Immune Checkpoint Inhibitors Encouraging for Perioperative RCC Treatment

Naomi Haas, MD

In renal cell carcinoma (RCC), multiple immune checkpoint inhibitors (ICIs), including combination regimens, are FDA approved. Therefore, the success of these agents has prompted the exploration of ICI treatment in the adjuvant and neoadjuvant settings.¹

Since 2021, when researchers investigated the clinical question of whether ICIs can be administered in the perioperative setting, 9 clinical trials commenced and are ongoing. The single-agent studies include investigation of neoadjuvant pembrolizumab (Keytruda; NCT02212730), neoadjuvant nivolumab (Opdivo; NCT02575222), and 3 trials of neoadjuvant/adjuvant nivolumab (NCT02595918, NCT02595918, and NCT03055013). The combination strategies under investigation are neoadjuvant durvalumab (Imfinzi) plus tremelimumab (NCT02762006), neoadjuvant spartalizumab plus canakinumab (Ilaris; NCT04028245), neoadjuvant axitinib (Inlyta) plus toripalimab (NCT04118855), neoadjuvant axitinib plus avelumab (Bavencio; NCT03341845), and neoadjuvant sitravatinib plus nivolumab (NCT03680521).

In an interview with Targeted Oncology™, Naomi B. Haas, MD, director, Prostate and Kidney Cancer Program, and professor of medicine at the Hospital of the University of Pennsylvania, discussed how the research has pivoted toward exploring neoadjuvant treatment for patients with RCC.

TARGETED ONCOLOGY: Recently, results from a study of neoadjuvant cabozantinib and immunotherapy were released. Can you discuss the success of this strategy?

Hass: I think a number of VEGF TKI approaches have been taken in the neoadjuvant setting. Given that cabozantinib is 1 of the VEGF TKIs that is thought to be 1 of the most active in renal cell carcinoma, the idea has been with this kind of approach, if it can be administered in a safe way and achieve as much tumor shrinkage as possible. One of the challenges with VEGF TKIs 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. Then, I allow enough time to stop where the patient can safely proceed with surgery, but also not be off the drugs so much that you get a rebound effect. We've seen with other trials, that is indeed possible.

The neoadjuvant approach has been an important approach for the immune checkpoint inhibitors in that people have made comments without really any data. It is just based on personal experience. 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 would that make surgery difficult. And so, there have been a couple of phase 2 trials [in the neoadjuvant setting]that have been conducted, which have really shown that it is a safe approach, and that it hasn't made surgery impossible in these patients. I think that increasingly, we're finding that immune checkpoint inhibitor therapy doesn't interfere with wound healing, and there are fewer concerns about things like pneumonitis and intubating a patient, increasingly, people are feeling a little bit better about offering that as a neoadjuvant approach.

What are the key challenges with designing an adjuvant trial for this disease?

One of them is good coordination between the neurology and the medical oncology teams. Usually, the neurologist 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 renal cell, but certainly, there's a lot of surgical experience in urothelial malignancies and in other disease sites such as colorectal cancer and breast cancer, where it is common. So, one of the impediments is just the neurologist bringing it up to the patients. The second is being able to coordinate care because generally these approaches are administered by a medical oncologist and they are speedy in getting patients and having a multidisciplinary approach. And 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 to.

During a panel discussion, you discussed this topic during the International Kidney Cancer Symposium. What were some of the important points raised by the panel?

I think one of the important points is just that one of the very valuable things that neoadjuvant therapy does is it allows people to really understand the biology of the tumors, and who's 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 has been that there's still a relative lack of consensus. And so, we do need to wait for some of the bigger trials, for example, the PROSPER trial is trying to address both the feasibility, safety and the signal that is achieved by offering neoadjuvant therapy to patients. I think 1 of the other take home 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 your expectations for neoadjuvant trial designs going forward?

I think it's not going to go away. I think that neoadjuvant therapy trials can also help to understand 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. And I think that one of the other values is understanding the duration of either the neoadjuvant or the adjuvant approaches.

Since lenvatinib has become such an important drug in the RCC space and there are ongoing trials of neoadjuvant lenvatinib in thyroid cancer and hepatocellular carcinoma. Do you think we’re close to a neoadjuvant trial of lenvatinib in RCC?

We are about to launch a lenvatinib/pembrolizumab trial at the University of Pennsylvania, and I think there was talk about another trial at Emory University. So, there are certainly phase 2 initiatives that are being done to understand the benefit in patients. Lenvatinib is an interesting drug because it probably also has some immunologic aspects that can augment its activity with immune checkpoint inhibitors. So, there's some data to suggest that it might help stimulate T regs 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. So, I think it's a very useful approach. So, I feel encouraged about that.

Were there any other key discussion points during the panel?

One question that didn't come up, which was on our list of questions was just whether there's a role still for doing a biopsy ahead of time. I think biopsy is valuable, in that it sometimes allows opportunity to look at tissue before and after surgery to see if there are changes and that sometimes will springboard understanding of how drugs work. It's still sometimes difficult to get drugs approved for patients unless you have a cancer diagnosis, and so that's something that we need to have a better idea of. Are there other ways that we could confirm a cancer diagnosis so we could get drugs approved without having to have additional tissue biopsy? I know in PROSPER, what we did was, if patients were randomized or assigned to the arm that got the immune checkpoint inhibitor, they had to have a biopsy. We didn't require that if patients on the standard therapy arm who were going to surgery. But also, not everybody had a biopsy that was diagnostic, and so we didn't keep people from enrolling, even if the biopsy wasn't diagnostic. So, I think we'll learn a lot about that approach and maybe that will move the needle that we don't have to require biopsies on everybody.

_Reference:

_{Martini A Fallara G, Pellegrino F, et al. Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma. World J Urol. 2021;39, 1369-1376. doi: 10.1007/s00345-020-03550-z}