ICI-TKI Therapy Appear Safe and Effective in Later-Line Setting of mRCC

Sarah P. Psutka, MD, discussed the efficacy and toxicity of later-line ICI and TKI therapy in mRCC during an interview with Targeted Oncology.

Immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) therapy is currently the standard of care for metastatic renal cell carcinoma (mRCC). However, the efficacy and toxicity of this combination strategy in later-lines of therapy remains unclear.

A retrospective analysis looked at adult patients who received ICI/TKI therapy in any line for the treatment of mRCC. End points of the study included objective response rate, progression-free survival, and safety.

In total, 85 patients, 81% of which were male and 79% of which had clear cell histologies, were included. Favorable-risk disease was seen in 24% of patients, intermediate-risk disease was seen in 54% of patients, and poor-risk disease was seen in 20% of patients.

Sarah P. Psutka, MD, a urologic oncologist and associate professor in the Department of Urology at the University of Washington Medical Center, discussed the efficacy and toxicity of later-line ICI and TKI therapy in mRCC during an interview with Targeted Oncology™.

TARGETED ONCOLOGY™: Can you explain the efficacy observed with the IO-TKI combination in the frontline setting of mRCC?

PSUTKA: ICI and TKI combination therapy is quickly becoming the preferred frontline option for metastatic renal cell carcinoma. Obviously, the recent National Comprehensive Cancer Network (NCCN) guidelines offer an early stratified approach [with] multiple different options in this area in this setting. The majority of category 1 recommendations rely on this type of strategy where we combine TKI's and IO therapy with an objective response rates in the 50 plus percent range.

What were you investigating in this retrospective analysis? And what were the key goals of this analysis?

Well, while the frontline therapy setting for metastatic renal cell carcinoma is increasingly well defined, recommendations for what we should use in the salvage setting actually are a little bit less clear at this point. And that's related to the fact that we don't necessarily have the same body of work, looking at the efficacy of combinations and second line therapies. And so really, this was a multicenter study, we partnered with The Ohio State University, and looked at our experiences in the salvage setting with combination IO-TKI therapy. If we look at the current NCCN guidelines in the salvage setting, the category 1 recommendations currently are, for at least in clear cell histology, cabozantinib, lenvatinib, everolimus, and nivolumab. But there is increasing utilization that's been reported in a couple of smaller studies that have looked at what happens when we use similar combination therapies, is that IO-TKI therapies that are used in the frontline setting are also used in the salvage setting. And so really, we were looking at our experiences looking at this off-label use and trying to characterize its efficacy and safety as well.

What were the results of this analysis?

This was a study of 85 patients of whom 33 patients received frontline immunotherapy or ICI plus TKI, and 52 patients received this combination therapy in the salvage setting. Our objective response rates with combination ICI-TKI therapy were 56.7% in the frontline setting and then 37.5% overall in the second line setting. PFS or progression-free survival was 15.2 months in the frontline setting, compared to 14.2 months in the second line setting. 

First with respect to safety. In general, this was the second line or salvage utilization of ICI-TKI therapy in this study, appeared to be safe. The grade 3 or greater adverse event rate was 52%. Within that occurred in 25, out of the 52 patients. The objective response rates in patients who were TKI naive in the salvage setting appeared to be the highest. So, patients for example, who'd received ipilimumab (Yervoy) plus nivolumab (Opdivo) as their frontline therapy, those patients had a much higher objective response rate when treated with the combination ICI or IO, TKI therapy in the salvage setting within an objective response rate of 50% and median progression free survival in that group of 9.1 months. And then obviously, we noted as patients were treated with subsequent lines of therapy, the objective response rates and PFS length decreased with each subsequent line of therapy, which is similar to what's been reported previously in the literature.

What are your key takeaways from this analysis?

Well, this work again, it's a small, retrospective cohort study. It is one of the larger studies that has been presented. There is relatively limited data regarding salvage combination, ICI, TKI therapy for metastatic renal cell carcinoma. We did include all histology, so this was not all clear cell patients. But what we noted was that ICI-TKI therapy appears to be both effective and safe in the salvage setting, It provides further data to support the use of these combination therapies. And it seems to be potentially more useful in patients who have not previously been exposed to TKI's. Of course, the data has to be evaluated within the context of the limitations of the study design, including the fact it is a retrospective analysis and the relatively modest sample size. However, it provides further evidence that this strategy utilizing combination IO-TKI therapy may have utility in the salvage setting for patients with metastatic renal cell carcinoma, and it certainly warrants further evaluation and investigation.

How do you think prospective trials should be designed to confirm these results? And do you have any agents in mind that are showing particular promise in this patient population?

Well, I think that the study design here becomes much more complex, because we have a relative embarrassment of riches at this point, which is a wonderful problem to have to look at the difference in the landscape of treating metastatic renal cell carcinoma today versus a decade ago. We have a lot more tools, a lot more agents, that we can look at. And the problem is, there's so many now that when you start looking at all the variable combinations, the number of strategies, increases fairly quickly. And so, creating a trial that is simply looking at one of these combinations is likely to be less impactful. And it's likely we're going to need to utilize more pragmatic trial designs that will allow us to evaluate the different combinations that are being used and track them prospectively. And with respect to specific agents, I am a urologic oncologist. And so while I work very closely with my partners in medical oncology, and certainly as part of our multidisciplinary team, I think that the specific agents obviously are utilized and elected based on specific patient characteristics, tumor characteristics and sort of what other trials we have available at that time. 

The exciting thing about treating metastatic renal cell carcinoma at this point is, as I said before, we do have a lot more agents at our disposal. Many of them have our efficacy that far outstrips what we were accustomed to having, even in the early TKI era. But I think that patient selection, and interval recertification remains absolutely critical and that we probably need to continue to work towards an increasingly re-stratified approach in how we approach these patients and treat them, both with respect to utilization of systemic therapy as well as tumor directed definitive therapy including things like surgery, ablation and radiation. But as our multidisciplinary sort of options armamentarium continues to evolve, I think we'll have many more options to offer these patients.


1.Parikh A, Psutka S, Yang Y, et al. Salvage immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) combination therapy for metastatic renal cell carcinoma (mRCC). Jour. Clin. Oncol. 2021;39(15). doi: 10.1200/JCO.2021.39.15_suppl.e16567