Dr. Rana McKay:
Welcome to The ASCO Post Roundtable Series on Later-Line Considerations in Relapsed/Refractory Renal Cell Carcinoma. I'm Dr. Rana McKay. I'm a GU Medical Oncologist at the University of California in San Diego. Joining me today are my awesome colleagues from across the U.S., if you all want to introduce yourselves.
Dr. Sumanta Pal:
Sure. I'm Monty Pal, a medical oncologist at City of Hope focused on kidney cancer.
Dr. Bradley McGregor:
I'm Brad McGregor. I'm also a medical oncologist practicing in kidney cancer at Dana Farber.
Dr. McKay:
All right. Today, we'll be discussing the treatment and management of relapsed/refractory RCC with three patient case studies, and our second installment will focus on the management of refractory RCC after progressing on adjuvant IO therapy. This is becoming an increasingly important topic in the post KEYNOTE-564 data with the approval of adjuvant pembrolizumab. First, I'll say we'll start out with a case. Mr. RJ is a 50-year-old man who underwent an early cancer detection test in 2020. He had an executive physical and had one of these multicancer early detection tests that actually came back positive and so didn't know what to do with this data. He ended up getting pan scanned. He got a CT of the chest, abdomen, pelvis to work up this positive biomarker test.
On that CT scan, he was found to have a 5.1-cm right upper pole mass in the kidney. He ended up undergoing a partial nephrectomy and was actually found to have T3 disease, had clear cell RCC grade 3. Actually, the resected mass ended up being 7.1 by 4.6 by 3.6 centimeters. He had perinephric fat invasion. He did have some invasion into the renal vein that was denoted.
First, I'll ask how do you approach this individual? Are you seeing these tests getting done more commonly? How do you strategize?
Dr. Pal:
I will say I'm seeing a lot of incidental diagnoses like this, maybe not so much from tests such as this one per se but folks getting more pervasive scanning when they go to the emergency room for car accidents and what have you, and so we're getting a lot of these incidental findings picked up on imaging. I think that as you've outlined the case, this patient would definitely be one where I would want to discuss the option, at least now in 2024, of adjuvant immunotherapy. Based on what you've described here, he has T3 with renal vein invasion, perinephric fat invasion, grade 3 as well. I think that those factors would probably steer the conversation in that direction to some extent. Brad?
Dr. McGregor:
Yeah, 100% agree. I mean, I think this is a patient who would've met the eligibility criteria for KEYNOTE-564, where pembrolizumab showed not only a DFS benefit, but now with the latest presentation, overall survival benefit. I think it is something that I certainly will discuss with all my patients and certainly a patient such as this who meets the criteria.
Dr. McKay:
Yeah. What do you all do for risk stratification? There's a lot of algorithms that are out there, just your bread and butter, AJCC staging, but there's a lot more, UISS criteria, Leibovich criteria. Do you all have one that you lean towards or just really stage and grade?
Dr. McGregor:
I often use the ASSURE nomogram in the clinic. I think it's very straightforward. You can, "Hey, you bring up this screen, you put in the different criteria for the patient," and it gives you that 2-year risk of relapse, which for a while, that's what we had the data for KEYNOTE-564. They would sort of take that hazard ratio and give some assessment of what that hazard ratio actually means to that patient, like that hazard 0.68, what does that actually mean in terms of your absolute risk reduction in recurrence? I find that to be a helpful tool as I'm talking with the patient trying to say, "This is your absolute risk benefit associated with a 10% risk of needing steroids." It allows that nice contextualization for the patient.
Dr. Pal:
Yeah. I totally agree with you, Brad. I think the ASSURE nomogram is a wonderful one to use. I will say that Rob Uzzo had this really elegant paper in JCO a couple of years ago that juxtaposed all of these nomograms. I want to say it was the SSIGN score and a handful of others that fell out as being perhaps some of the better predictors of outcome, but I don't think you can necessarily go too far wrong with any of these nomograms. I think the best thing about them is they really reassure the patient that chances are, especially in a scenario like this, that the cancer will not come back at that 5-year mark. It is not an absolute as it might be with other aggressive malignancies.
Dr. McKay:
Yeah, very helpful. Yeah, I think it's important to risk stratify. I think there's other tools that hopefully will be developed. Right now, our risk stratification is largely based off of clinical parameters. We don't really have a lot of additional diagnostics, pathology, ctDNA, other things like that to help.
This patient did in fact go ahead and start on pembrolizumab therapy because of the high-risk features that were detected on his pathology from his nephrectomy. He went on and received a year of therapy in August of 2022 to August of 2023, actually overall tolerated treatment quite nicely and didn't really have any issues with surveillance on his surveillance scans. When he completed therapy, set him up on a 3-month surveillance schedule for a typical stage 3 patient. On his first subsequent scan, after completing his treatment, he was found to have new pulmonary nodules that were detected, not very large, but new pulmonary nodules and ended up undergoing a VATS.
I'll probably stop here and say, these pulmonary nodules were quite small. He just completed adjuvant therapy and maybe our impetus to jump and do surgery right away. Some may watch for a little bit, get a sense of "Okay, do I do surgery right now? Do I get another scan?" VATS, it's not the simplest of surgical procedures, but ultimately, he did undergo a VATS and it came back as clear cell RCC. What's your monitoring paradigm after IO therapy? What's your impetus to act on something, the pulmonary nodules, little small stuff that comes up on imaging?
Dr. McGregor:
I think it's going to depend on the patient. I mean, this is a patient that undergone a blood test to look for early signs of cancer, so I imagine this is a very anxious patient. I don't think a situation like this is going to, "Oh, there's these nodules there. I'm not sure what to make of them. We can just watch them." You just have to have the discussion. Based on the comfort level of the patient, I think anything would be appropriate at this point in time. "There's clearly a change. It's concerning. I agree the only way you get a tissue diagnosis is going to be through VATS." It's just going to come down to that discussion of the patient. Are they comfortable to say, "Hey, we can see a scan in a few months," or, do they want to..." I don't have the answer right now.
Dr. Pal:
I actually completely agree with you, Brad. I think the diagnostic confirmation is so essential in cases like this, because in such close proximity to immunotherapy, it's hard to rule out any fibrotic change that might be a consequence of treatment. From the images that you're showing us, it does have more of a nodular appearance. But nonetheless, I think it's really helpful to have that diagnostic confirmation. If this is one of dozens of small pulmonary nodularities, I would probably be influenced to maybe consider systemic therapy in that setting. If it was isolated, then perhaps I might try to convince the patient to pause on systemic treatment for the time being.
Dr. McKay:
I think this brings up the point too, when we look at the KEYNOTE-564, many patients screen failed at the beginning of the study because of pulmonary nodules or other kind of low volume actual metastases that they had, and so I think ensuring that that diagnostic workup is happening. I think this brings us up to, well, what do you do next for this gentleman? He's got a pulmonary nodule that was resected. He's recurred after a year of immunotherapy. What is the next best thing that you would do?
Dr. Pal:
If this gentleman unfortunately progressed one month out from immunotherapy, if I were going to consider systemic treatment, I would probably consider him to be an IO failure. I would suggest that he just go on to a VEGF-TKI alone. In that setting, I'm pending to use cabozantinib more so than other agents just because we have a plethora of data to support its activity following frontline IO, as you might consider this to be in this patient's case. I don't know, Brad. What do you think?
Dr. McGregor:
Yeah, 100% agree. I think there's this whole debate of what do you do after adjuvant IO, how long do you wait. I think this patient progressed essentially on IO. I mean, he had a dose in August, and by September, he had disease. I would agree. I worry that this is immune checkpoint resistant. Then given the CONTACT-03 data extrapolating from different settings, the minimal patients in that trial that had adjuvant IO therapy, I agree. Switching to a TKI and cabo would probably be my choice as well.
Dr. McKay:
Yeah. No, absolutely. I think, here, it also brings up the whole concept of, well, could you monitor? Could you watch this individual? But I think the kinetics of this individual's disease makes me a little bit concerned. His primary renal mass was quite small, 5 centimeters on imaging, but then he had T3 disease with renal vein invasion, and then completes 1 year of pembrolizumab, and then is developing pulmonary nodules so quick after that. While we did resect the dominant nodule, you could make a case, "Okay, I'm just going to watch this individual," but the tempo of this individual's disease certainly has me concerned to start systemic therapy. It's hard to think about application of IMDC. Here, technically, we're timing things from the timing of nephrectomy.
His labs were otherwise okay, but he doesn't smell like a favorable risk patient to me had he not received the adjuvant therapy and so we did go ahead and actually start him on cabozantinib. I think there's a lot of really just robust data of cabozantinib's activity in the post IO setting. Several clinical trials have looked at cabo in the modern era. Certainly, CONTACT-03 is the most compelling where all of those individuals had been pretreated with IO therapy. In the control arm of cabozantinib alone, we saw very impressive PFS of around 10 months. Primary PD rate was really quite low in the context of that study, less than 10%, response rates on the order of 40% in the second line setting. Of course, also from the CANTATA study, not 100% of those individuals had received modern day IO therapy, but the control arm there also is telling of cabozantinib's activity in the modern era, and this patient did go on to receive cabo. Any thoughts from you all about cabo in this context?
Dr. Pal:
I couldn't agree with you more, Rana. I think with trials like cabo seek more recently and so forth, I think there's even more compelling evidence for cabozantinib specifically after IO and context like this. I think that makes a lot of sense.
Dr. McGregor:
Yeah. I mean, I think, for the longest time, we're based on these different retrospective series that we're publishing. We had published one series, but now we have really good prospective data that really has established cabozantinib has strong clinical activity following IO without a clear increase in toxicities, which I think is an important aspect of its use.
Dr. McKay:
Thank you all for sharing your insights on this case. I think there is limited data to guide clinical decision making in patients that are progressing post adjuvant therapy. There's several clinical trials that are currently ongoing that are integrating the utilization of IO in the adjuvant setting and some IITs that are actually looking at this as well. I think, in general, IO, post IO has really been associated with low to modest at best benefit and should not really be utilized out of the context of a clinical trial right now. In the context of patients having immediate progression post adjuvant therapy, I think the standard is really leaning towards VEGF monotherapy in this context of a clinical trial.
Well, thank you all for providing your insights on this case. This brings us to the end of case 2. Please see the other segments for further discussion about the latest research in RCC or visit ascopost.com. Thank you.
