Advances in the Treatment of Advanced Renal Cell Carcinoma

Clinical trials in the advanced renal cell carcinoma (RCC) space, including KEYNOTE-564 and NEOAVAX, are having an effect on the evolving treatment paradigms for patients with advanced kidney cancer. In this Precision Medicine Perspectives series “Recent Advances in the Management of Advanced Renal Cell Carcinoma (RCC)”, Hans Hammers, MD, PhD, a genitourinary medical oncologist at UT Southwestern Medical Center, gives an overview of the management of advanced RCC and discusses the effect of research on the future of kidney cancer treatment.

Targeted Oncology™: Overall, how is advanced renal cell carcinoma managed? In practice, what is considered standard of care? Are there points of non-consensus that are discussed among fellow oncologists in this space?

Dr Hammers: Very good question. We’ve seen a dramatic change in the way we treat renal cell carcinoma over the last few years, starting with the welcoming change and arrival of immunotherapy in the first line in 2018. We now have a plethora of doublet therapies in that space. The standard of care for patients with advanced metastatic renal cell carcinoma is immunotherapy, which should come in doublets. There are 2 major flavors of [immunotherapy]. One is dual immune checkpoint inhibition with antibodies targeting the PD-1 and CTLA-4 pathway, and the other is an inhibitor of the PD-1 pathway in combination with your favorite TKI [tyrosine kinase inhibitor]—there are several to choose from. One of the flash points and discussions is around those 2 because they have different flavors, and some of us advocate for one vs the other, although patient selection plays a role and one of these regimens might be better for one patient vs another.

The main discussion is which regimen is best for which patient. For patients who are highly symptomatic and have a large tumor burden, you want to use the regimen that has the highest response rate. That would be the combination of a PD-1 inhibitor and a TKI. The different flavors you can choose from are axitinib, cabozantinib, and lenvatinib. The most recent arrival is lenvatinib, a very potent VEGF inhibitor with a very high response rate. Clearly, if response rate is everything and you need to get the disease under control, you want to choose one of those.

For patients who are often asymptomatic and have a reasonable tumor burden, you can choose from any of those. In fact, dual immune checkpoint inhibition with PD-1 and CTLA-4 is very attractive because the long-term follow-up data show some very durable responses. We see a tail in the progression-free survival [PFS] curve that we don’t yet see with a PD-1/TKI combination. That’s one of the eternal debates. What’s the role of CTLA-4? Is it an absolutely critical component?

Another discussion point centers on some of the toxicities. You clearly have a mixed picture of adverse effect profiles if you combine a TKI with immune checkpoint inhibition. You have the daily fatigue, diarrhea, and hand-foot syndrome that you probably see less with immunotherapy. However, if you use dual immune checkpoint inhibition, you get a higher rate of autoimmune adverse effects, so the difference is roughly double the rate for prednisone to get some of these adverse effects under control. About 10% to 15% of patients on a PD-1/TKI combination require prednisone for the management of autoimmune adverse effects vs around 30% of patients with PD-1/CTLA-4 inhibition. They’re different flavors, and some of us find ourselves on one fence or the other. There’s also a trend to maybe combine some of these developed triplet therapies. That’s one of the major flash points and discussion points in kidney cancer.

Targeted Oncology: There’s a 30-month follow-up on KEYNOTE-564 as well as the phase 2 NEOAVAX study that has been under investigation. What impact can adjuvant and neoadjuvant therapies have on patients who are at higher risk of disease recurrence, either pre- or post-nephrectomy?

Dr Hammers: Adjuvant therapy is another heavily discussed topic in renal cell carcinoma. We’re excited about the arrival of immunotherapy in the adjuvant space. However, there is some controversy. Not all of the clinical trials were positive. Three major trials were negative for the use of adjuvant immunotherapy with regard to progression-free survival benefit. There are several reasons for it, but we don’t understand why that is for some of them.

The trial that was positive is KEYNOTE-564, leading to the approval of pembrolizumab for 1 year of treatment in patients with higher-risk disease. Clearly, there’s a disease-free survival benefit with a very nice hazard ratio, with a relative risk reduction of more than 30% of patients, which was nicely confirmed in the 30-month follow-up that was presented by Dr [Toni] Choueiri [Dana-Farber Cancer Institute, Boston, Massachusetts]. However, the overall survival isn’t yet positive, and we have to see if it ever will be. [If it becomes positive, we have to see] how much and whether it’s caused by having some patients enrolled in other parts of the world who don’t have access to immunotherapy in the control arm.

It isn’t clear that we’re curing more patients with immunotherapy in the adjuvant space. We are certainly going to cause more adverse effects. This isn’t necessarily something that we have to blindly give to everyone. For patients who are at higher risk of recurrence who want to choose a treatment option, it’s an FDA-approved option that is certainly fine to choose. We have clinical trials exploring other combinations in that space. But what we would really love to see, and what we have used in other adjuvant settings, is that we are improving overall survival, meaning patients live longer or more patients survive because we give immunotherapy earlier. It isn’t yet fully clear that we absolutely have to be in that space.

The NEOAVAX study is a completely different type of study that was more like a feasibility study. It has much fewer patients: around 40. This is studying axitinib and avelumab in combination to see if it’s safe and to look at the activity profile. Response rates were roughly in the range of what you would expect with a single-agent TKI: 30% of patients were responders by RECIST [Response Evaluation Criteria in Solid Tumors] of the primary tumor, with an average shrinkage of the primary tumor of around 20%. That’s roughly what you would expect with a TKI alone. There was some disease-free survival benefit. It was a small number of patients, and we still have to figure out how we want to move forward in that space, with some data being negative in that space, including the neoadjuvant treatment with nivolumab in a phase 3 trial. That is still evolving, but it’s important to get some of the data to guide further development.

Targeted Oncology: With IO [immuno-oncology]–IO and IO-TKI regimens at the forefront for advanced RCC, and given there are several options, what strategies and factors do you consider in determining the most optimal treatment selection for your patients?

Dr Hammers: It varies, and I will have a different strategy than others. The most important thing is that we move away from single-agent TKIs and that we’re using immunotherapy doublets. Unfortunately, we still see some patients who may just get a single-agent TKI, which isn’t the standard of care anymore. But there are discussions, such as, what’s the durability of the response? How do the data sets differ as we get more follow-up, in particular with regard to the PFS curve? Is it a continuous decline? Or are we going to see a plateau formation, as we saw with the PD-1/CTLA-4 inhibitor?

Clearly, there’s an advantage of the IO-TKI combinations in the initial response rate, which is around 60% to 70% vs around 40% for patients with the dual immune checkpoint inhibitors. But the question is also upfront benefit vs the long-term outcome, how many patients are potentially cured from immunotherapy. There are some questions. We’re still waiting for more data to come to a conclusion, more follow-up data from the IO-TKI combinations and some other registrational studies or post-registrational studies, such as CheckMate 8Y8, which is a European study pitting PD-1 monotherapy against PD-1/CTLA-4 to confirm the contribution of CTLA-4 for kidney cancer immunotherapy. Those are some of the main ongoing discussions.

Some of us may choose depending on patient characteristics. Patients who need a response should be on an IO-TKI. For patients who are asymptomatic with a reasonable disease burden, I personally like to use a PD-1/CTLA-4 combination because of the durability of response, and because I can use a TKI when I need to if the patient progresses on it. Those are the 2 major flavors. We choose depending on the patient characteristics. There’s some histological consideration. If somebody has a sarcomatoid differentiation, then we prefer IO-IO, meaning a PD-1/CTLA-4 inhibitor with very high response rates and very durable responses. It’s probably the single best chance to cure those patients with otherwise very aggressive disease. But otherwise, we don’t have great biomarkers to guide us. It primarily depends on clinical characteristics as well as physician familiarity with the regimen of what they would like to choose.

Targeted Oncology: There were 2 studies: KEYNOTE-146, which is doing an exploratory analysis, as well as a serum biomarker analysis with lenvatinib and everolimus. With that said, how can biomarkers and clinical outcomes shape future patient stratification and treatment selection in advanced RCC?

Dr Hammers: Right now, the state of affairs is one of desperation. We don’t have great biomarkers. PD-L1 has not been a successful biomarker in selecting patients who should get, for example, immune checkpoint combination with PD-1/CTLA-4 vs PD-L1–positive patients vs PD-L1–negative patients. People are now looking at gene signatures, often taken from one regimen, and seeing how that might apply to other regimens.

With many of these studies, including the ones that you just mentioned, when you look at the IO-TKI combinations or even CheckMate 214, PD-1/CTLA-4 combinations, many of these signatures don’t seem to enrich well. Data sets like gene signatures from IMmotion151 with atezolizumab-bevacizumab don’t seem to differentiate patients who benefit in the biomarker analysis in the pivotal trials on CheckMate 214, meaning nivolumab-ipilimumab vs axitinib-avelumab, vs CheckMate 9ER, cabozantinib-nivolumab, for example. In the same one, they didn’t see a signal when they looked at lenvatinib-pembrolizumab. Biomarkers still aren’t guiding us.

There are some clinical trials to look at [biomarkers], but I fear that they have an uphill climb. It’s difficult. I wish we had better biomarkers, but we need to go back to the drawing board and see how we want to develop some of these. In general terms, biomarkers that look at the tumor microenvironment and angiogenesis inhibition is complicated. Immunotherapy certainly is complicated. If you combine these 2, it’s even getting more complicated. The clinical development of many of these combinations is still marching ahead. We’re now looking at phase 3 pivotal trials with triplet therapies, so it’s going to get even more complicated. How can we expect the gene signatures developed in doublet therapies to apply to triplets, where another agent has been added to the mix? It’s getting really complicated, and the field is moving ahead much faster than what we can do currently with biomarkers.

The other thing is also that the response rates are getting so high now that if the majority of patients respond, there’s almost a question of whether we need a biomarker. If the vast majority of patients don’t have a progressive disease as best response, meaning 95% of patients have some kind of benefit, then how do we move forward? How important are biomarkers? There are many arguments on both sides of the aisle. It’s a very difficult topic. We need to keep looking and keep encouraging the industry to help us with some of those biomarker approaches. But there’s no clear light at the end of the tunnel at this moment.

Targeted Oncology: For patients who are treatment naïve as well as previously treated patients in advanced RCC, could you provide an overview of novel agents or regimens that are currently being investigated?

Dr Hammers: For treatment-naïve patients, we have some recent data that came from a triplet therapy. In COSMIC-313, treatment-naïve patients with intermediate- and poor-risk disease were randomized to receive cabozantinib, nivolumab, and ipilimumab vs nivolumab plus ipilimumab. The trial was positive with regard to the hazard ratio for progression-free survival, but that trial really demonstrated that there were significant toxicity issues that were probably related to the TKI, which probably has more liver toxicity issues than some of the other tyrosine kinase inhibitors. The liver toxicity was almost prohibitive. That’s clearly a warning sign that if you’re moving into triplets, you really want to have combinable agents. I’m not sure how much that regimen will change the landscape.

There are other triplet therapies moving forward that are probably going to be better tolerated. There’s a phase 3 trial looking at 2 triplet therapies, one combining lenvatinib with pembrolizumab plus a CTLA-4 inhibitor, and another combining lenvatinib and pembrolizumab with belzutifan, a HIF-2 inhibitor. Those 2 are pitted against lenvatinib-pembrolizumab. It’s a gutsy trial because lenvatinib-pembrolizumab is a very active combination. We’ll have to see if that can be demonstrated in those phase 3 trials. But clearly, the field is moving into maybe combining some of the benefits of dual immune checkpoint inhibition with a tyrosine kinase inhibitor. It’s a very interesting clinical trial.

ln the pretreated space, the class of agents that we are waiting for with a track record even outside of phase 3 clinical trials is HIF-2 inhibition. We’re waiting for the arrival of belzutifan, which is now approved in patients with VHL syndrome and dramatically changed the management of those patients, with phase 3 clinical data for patients with sporadic renal cell carcinoma. Expected response rates are probably going to be around 25%, but it’s a uniquely well-tolerated drug that can have a major impact on quality of life for those patients. In pretreated patients, we’re waiting for that agent and some of the phase 3 clinical trial data.

Targeted Oncology: What are some remaining unmet needs in the treatment of patients with advanced renal cell carcinoma?

Dr Hammers: The big questions are along the lines of the treatment history. For patients who just had surgery, how do we identify patients who are at highest risk of recurrence? Just looking at the adjuvant space, where 70% of patients are already cured from surgery, depending on how we select patients, can we find ways to avoid treating those by identifying patients with minimal residual disease development we see now happening in bladder cancer? Getting smarter about the patients who still have residual cells in their body after nephrectomy will be one of the big questions. Big efforts are being made in that, and that will really help us select patients more carefully.

How do we cure patients with metastatic recurrence? How can we improve immunotherapy? We have high response rates. Tyrosine kinase inhibitors increase the response rate, but they probably aren’t adding to the curative approach of those patients. So how can we potentially improve the immunotherapy backbone? How can we use other additional agents to make immunotherapy more effective? That’s another big question. If we conclude that we cannot cure our patients, how can we most effectively prolong their life while maintaining a good quality of life? That goes in the direction of the HIF-2 inhibitor, for example. Clearly, we need to improve in kidney cancer on many fronts and support our patients.