are the current standard of practice and treatment guidelines in RCC?

Dr Hutson: The 2023 standard of care is frontline management for patients with clear cell RCC involves really four major choices for most patients. We think that now it is the standard of care to consider an IO, a PD-L1, or a PD-1 antagonist antibody therapy as the pivotal backbone for any regimen as long as patients would be acceptable to receive it. So there are certain patients where a PD-1 or PD-L1 would be contraindicated. This is a small list of patients with ongoing active severe autoimmune disease, patients with organ transplantation, etc, but that's a minority. The bulk of patients should be considered for one of these agents as a backbone. And there are really two major classes, if you will, in encompassing these four different treatments. The only FDA approved class of IO/IO is a combination of ipilimumab and nivolumab, and that is a double antibody treatment and it's in its own class.

The other class would be the IO/TKI class, which combines an oral VEGF receptor, usually a multitargeted TKI combined with one of two different IO type of agents. And they would include things like axitinib plus pembrolizumab, cabozantinib plus nivolumab—which is the topic of today's presentation—or alternatively would be lenvatinib plus pembrolizumab. There are other IO/TKI combinations that are currently under investigation, but as it stands now, you have really those two main classes or four treatments for the majority of folks who would be candidates to receive an IO-based treatment. And then for those rare patients that cannot receive IO, then we have single agent therapy such as cabozantinib plus some of the traditional oral agents such as sunitinib and pazopanib, which are often considered for those patients.

Can you talk about the CheckMate 9ER trial and its findings?

Dr Hutson: So I'm pleased to present the updated three-year follow-up from the Phase 3 CheckMate 9ER trial. As you recall, its original presentation was by my good friend and colleague Toni Choueiri, who serves as the senior author of the update. And based upon those results, we found superior efficacy, similar tolerability, improved health-related quality of life that resulted in the regulatory approval of the combination cabozantinib plus nivolumab as a first-line standard of care regimen in many countries around the world. What this most recent presentation was, was just a three-year follow-up. It's important for us to look at follow-up because with the immune therapies in particular, there is a real chance for durable responses, both durable partial responses and durable complete responses. And as we try to compare across these various options for us, we want to be able to be truthful.

We're limited in our comparisons because their trial populations were somewhat different, and we're always told not to do cross-trial comparisons. So any type of additional information is very useful. And so, what we presented then was a follow-up of median of 32.9 months from the CheckMate 9ER and we reported survival response by blinded independent central review safety in patients with all types of IMDC risk score. And just to recall, as I mentioned earlier, this was a one-to-one stratified by IMDC risk score tumor PD-L1 expression in region Phase 3 trial. The combinations were that the cabo starting dose of 40 milligrams with nivolumab 240 milligram flat dose administered IV every two weeks. And that was compared to traditional dosing of sunitinib 50 milligrams four weeks on, two weeks off in six-week cycles. We talked about treatment until unacceptable toxicity or disease progressing, which meant a maximum of nivolumab treatment of two years.

We must remember the primary endpoint of the trial was progression-free survival by blinded review. Secondary endpoints were overall survival response rate by blinded review and safety. And what I'm pleased to report is the median progression-free survival was 16.6 months versus 8.4 months. And a median overall survival was 49.5 months versus 35.5 months. The hazard ratio for the PFS was 0.58. The hazard ratio for the median overall survival was 0.70. And then if we look at individual response categories, so for instance, if we look at patients with nivo plus cabo versus sunitinib who had achieved a complete response, we saw the response rates ultimately 12%, complete response rates with the nivo-cabo regimen versus 5% with sunitinib. The median duration of response of 23.1 months versus 15.2 months. And then moving into the presentation a little bit more in depth, there were several slides that broke down these different response rates, PFS survival by intermediate, favorable, and poor IMDC risk group, and showed those results; and these have been updated results again with this three-year follow-up.

And what we essentially see is maintained degree of benefit across all three IMDC risk groups [of] maintained or improved hazard ratios. And importantly, improvement in hazard ratio and maintenance of hazard ratio with overall survival. It tends to be the efficacy endpoint where over time one can lose benefit. And in this situation, it was maintained, and some of that benefit as investigators we recognize can be confounded by a variety of different things, including patients going on to receive other active agents in later line therapy, especially active agents that have survival impact. So to be able to see in a clinical trial where that could have happened, this maintenance and improvement of hazard ratio is very important, and it speaks to the durability and the long-term treatment effect of the regimen. In regards to side effects, those were also updated. We did update treatment related adverse events.

We recognize that they occurred, and in my opinion, in virtually all patients, but the statistics would be 97% in the combination versus 93% in the sunitinib arm. And these were grade 3. If we look at grade 3 or greater, it was 67% versus 55%. Important to note is that the treatment related adverse events led to discontinuation of cabozantinib only in 10% of patients. For the nivo it was 10% in the combination in 7% of patients, whereas [for] sunitinib [it] was in 11% of patients. So what we see is with this high level of potential side effect, most of the side effect is level grade 1, 2 and can be handled really with both regimens, both the sunitinib and the nivo-cabo with dose interruption, dose reduction. And we encourage that. We encourage the recognition, the best practice medical management of side effect, and then when that cannot happen for dose interruption and then dose reduction. And if you do that, the vast majority of patients are able to stay on therapy at a reduced dose and achieve the continued benefit from the treatment.

So, in conclusion, I'm pleased to report that after three years minimum follow-up, survival and response rates were maintained with nivo-cabo remained consistent with previous follow-ups. The median overall survival improved an additional 11.8 months since the previous data cut. All of these responses were durable with higher CR rates noted in the nivo-cabo versus sunitinib regardless of the IMDC risk group. There were no new safety signals. And these results continue to support the status of nivo-cabo being a preferred first-line treatment option for patients with advanced renal cell cancer.

Looking ahead, what is the potential impact of your findings and other recent studies like the Phase 3 CheckMate 9ER trial on the current standard of care in RCC?

Dr Hutson: Well, I think the current standard of care continues to be maintained where we have really four of these IO checkpoint inhibitor type of trials and regimens that have become standard of care and they remain so. We really can't unfortunately choose one regimen over the other without a head-to-head comparison trial. They all are doing quite well with maintained degrees of benefit. And so what has been strongly encouraged is with the understanding that virtually all of these patients around the world are being treated in community oncology centers, whereas such, the doctors treating them may not have extensive experience enough to have treated patients with all of the regimens. And there are some nuances between the different regimens to optimize benefits. So if that's the case, it's most important for the doctor to choose a regimen, have their office staff become very familiar with the management of side effects with it so that they can optimize outcome and use that as their preferred regimen.

And the data would support that. The data would support comfort no matter which regimen you choose. And in the case of cabo-nivo, clearly it is one of our most potent regimens. And so someone who is choosing this as their go-to regimen for advanced renal cell carcinoma, they should feel very comfortable with this mature data that that should not sway them in any way to change their therapy. That they are on one of the strongest regimens to date that we have as therapy for their cancer. Now the future holds, we do have some other IO/TKI combinations that are being studied, and we need to put those side by side and see are there any unique benefits to those or would they just give another choice option for patients and doctors? The other thing is that we have a couple different new combinations that are entering evaluation in late stages, and some of these are new types of pills that target other pathways such as belzutifan as a HIF inhibitor being combined with checkpoint inhibitors.

We have triplet therapies that are being explored to see if there's any advantage to adding a three-drug regimen. We certainly worry about cost with those type of regimens and toxicity. And then there are novel agents that are ways to overcome checkpoint resistance. And we know that unfortunately the majority of patients are not getting CRs with these regimens, and that a lot of patients do acquire some type of immune resistance that happens. And as we discover the mechanisms for that, therapies are being designed that can be combined to or replace the current checkpoint inhibitors. So I think the future looks very bright for patients with kidney cancer as we fine tune our current regimens, and we look forward to the future of novel agents that push the field further and push the goal, if you will, to having patients become CRs, complete responders, even higher.