Researchers look to neoadjuvant setting to advance RCC paradigm

Researchers hoping to improve outcomes in patients with locally advanced renal cell carcinoma (RCC) are increasingly focusing on the adjuvant and neoadjuvant settings.

For example, adjuvant pembrolizumab (Keytruda) was recently approved for the treatment of patients with RCC at intermediate or high risk of recurrence following nephrectomy,¹ and further research is looking to bringing this approach to therapy—not just with immunotherapy but also with targeted therapy—into practice ahead of nephrectomy to further prevent the risk of recurrence.

Naomi B. Haas, MD

One such trial is the global phase 3 PROSPER RCC trial (NCT03055013) looking at neoadjuvant and adjuvant nivolumab (Opdivo) in patients with high-risk RCC scheduled for radical or partial nephrectomy. Naomi B. Haas, MD, is the medical oncology study monitor for the trial and expects this will have a significant impact on the future role of neoadjuvant and adjuvant immunotherapy for patients with RCC.

In an interview during the 2021 International Kidney Cancer Symposium, Haas, the director of the Prostate and Kidney Cancer Program and professor of medicine at the Hospital of the University of Pennsylvania, discussed the potential of the neoadjuvant approach in treating patients with RCC as well as ongoing research in this setting.

Can you discuss what has been the success of the neoadjuvant targeted/immunotherapy strategy in the treatment of patients with RCC?

A number of VEGF TKI [tyrosine kinase inhibitor] approaches have been taken in the neoadjuvant setting. The general approach has been, given that cabozantinib [Cabometyx] is one of the VEGF TKIs, that it is thought to be one of the most active in RCC. [With this approach], the idea has been if it can be administered in a safe way and achieve as much tumor shrinkage as possible. One of the challenges with VEGFR TKIs, in general in the neoadjuvant setting, has been that they interfere with wound healing to some extent. Cabozantinib has a half-life of about 5 days, so the timing of it has to be such that it can be administered, and then I allow enough time to stop [treatment] where the patient can safely proceed with surgery but also not be off the drug so much that a rebound effect [occurs]. And I think we’ve seen with other trials that that is indeed possible.

The neoadjuvant approach has been an important approach for the immune checkpoint inhibitors. People [previously] have made comments without any data, only based on personal experience [about immune checkpoint inhibitors’ efficacy]. Several years ago, somebody stood up at a meeting and made the comment that there might be more scarring seen with immune checkpoint inhibitor therapy before surgery, and that makes surgery difficult. There have been a couple of neoadjuvant phase 2 trials that have been conducted that have shown that it is a safe approach and it hasn’t made surgery impossible in these patients, because immune checkpoint inhibitor therapy doesn’t interfere with wound healing, and I think the concerns about things like pneumonitis and intubating a patient have not borne out, that increasingly people are feeling a little bit better about offering that as a neoadjuvant approach.

What were the important points made by the panelists during the session regarding neoadjuvant therapy?

One of the very valuable things that neoadjuvant therapy does is it allows people to understand the biology of the tumors and who is benefiting and who isn’t benefiting from these approaches by doing some of the valuable correlative and molecular work that is needed. I think that one of the other take-home messages is that there’s still a relative lack of consensus, so we do need to wait for some of the bigger trials. For example, the PROSPER trial is trying to address both the feasibility, the safety, and also the signal that is achieved by offering neoadjuvant therapy to patients. I think one of the other [important] messages is that we need to figure out how to address these kinds of trials so they’re available to everybody and not just at tertiary cancer centers.

What are the key challenges with designing neoadjuvant trials in this disease?

One of them is good coordination between the urology and the medical oncology teams. Usually, the urologist is the first person to see the patients. So urologists have to be aware of neoadjuvant approaches and have to be willing to have that conversation with patients ahead of time to alert them to clinical trials. It’s not the standard of care right now to offer neoadjuvant [treatment] for RCC, but certainly, there’s a lot of surgical experience in urothelial malignancies and also in other disease sites, such as colorectal cancer and breast cancer, where it is common. One of the impediments is the urologist bringing it up to the patients. The second is being able to coordinate care because generally these drugs are administered by a medical oncologist. So [it is the] speed in getting patients [to treatment that is key] and having a multidisciplinary approach. The other [challenge] is making a trial simple enough for the medical oncologist, the urologist, and the patient to all feel that it’s easily accomplished and easy to enroll.

What are your expectations for neoadjuvant trial design going forward?

I think it’s not going to go away. I think that neoadjuvant therapy trials can also help to understand, in addition to who benefits from any kind of perioperative treatment, whether it’s adjuvant or neoadjuvant based on the correlatives, but I also think that people are getting more comfortable with this approach. It was a real learning experience several years ago when the PROSPER trial launched, but I think a lot of urologists now have a comfort level that they didn’t have before. I think that one of the other values is understanding the duration of either the neoadjuvant or the adjuvant approaches.

Since then, lenvatinib (Lenvima) has become such an important drug in the RCC space, and there are ongoing trials in the neoadjuvant setting and for other diseases like thyroid cancer and hepatocellular carcinoma. Do you think we’re close to having a study of neoadjuvant lenvatinib in RCC?

We’re about to launch a lenvatinib plus pembrolizumab trial at the University of Pennsylvania. I also heard Dr [Viraj] Master also talk about [a trial] at Emory [University] [NCT04393350]. There are phase 2 initiatives that are being done to understand the benefit in patients. Lenvatinib is an interesting drug because it probably has some immunologic aspects that can augment its activity with immune checkpoint inhibitors. There [are] some data to suggest that it might help stimulate Tregs [regulatory T cells] and it might be a way to prevent T-cell exhaustion, which are 2 reasons that immune checkpoint inhibitors sometimes don’t work in patients. I think it’s a very useful approach, and so I feel encouraged about that.

Reference

1. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed December 9, 2021. https://bit.ly/3rNXC3R