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Sumanta Pal, MD: Hi. My name is Monty Pal, and I am a medical oncologist at the City of Hope Comprehensive Cancer Center in Los Angeles. Welcome to season 2 of Medscape's InDiscussion series on renal cell carcinoma (RCC). Today, we'll discuss neoadjuvant therapy for kidney cancer. We'll discuss what's really hot and new in the field with our guest, Dr Jose Karam. Dr Karam is an associate professor in the Department of Urology at the MD Anderson Cancer Center in Houston, Texas.
Welcome to InDiscussion, Jose. How are you doing?
Jose A. Karam, MD: Good. Thanks, Monty, for having me. It's a great pleasure to be here with you discussing neoadjuvant therapy.
Pal: Today we're going to start off by talking about something we always talk about right at the outset of these programs, which is what got you into kidney cancer. It's a narrow field, and I have to say that it's sometimes an off-the-beaten-path choice for doctors. How did you find yourself leaning toward RCC?
Karam: When I initially started doing research, even before residency, I was doing exclusively prostate and bladder cancer research. Then, in the end of my year as chief urology resident, Jim Brugarolas joined UT Southwestern. He had a lot of great ideas, and he was a good mentor. I started working with him on some projects and knew that this was what I wanted to do. When I interviewed for a fellowship specifically at MD Anderson, I met Chris Wood, talked to him, and knew that this was what I wanted to do as far as a career, both clinically and in research. That's what I've been doing for the past 12 years now at MD Anderson.
Pal: That's so interesting. I've known you for eons, and I never knew that you actually started out in Jim's lab, but I can see how that would be inspiring and a path toward kidney cancer. Chris Wood is sort of a mentor to mentors, and I certainly want to get your tips on mentoring toward the end of the program.
What we're here to talk about today is neoadjuvant therapy for kidney cancer. As I recall, the first talk that I ever gave at the American Society of Clinical Oncology (ASCO) meeting was a review of poster discussion sessions. I remember I was covering the trial that you presented for neoadjuvant axitinib in patients with localized RCC. To this day, I still see it cited at meetings. Can you give us an overview of that study?
Karam: This was a study that was published almost 8 or 9 years ago. I designed that trial with Chris Wood when I was a fellow and started it early on during my tenure as a faculty with Chris. What we thought at the time is that we wanted to use an agent that was very active, and that's how we chose axitinib. We wanted to focus specifically on patients with clear cell kidney cancer, and that's why we mandated the biopsy ahead of time. As you know, at around the time, almost 10 years ago, some of these neoadjuvant trials had not mandated biopsy, so we had patients with benign tumors or different types of histologies. We thought we'd keep the trial as clean as possible by mandating biopsies.
We ultimately ended up enrolling 24 patients with clear cell kidney cancer, all biopsy proven, all locally advanced disease, and gave them axitinib for a total of 12 weeks. We started with the standard dose and then tried to increase it as much as the patient would tolerate and as much as we thought it would be safe to maximize the activity. The patients in general did quite well. Most of the patients, 23 of them, were able to continue therapy for 11-12 weeks, which is what we wanted. Only one patient had to stop a few weeks early. Everybody had surgery, and there were no delays in surgery, which was encouraging. Remember, what we think now with neoadjuvant therapy is very different from what it was 10 years ago. It was a bit scary to do it at the time with such a powerful agent.
We also tried to do a scan in the middle of the trial to make sure that patients were not progressing on therapy because we did not know any better at the time. Thankfully, there was no progression of disease on therapy. We had, I believe, 11 out of 24 patients with a partial response — about 46% of patients who had a partial response by the response evaluation criteria in solid tumors (RECIST) criteria — which was quite encouraging, with a relatively short duration of therapy.
Pal: That's really compelling. There have been a lot of other trials reported since then that looked at neoadjuvant tyrosine kinase inhibitors (TKIs). Tell me about how those have panned out. We have trials of pazopanib and sunitinib. Are any of those other trials particularly compelling, or do they at all perhaps reinforce or negate some of the findings from your study and others?
Karam: I think the studies generally go along the same path, and it's encouraging to see that we know these drugs work for our patients with kidney cancer, especially the vascular endothelial growth factor (VEGF) TKIs — specifically the ones you mentioned, sunitinib and pazopanib — and axitinib, which was worked on by our colleagues from France and was published about 3 or 4 years ago with a smaller study. Most of these trials enrolled patients with clear cell disease and the response rates were somewhat different, which is not surprising, given that the vast majority of these studies are quite small — in the range of anywhere from 13% to about 46% in our study. For example, in the pazopanib study that Brian Rini published, it was about a 36% response rate; in the axitinib study from the French group, it was a 22% response rate.
As you know, it depends on the size of the tumor, if you do any dose reductions, how long you give the therapy, and the actual agent itself. In general, these VEGF receptor TKI agents are quite significant as far as downsizing locally advanced tumors. We don't see that as much with bevacizumab, for example, or everolimus, which is not surprising given the mechanism of action for these drugs.
Pal: That's interesting. As all of these trials are being conducted, the field has shifted so much from my standpoint in metastatic disease. We migrated away from just single-agent therapy with a TKI and moved toward combination therapies that incorporate immunotherapy, which we have discussed on this podcast series in the past.
Before we jump into the strategy of combining TKIs with immuno-oncology (IO), I am curious to get your perspective on what IO alone does. I always think of the trial that Ari Hakimi did with Martin Voss and the Sloan Kettering folks with neoadjuvant axitinib. In my conversations with them, that was a bit of a challenging study to accrue to. I think they reported it in European Urology as a brief communication. Response rates were modest there, but I think there were a bit more compelling data among some of the data that your group at MD Anderson presented with this neoadjuvant platform, if you will, looking at bevacizumab-based IO combinations with IO/IO and so forth. Can you tell us a little bit about that, the data with J.J. Gao?
Karam: Several colleagues have worked on immunotherapy in the neoadjuvant setting or the presurgical setting, and I know we didn't cover it earlier, but when I use the word "neoadjuvant," I try to limit that mostly to patients with no metastatic disease, just to make it easier to refer to the data when we're talking about it and refer to patients with metastatic disease when we're using preoperative therapy as either "preoperative" or "presurgical."
As you mentioned, our colleagues from Memorial Sloan Kettering — Martin Voss and Ari Hakimi and their group — published on nivolumab in patients with metastatic and those with nonmetastatic disease, and Michael Gorin and Mo Allaf from Hopkins worked on nivolumab as well. The data are pretty consistent: If you use a single-agent immunotherapy, you don't really see any significant partial responses or complete responses in the primary tumor, at least not with the standard RECIST criteria. The vast majority of the patients, if not all, generally experience stable disease.
On the other hand, what we saw in the trial that was based at MD Anderson, in collaboration with our colleagues from genitourinary (GU) medical oncology, is a bit different. The trial was for metastatic clear cell patients. It's a bit of a different design. What we've noted in these patients is a more significant response. The trial that J.J. Gao and Pam Sharma spearheaded is a randomized trial. All patients in that trial had clear cell and metastatic disease. There were three arms, including either single-agent nivolumab, nivolumab with bevacizumab, and nivolumab plus ipilimumab. The patients received essentially three cycles of those drugs. Then they either had cytoreductive nephrectomy or metastasectomy, or just biopsy if they were not surgical candidates. After a break of about 4-6 weeks, the patients restarted on maintenance nivolumab.
The trial accrued about 104 patients, and almost 100 were evaluable for responses. Forty-one patients ultimately were able to have surgery. In those patients, what was termed as the best overall response was 79% in the nivolumab arm alone. This is not partial response or complete response; it's any response. When you go to the nivolumab plus bevacizumab arm, it was 93%. When you go to the nivolumab plus ipilimumab arm, it was 69%. Each of these arms had one patient who had a complete response, which we are seeing more and more of now, especially with the IO therapies either alone or in combination.
Pal: To be clear, you don't necessarily see that sort of a pathologic complete response disappear on scans, but you see it clear on the specimen. Is that right, or is it actually a complete response on imaging?
Karam: No, these are patients who had surgery, so we did still see something on imaging that looked like it was real, either in the metastasis sites or in the primary large kidney tumor. These are tumors that are 5, 6, 7, 10, 12, 14, 16 cm that looked like they were still viable on imaging. We went for surgery, and then the final pathology was a T0 or complete response in something that you actually see on imaging. It's a great question.
Pal: It's just amazing to me because I have so many patients in clinic and we oftentimes struggle with this dilemma. I look at the scans and see what I assume to be just this residual sort of shell around where the tumor used to sit within the kidney. I try to convince the patients that there's no active disease there. I think that experiences like this really speak to the potential of this neoadjuvant or perioperative approach, depending on the scenario to really clear tumor from the primary site.
Karam: Unfortunately, we do not see it as often as we would like to. It's still the minority of patients that have a complete response in the primary tumor. It could be because it's a large tumor and there's a lot of heterogeneity within the tumor, but we really don't know. Like you said, it's hard to know that for sure ahead of time, and it's hard to even get a biopsy and get a good result because most of it is necrotic on the inside and we try to aim for the periphery and get a sample that you can trust to tell you whether this is completely not viable. This is very hard to do ahead of time. Maybe with newer imaging, we can figure that out a little bit better. We will have to see.
Pal: Absolutely. We touched a little bit on that premise of VEGF inhibition with IO, with the data for bevacizumab, with nivolumab in the context of that study. Dialing back to that original conversation around TKIs, Axel Bex has some data looking at that combination of axitinib with avelumab. It's not something we use often for metastatic disease nowadays. Big phase 3 trials looking at axitinib plus avelumab didn't necessarily pan out in terms of overall survival. There's a really clever study that he did with axitinib plus avelumab in the preoperative setting, and it seems like sort of a nice continuum of some of the work that you've done previously. Can you tell us about that?
Karam: Yes. That was the next study that had to happen. Axel Bex and his team did a great job putting this study together called NEOAVAX. It's basically axitinib plus avelumab, so a TKI plus an IO. They gave patients axitinib and also injections of avelumab for a total of 12 weeks, I believe. Ultimately the patient underwent surgery. They enrolled 40 patients on this phase 2 trial with a median follow up of about 2 years. The patients had pretty aggressive and advanced pathology. The vast majority of the patients had T3 and higher disease, including eight patients with T4 disease on pathology. Interestingly, 42% of the patients had clinical node-positive disease. Patients with quite aggressive histology and disease were enrolled in this trial. The primary endpoint of this trial was similar to our trial with axitinib, which is the partial response was at week 12; they noted about 20% downsizing of the primary tumor. This is the actual kidney tumor, and it ranged anywhere between 4% and 43% downsizing of the primary tumor. Ultimately they found that 12 patients, or 30% of the patients, had a partial response by the RECIST criteria. Interestingly, at the 2-year median follow up, 10 out of the 12 patients with a partial response were still disease-free at the data cutoff. As you can imagine with this short follow-up, the median overall survival and progression-free survival were still not reached.
Pal: I think it's interesting. I didn't feel that the response rate was tremendously above and beyond what you saw with your axitinib alone study in the neoadjuvant setting. You bring up a great point about the risk in this particular group, and certainly that could potentially account for that, wouldn't you say?
Karam: For sure. One of the things that we've noticed is that the higher you can go on the dose of the axitinib, you'll probably see better responses. I'm sure you see it in your clinic all the time in your patients with metastatic cancer. Here it's somewhat easier to try to maximize the dose when you have a short period of time of 12 weeks. I know it's much harder to do that for years on end when you have a patient with metastatic disease and you don't really know when you can go back down on the dose. I think the timing as far as how long you give these drugs and how high you can go on the doses with the TKI is what gives the best responses. Like you stated earlier, IO therapy alone is probably not effective as much. We've seen that with nivolumab and other single agents. If we need to see primary responses, either TKIs alone or TKIs with immunotherapy would be the way to go.
Pal: I think that neoadjuvant therapy on the whole is not necessarily considered to be the standard of care at this moment. Having said that, I do find myself sitting on tumor boards in scenarios where we do decide to jump into neoadjuvant therapy. That's in the context of maybe really aggressive tumors, where you see the tumor thrombus is going to be hard to resect. Maybe that patient might be given systemic therapy in an attempt to potentially convert them into a surgical candidate. Do you see that scenario as being the principal one where you use neoadjuvant therapy, or are there others that you might contemplate?
Karam: Yes. I would want to strongly echo the point you made that neoadjuvant therapy is not standard of care and should not be routinely given by any urologist or medical oncologist. The way to go is to discuss difficult patient scenarios in a multidisciplinary conference, like you mentioned, before deciding to proceed with this.
There's many reasons why one might think that we need to give neoadjuvant therapy. One of it is to decrease the tumor size, for example, and make the resection easier, or to try to change a tumor that you have to do a radical nephrectomy for from a radical to a partial nephrectomy, especially in patients with one kidney, who otherwise would be on dialysis. Another reason to give it is to try to change unresectable disease to a resectable disease, but also unresectable kidney cancer is not very common. This is not like pancreatic cancer or other types of cancer. Having truly unresectable kidney cancer is not a common scenario.
Now, one scenario that has been used before is to try to downstage an inferior vena caval (IVC) thrombus; most of the data on this topic have been retrospective with minimal responses. Only very recently Grant Stewart published his work, an excellent prospective study using axitinib in patients with an IVC tumor thrombus for up to 12 weeks, either metastatic or nonmetastatic, in order to down stage to thrombus. He showed some encouraging results. The trial was called NAXIVA and enrolled 20 patients; it found that seven out of the 20 patients had the reduction in the Mayo Clinic level of the tumor thrombus, and ultimately, several patients had a change in the surgical approach thanks to this neoadjuvant therapy. This is the only trial that I'm aware of that has shown some encouraging results in this setting.
But we have to be cautious when using this in patients with IVC thrombus. Generally speaking, if a patient has a resectable IVC tumor thrombus, they should still undergo upfront surgery unless they're enrolled in a clinical trial, because it's very difficult to figure out who's going to respond to these therapies and who's not. We might miss a window of opportunity for curing this patient with surgery without any neoadjuvant therapy prior.
Pal: I think those are terrific take-home points to wrap up with — essentially the fact, and the certainly true statement in my mind as well, that neoadjuvant therapy isn't a standard of care. We could probably go on for eons and eons talking about this topic and other surgical topics and management.
I have a question for you before we wrap things up here. What do you tell people getting into the field of kidney cancer these days? What's the best way to carve out a path to this niche field?
Karam: I think the most important point in my mind is to have a great mentor that wants to support you and to have the appropriate training in order to do the things you want to do. You want to read as much as you can on the specific topic and try to figure out what is missing and where you can make a big difference. It's hard to do it alone, especially at the trainee level, whether it's postdoc or resident or fellow. You absolutely need a mentor that's invested in you and in your career in order to do this successfully. I was extremely fortunate to have that both in residency and in fellowship. The epitome of that is when my mentor, Chris Wood, would tell me that your success is my success, and he's referring to me. For a mentor, if their mentee's success defines the mentor's success, I don't think one can be more selfless than that when they're advising and helping their mentees. For all the people out there that are looking for a mentor, this is what they need to look for.
Pal: Well said. There's no better way to end this than with some thoughts from the late, great Chris Wood. What a terrific guy who made so many amazing contributions in the field. You've done the same. I'm sure he's incredibly, incredibly proud of you, Jose.
Today, we've talked about neoadjuvant therapy — lots of great historical perspectives on what TKIs have done in the neoadjuvant setting; what IO has done in this context; and the reiteration that although now it's not standard of care, we really do need more studies in this space to explore its role.
Thank you so much for tuning in. If you don't mind, take a moment to download the Medscape app to listen and subscribe to this podcast on RCC. This is Dr Monty Pal for InDiscussion.
A Pilot Randomized Study Evaluating Nivolumab (Nivo) Or Nivo + Bevacizumab (Bev) Or Nivo + Ipilimumab (Ipi) in Patients With Metastatic Renal Cell Carcinoma (MRCC) Eligible for Cytoreductive Nephrectomy, Metastasectomy or Post-Treatment Biopsy (Bx).
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Cite this: What's New in the Field of Neoadjuvant Therapy and Renal Cell Carcinoma? - Medscape - Sep 07, 2023.