Challenges With Adjuvant Therapies in RCC Warrant Further Research

Chung-Han Lee, MD, PhD

In recent years, different therapeutics have been made available for patients with metastatic renal cell carcinoma (RCC) in the first-line setting, including VEGFR inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. However, little is known about the approach to adjuvant therapy as most studies in this space have failed to produce effective results.

“There were multiple studies looking at the use of tyrosine kinase inhibitors for the adjuvant space. Most of those clinical trials ended up reading out negative. It was only the S-TRAC [NCT00375674], which looked at adjuvant sunitinib [Suntent] at a high dose, and the dose that was used in the metastatic space, showed a progression-free survival benefit,” explained Chung-Han Lee, MD, PhD, in an interview with Targeted Oncology^TM.

With the positive findings from this study, as well as data from ASSURE (NCT00326898), the FDA granted approval to sunitinib as adjuvant treatment following nephrectomy for adult patients with high risk of recurrent RCC in 2017. However, since the majority of trials in this space have resulted in unfavorable data, more studies are warranted to fully understand the potential role of adjuvant therapies in RCC.

During the interview, Lee, vice president of early clinical development at Exelixis, walked through the challenges, studies, and outcomes observed when studying adjuvant treatments for patients with RCC.

Targeted Oncology: The adjuvant space for RCC has been challenging over the past 30 years or so. Can you discuss some of the challenges?

Lee: For a long time now, we've been interested in seeing whether any sort of treatment in the adjuvant space would be helpful to determine and improve the accountability rates for kidney cancer. The main way that we have treated kidney cancer, especially for localized disease, is surgical resection. For people with high-risk of recurrence, often those patients will recur. Previously, the concern had always been that there weren't effective systemic therapies. As of about 2006 or so is when we first started getting active systemic therapies for RCC. Then, the question for the field was for the treatments that were effective in the metastatic space, whether they'd be effective in the adjuvant space.

During that time, the bulk of the treatments that we had were tyrosine kinase inhibitors targeting VEGF. There were multiple studies looking at the use of tyrosine kinase inhibitors for the adjuvant space. Most of those clinical trials ended up reading out negative. It was really the S-TRAC [NCT00375674], which looked at adjuvant sunitinib [Suntent] at a high dose, and the dose that was used in the metastatic space, showed a progression-free survival benefit. One of the big lessons that we had learned during that period is that, especially in the adjuvant space, tolerability became a very big issue. Patients in general, especially in the absence of visible radiographically evident metastatic disease, were challenging to give those types of treatments and have them be willing to continue for that year's worth of duration. Most of the studies with TKI have started off with the upfront dose reduction, to see whether that would improve the tolerability. There is the possibility that that dose reduction that was used up front popularized some efficacy, and that's what translated to not actually demonstrating a progression-free survival benefit, except for the S-TRAC trial.

Fast forward a little bit further, now that we had adjuvant immunotherapy issues in the adjuvant or the metastatic space, we started investigating and seeing whether there's any utility and using those medications in the adjuvant space. There are still multiple clinical trials investigating the role of immunotherapies in this setting, most notably, has been adjuvant pembrolizumab [Keytruda], which as a monotherapy, and is not FDA-approved for the metastatic space. However, it did show a progression-free survival benefit and possibly also an overall survival benefit in the adjuvant space. Some of the other regimens or immunotherapies have not been able to replicate that type of success, so it remains a bit of a question as to why that is the case.

Can you further discuss pembrolizumab in the KEYNOTE-564 trial?

The KEYNOTE-564 trials was a large, randomized trial looking at adjuvant pembrolizumab vs placebo. It involved a high-risk population. It included people with stage II high-grade, and it included anyone with stage III, and stage IV, but no evidence of metastatic disease. They put people at high-risk, and for people who had known metastatic disease, the benefit towards using adjuvant pembrolizumab did seem to be significantly higher, especially for people with stage IV disease that had no evidence of disease, and in some ways that's somewhat expected. The best way to think about any sort of adjuvant therapy is that there's 2 main components of it. One is what is your risk of recurrence, and the other component of it is how effective is your treatment going to be based on that recurrence risk? Certainly, if you have a population that's at a very high-risk of recurrence, giving them systemic therapy is likely to be beneficial. On the flip side, if someone has that very low-risk of recurrence, there's no disease to be treated, and then the ability to to show some sort of benefit in that sort of setting certainly is significantly lower.

What are some ongoing trials in this space?

For adjuvant pembrolizumab, that this is a standard-of-care, especially in the adjuvant space, there's been a lot of interest in understanding whether the addition of any other agents to that pembrolizumab could be helpful. There's a clinical trial looking at adjuvant pembrolizumab plus or minus belzutifan [Wielreg], which is a HIF-2 inhibitor. This is something that we've been excited about, in terms of having a drug that targets a key mechanism in kidney cancer pathogenesis. Essentially, the most common mutation that we see within kidney cancer is loss of VHL, and this leads to very high levels of the transcription factor HIF. The HIF-2 inhibitor works in preventing and blocking the downstream transcription related to HIF-2, so 1 of the downstream targets of the VHL mutation. I think that there's a lot of excitement in the field to see whether using that sort of treatment that's fairly specific to RCC, and reasonably well-tolerated, could be more successfully combined from the adjuvant therapy sense.

In your practice, how do you typically treat patients with RCC?

In my practice when we get the referrals from urology for the consideration of whether to do something like adjuvant therapy, it is a fairly long discussion with the patient's thinking about their own understanding of risk, and what the tradeoffs would be? First off, it's getting a good assessment with the patient and having them understand what's their risk of recurrence. The second part of it is certainly going through the data for adjuvant pembrolizumab and making it clear that what they've been able to show thus far has been a disease-free survival benefit. Because the treatments are so new, it remains to be seen how robust of a difference there is in the overall survival, while also talking about the potential risks related to immunotherapy. Immunotherapy in of itself is a treatment with potential adverse effects. [With any] treatments we involve patients to understand how to balance that potential of risk vs their potential of recurrence to make that joint decision with them.

What is needed to move research with adjuvant therapies forward for RCC?

I think that there are multiple steps in which we can move this forward. One is coming up with better predictive markers on whether people have recurrent disease. Right now, most of the ways that we've predicted nomograms have been strictly clinical, and based on the pathology report, based on some clinical features of the patients, and then the surgical pathology and seeing what that looks like, the size, and the grade. One of the things that would be interesting to move forward is now that we've developed so many prognostic markers from the genomic sort of sense, whether any of that can be integrated into the nomograms to help predict your risk recurrence. If we can predict with better accuracy, that will also help us better stratify patients. That's 1 component that's going to be beneficial.

The second part that would be beneficial is to get a better sense of, you know, predicting who might respond to treatments. If we can predict even that with better accuracy, then again, we can move the needle a bit more forward in terms of, you know, those types of treatment algorithms. The other part is our ability to predict who might develop toxicity. I think that working on all 3 of these fronts are going to be critical for defining the patients that would benefit the most.

What should community oncologists know with research moving forward in the adjuvant RCC space?

The key takeaway right now is that the adjuvant space within RCC is exciting. We now have something that's reasonably well-tolerated and that has demonstrated a progression-free survival type of benefit. This is something that certainly warrants discussion with the patients as to whether they would consider doing treatment with immunotherapy for a year. I think it's very important to discuss both the benefits and the potential risks related to this.