Dr. Rana McKay:
Welcome to The ASCO Post Roundtable Series on Later-Line Considerations in Relapsed/Refractory Renal Cell Carcinoma. I'm Rana McKay, a GU medical oncologist at the University of California in San Diego. And joining me today are my two esteemed colleagues from across the U.S. If you all want to introduce yourselves?
Dr. Sumanta Pal:
Hey there. I'm Monty Pal, medical oncologist at City of Hope in Los Angeles.
Dr. Bradley McGregor:
And I'm Brad McGregor. I'm a GU oncologist across the coast in Boston at Dana-Farber.
Dr. McKay:
Well, welcome today. We're going to be discussing the treatment and management of relapsed/refractory RCC with three patient cases. And our final installment will focus on the management of metastatic RCC after progression on VEGF and IO therapy. So we're going to just dive right into the next case.
Ms. CS is a 56-year-old female who presented in 2015 with sharp abdominal pain, and ended up ultimately undergoing some imaging which revealed a large renal mass, and her CT, chest, and MRI were negative. She underwent a left nephrectomy revealing clear cell RCC, 10.9-cm mass, grade 3, stage T3B, renal vein invasion was identified. She was being monitored and ultimately ended up developing disease progression with disease in her lungs, disease in her adrenal gland, and had otherwise normal labs with the exception of a low hemoglobin. And so at the time of her presentation of metastatic disease, she had IMDC intermediate-risk disease.
And so first I'll ask how do you risk stratify in this context? I know we've integrated across the other cases sort of IMDC in the modern era. I think it's certainly still applicable here and just want to understand how you approach patients newly getting presented with metastatic disease?
Dr. McGregor:
Yeah, I mean I think the IMDC still remains an important prognostic factor and I think once you've reached that point, are you going to treat, which I think in this situation it's like with the anemia, I think we're likely to reaching a point where you do need systemic therapy. Then I sort of look at the big picture and I think there's a two big classes: the IO/IO or IO/TKI, and which way do you want to go there?
I think we've seen a lot of really encouraging data for it being long-term follow-up. The median duration of response now with 8 years follow-up is 80 months. And so that's really, really appealing. So I think the question I always ask myself in the clinic is while there's this really impressive mean duration of response, there's a 20% progression of disease as best response. So can that patient afford to have that disease progression and get onto second-line therapy? Or in a situation where if you're wrong and they progress, they're not going to get there. And so that to me is sort of a gestalt and talking to the patient and their comfort level overall. But I think that's something I sort of think about often in this situation beyond just the IMDC.
Dr. Pal:
Yeah, I have very little to add to that. Honestly, Brad, I think I'd think through it the same way. I've been very impressed with the upfront data for nivolumab as time has sort of gone on with it. I do think that I'm excited to see longer term follow up from data sets like CheckMate 9ER to reflect the activity of cabozantinib/nivolumab. And I have been pleased to see that there seems to be some maintenance of benefit over time. But those considerations that you mentioned, just spot on with what I'd typically do in this setting.
Dr. McKay:
And so this patient did go on to start treatment with nivolumab and ipilimumab. She did well with therapy initially, didn't really have too many side effects, had a little bit of hepatitis when she was still getting her ipilimumab and then was on maintenance nivolumab. But actually in the context of being on maintenance nivolumab after about a year of therapy, she did develop a retinal detachment, which actually was suspected to be related to immune infiltrates in her retina. And so we actually ended up permanently discontinuing therapy and she was monitored for a period of time. Her main area of disease was a growing right adrenal nodule, and everything else was actually stable on her imaging as we were scanning her.
Now you've got an individual who's progressed on IO but kind of had some toxicity on IO with a short off-period before she actually ended up having radiographic evidence of progression. So what do you lean towards here actually?
Dr. Pal:
Yeah, this is an interesting case. I think that given your description of the challenges she had with prior systemic therapy and given that this is just sort of one isolated site of growing disease, I'd love to look to local therapy options. I'd be thinking about surgery or perhaps radiotherapy in a situation like this maybe to sort of stave off any need for further systemic treatment. Brad what do you think?
Dr. McGregor:
Yeah, 100%. I think we know often these patients who get nivolumab/ipilimumab upfront, the pattern of progression often may just be a single site of disease and hopefully through aggressive local therapy to that site we can offer a prolonged treatment-free interval, which I think would be really important in a situation like this where I had pretty significant toxicities from immunotherapy. So I would engage with my radiation oncology colleagues to see if SBRT could be an option vs consideration of surgical management.
Dr. McKay:
Yeah, that's exactly what we did in this case. She was coming off of her immunotherapy, recovering from the retinal detachment, had one site that was progressing. So she did ultimately end up undergoing SABR, and then we continued to watch her for some time and did okay for about a 6- to 9-month period and then developed disease progression within her lungs with multiple several new pulmonary nodules. And so kind of in this scenario as we transition through, she's seen nivolumab/ipilimumab, she's had SABR, she's VEGF-naive. What would you all kind of lean towards?
Dr. McGregor:
I think as we discussed in the case, our second case, the adjuvant after IO I think, cabozantinib remains a very appealing option for a patient who has progressed on immunotherapy given the plethora of data we've previously discussed. So I think in these situations we often think about switching to cabozantinib monotherapy.
Dr. Pal:
Yeah, I completely agree with you, Brad. I think it's a very reasonable option following a regimen like nivolumab/ipilimumab and really supported by more and more very sort of specific and tailored evidence with trials like CONTACT-03 and CABOSEQ and so forth. Makes a lot of sense.
Dr. McKay:
Yeah, that's exactly what we did. We initially transitioned to cabozantinib and did okay with the cabozantinib at 60 mg, and we dose titrated for some diarrhea, some elevated LFTs, but ultimately got her on a stable dose at 40 mg daily doing well. But unfortunately, about 8 months after she started the cabozantinib, she developed some continued progression within the pulmonary nodules within her lungs. No other sites of disease, no bone metastases or liver metastases. And here now we're post-IO, we're post-VEGF in the later-line setting. And what do you all kind of lean for in this context? How do you frame that discussion when you have the patient there before you?
Dr. Pal:
I would probably lean heavily on understanding how she tolerated her prior regimen. So with cabozantinib, if she had issues with hepatitis and diarrhea and so forth, I would probably lean towards maybe a more selective TKI in this setting. I think that tivozanib represents a terrific option when you sort of weigh the other regimens, for instance, lenvatinib and everolimus. I think it brings to mind the same possibility for challenges with diarrhea. I've been leaning away from using belzutifan too often in situations like this just because of the time to response. When we have patients in this salvage setting, I think typically we need to get that response a little bit sooner. And I have to tell you just with boots on the ground practical experience, the anemia has also been an issue in my third- and fourth-line patients. So by the time they're getting out to that timeframe, their hemoglobin sitting at 8, 9, maybe 10, right? It's really hard to get in belzutifan effectively without significant dose reductions when you're starting at that level.
Dr. McGregor:
Yeah, I mean, I agree with you Monty. I think that we do have a lot of different options in this situation. I think tivozanib is certainly appealing, right? There's really minimal LFT abnormalities, at least grade 3 or higher with tivozanib. It is well tolerated. You get that built-in week off, which patients often like after they've been on a TKI daily for a while, that ability take that one week off is nice. And I think ultimately, I think one of the really intriguing, one of the most intriguing parts about that TIVO-3 data set is that potential for that 15% to 20% or so that have that really durable response that you can start it and then maintain that response at the 2-year follow-up, 3 year follow-up. And I think that that is certainly something that's incredibly appealing about tivozanib. And we see some of that, hopefully that same little hope with extended thought, we may see some of that hints of the same thing with belzutifan that well, the response rate's only 20%. There's that group of patients that maintain that response for some period of time.
Dr. McKay:
Yeah. I think too, to speak, in my experience, tivozanib has been a pretty well-tolerated TKI. I think advising patients to closely monitor around the high blood pressure, but patients do quite well with it when we think about hand-foot syndrome, diarrhea, mucositis, those sorts of side effects. So I think it is a nice agent to utilize. And I think our goals of care differ in later line and really thinking about quality of life in addition to disease efficacy and life prolongation. I think integrating, they don't need to be mutually exclusive, I guess you can say. I think integrating into a strategy that's going to improve quality of life is a good thing.
Dr. McGregor:
And I think with all these agents, that's going to be critical. You pick an agent and then you have to adjust the dose and constantly reassess where we're at with the toxicities and manage appropriately. And so I think it's early on from before we would start therapy, I think it's really important to educate the patients that when you start at one dose, we're probably not going to end up at that dose in the end. And it is okay if we have to dose reduce for toxicities going on and it's not going to compromise efficacy. It's going to allow you maintain on the therapy longer and hopefully give you better long-term control.
Dr. McKay:
Yeah. No, very good points. I think if I think about this case, if the patient in addition to pulmonary nodules had progressive liver metastases and bone metastases, I may lean a little bit towards lenvatinib or everolimus, but knowing that we are going to compromise on quality of life and toxicity.
So I think understanding the kinetics of patient's disease, their burden of disease and that shared decision-making with the things that are important for them, I think is key.
So kind of summarizing this case, I think certainly for those individuals that have oligometastatic or oligoprogressive disease, I think we're ever-increasing focal therapy into the context of treating RCC. And I think it's something to think about as a means to just prolong time on any given therapy. In the post-IO setting, the strategy has been single agent VEGF TKI or a VEGF pathway targeting agent. Tivozanib is certainly an option that can be considered in the post-IO and post-VEGF TKI setting.
So this brings us to the end of this case. So please see the other segments for further discussion about the latest research in RCC or visit ASCOpost.com. Thank you so much for being with us today.
