Dr. Daniel George:
Hello and welcome to The ASCO Post Roundtable Series on New Approaches to Treatment Sequencing in Advanced Renal Cell Carcinoma. I'm Dr. Daniel George. I'm a Professor of Medicine, Surgery, and Urology at Duke University Medical Center. And joining me today are two of my colleagues. Dr. Harrison?
Dr. Mike Harrison:
Yes. Hi everyone. I'm Mike Harrison. I am an Associate Professor of Medicine at Duke Cancer Institute and medical oncologist
Dr. Daniel George:
And Dr. Fahey.
Dr. Catherine Fahey:
Hello everyone. I'm Dr. Catherine Fahey. I'm an Assistant Professor of Medicine at the University of North Carolina.
Dr. Daniel George:
Fantastic, thank you and welcome you both Catherine and Mike to this discussion and roundtable. Today we'll be discussing the treatment and management of advanced renal cell carcinoma with three patient cases to focus on. Our first installment will focus on the treatment of metastatic renal cell carcinoma in a 67-year-old patient with multiple risk factors. In case 1 here, Mrs. PB is a 67-year-old retired nurse who presented to her primary care physician with a 20-pound weight loss, anemia, low appetite, and new-onset hypertension. As part of her workup, she was referred to hematology for her anemia. Her hemoglobin was actually 8.4 and was noted to have a leukocytosis with a white count of 13, a left shift in neutrophilia of 10.1 and thrombocytosis of 570,000. She saw her hematologist 2 months later and the workup began but was nondiagnostic at first and although hypercalcemia at that time was noted with a calcium level of 11. A month after that concept, now 3 months from her initial presentation, she presents to her PCP with a severe headache and she's also noted to have an enlarged liver and several centimeters below her rib cage. At this point in time, her primary care doctor orders a CT of her abdomen/pelvis with contrast. And what you can see here on the right is a large renal mass on both the axial and sagittal views. Mike, what do you think is particular about this renal mass that strikes you?
Dr. Mike Harrison:
Yeah, so Dan, it looks very necrotic on the interior that we can see commonly with renal cell carcinoma. It is, as noted on the slide, it's kind of butting up against the liver, so it's not really clear if it's invading or just adjacent to, and that can happen with right-sided renal masses.
Dr. Daniel George:
Right, right. And obviously something this large and invasive can be difficult to resect nonetheless. Obviously she is referred to a urologic oncologist for treatment discussions and the overwhelming likelihood is that this is some form of renal cell carcinoma growing out of her kidney. She's noted to have multiple risk factors. Catherine, what do you think about her presentation and particularly the initial presentation with the anemia and leukocytosis? Any thoughts with that?
Dr. Catherine Fahey:
Yeah, so her initial labs as she was even getting the workup started all have some really concerning features for a very poor-risj renal cell carcinoma. When we think about our IMDC risk factors, the elevated white count, the anemia, the calcium, these are all things that make me really concerned about how her course is potentially going to go even before we've gotten a formal diagnosis with tissue.
Dr. Daniel George:
Yeah, in fact, I mean it is hard to think of a risk factor she doesn't have at this. She really checks all the boxes for a very high risk, 5 or 6, poor risk of renal cell carcinoma and this larger renal mass really confirms that. So in terms of a workup, Mike, what are you thinking when you see somebody like this? What are the types of diagnostics that you want to perform?
Dr. Mike Harrison:
Yeah, so I think she had a CT of the abdomen/pelvis, so of course we're going to get the chest CT or preferably because that's a common place renal cell carcinoma can spread to. I think with her poor-risj presentation, getting an MRI of the brain and a bone scan or some type of bone imaging would be reasonable. If we're thinking about resection, certainly there's the question about liver invasion; an MRI or some other imaging to clarify that could be helpful as well.
Dr. Daniel George:
Yeah, I think that's right and sometimes we'll get the MRI of the abdomen just to sort of clarify, like you said, sort of this invasion of the liver or not, and is this potentially into the renal vein? Is there any risk of PE or tumor thrombus or whatnot? So what about PET scan? Do you use PET scan in renal cell carcinoma?
Dr. Mike Harrison:
I'll speak for myself. I use PET scan relatively sparingly. I think bone scan with the lytic lesions that renal cell carcinoma typically produces does not usually capture the full burden of disease in bone. So I will sometimes use an FDG PET to clarify bone disease, but I'm not getting an FDG PET in all-comers.
Dr. Catherine Fahey:
Yeah, I completely agree. We know that in renal cell carcinoma a lot of times it just doesn't uptake FDG. So if I'm looking at lung lesions on a CT chest, if they're negative on a PET scan, that doesn't necessarily tell me that they're not the renal cell carcinoma. So if I'm not going to do anything differently with the results, it's not something I'm routinely getting. I do think that there is some new data coming out on PSMA PET potentially, and there's also that new radio tracer that's being established in RCC, but I think it'll be interesting, but certainly not anything I'm integrating into my practice currently. I'm curious if either of you two have any more knowledge on those.
Dr. Daniel George:
Yeah, I'll just say I completely agree. I think this story of PET is just beginning and there are renal cells that are positive by FDG, but I don't think it's going to add anything. As I said before, to me this is about as poor-risk a patient you can get. So I don't think adding FDG uptake is going to change that prognosis and you've covered all the scary bases with the bones, the lungs, the brain, and the abdomen. So I'm pretty comfortable even if there is something slightly outside those fields that we're missing, it’s okay. We really want to get on with therapy and sometimes waiting for a PET is just a further delay and somebody's already had 3 months of waiting around feeling sick and not knowing what's going on. To me, the only other piece here that's missing is a biopsy. So we did the CT of the chest, the MRI of the abdomen, the bone scan and brain MRI and the patient gets an ultrasound biopsy of the kidney mass. Now I've heard some people say, hey, a biopsy of a kidney is risky, they could bleed or whatnot, or you might not get a tissue diagnosis. It's got a lot of necrosis. What do you all think about those concerns?
Dr. Catherine Fahey:
I mean, I think that you need to biopsy something and we don't, on the scan that we have thus far, we don't have a clear target because what the path is, is going to dictate what options we have and we'll talk about this in some of the cases. We're all suspicious this is a clear cell renal cell carcinoma, but there are other types of renal cell carcinoma. So I think proceeding with a biopsy is the right choice. Now what we don't know is does she have something easier to biopsy, potentially, if we looked at any of the other scans that we're going to be getting like the CT chest, but I think it's very reasonable to go after the kidney for tissue.
Dr. Mike Harrison:
And I think the conventional wisdom now is that we used to worry about seeding a track or something when we do a kidney biopsy. I don't think we're that concerned about that now. And so like Catherine said, just kind of going after something that we can get to easily. It's a very, very large mass. So presumably they could target a solid portion of it that's relatively accessible.
Dr. Daniel George:
Exactly, exactly. And I think for all of those kind of historical concerns, the truth is we can manage that and this patient probably you can see the areas that are solid and vascular to make sure we can biopsy those and avoid the necrotic areas. So the yield on this to me is still very high. Excellent. Excellent. So moving forward on this case now we get further imaging and you can see here on this slide that there is some evidence of metastatic disease. Mike, want to walk us through that?
Dr. Mike Harrison:
So these are showing kind of representative images, but on the left you can see the CT of the chest. There were multiple bilateral pulmonary nodules. This is just showing you kind of the one of the maximum diameter ones in the lingula measuring about 1.3 cm. On the right, you can see the brain MRI, which did not show any evidence of intracranial brain parenchymal disease, but did show this marrow replacing contrast enhancing 1.4-cm lesion in the right parietal bone. And again, it was kind of adjacent to the dura and so unclear if it represented invasion. The MRI also clarified that there was at least one enlarged retroperitoneal lymph node and there were two hyperenhancing lesions in the pancreatic tail.
Dr. Daniel George:
Excellent, excellent. What do you think about, Catherine, that volume of metastasis compared to the primary tumor volume?
Dr. Catherine Fahey:
Overall, it's not an overwhelming amount of disease. We're just getting the one slice of the lungs, but with the largest being 1.3 cm, it's not a ton of disease. It certainly though is enough that there's this question of oligometastatic and other cancers. I think we've exceeded that with the multiple pulmonary nodules, but the vast majority of her disease is still that large renal mass.
Dr. Daniel George:
Perfect. I agree. So moving on here. She finally gets in with medical oncology now after an initial delay in her workup. Her symptoms at this time include pain in her right shoulder that radiates to her right temple, that continuous right parietal headaches. She doesn't have any bleeding. She's got some oxycodone for her pain. She's in bed most of the day, very fatigued, lots of weight loss, nausea, constipation. We've gone over IMDC risk score and it's very poor. It is probably a 5 or 6 really with that performance status, a 6, what do you see as her treatment options? Catherine, maybe I can start with you first. I mean, do you consider local surgery or radiation sort of an initial option? And if so, where or what part of the body would you start on?
Dr. Catherine Fahey:
Yeah, I am concerned about her performance status and certainly we just touched on the fact that she doesn't have a ton of other disease, so I think we should at least be talking about “Is this someone who would benefit from a cytoreductive, nephrectomy upfront?” This is also a patient though where there's this question of invasion into the liver. There's a question of renal vein involvement. So I worry with her performance status, how she's going to do with a large procedure and I would probably favor, is there anything that we can do to try to shrink this down before we pursue that route? We are doing some radiation upfront if people are having a lot of symptoms from their renal mass. Again, I think a question of how much of her symptoms are related to her having this advanced kidney cancer and might improve with systemic therapy vs overall performance status. And that's always a tough question in these poor-risk patients.
Dr. Daniel George:
Absolutely, absolutely. So Mike, moving on here. It sounds like due to her related symptoms, she just felt like the tolerance of a tyrosine kinase inhibitor with somebody with this much time in bed is probably not going to be reasonably tolerated. Goals of care discussion is reasonable. What do you think her prognosis is with no treatment at this point in time and ultimately how would you treat her?
Dr. Mike Harrison:
I would quote her prognosis without treatment is pretty short. I mean, she's got all of the poor risk factors. If you look on the IMDC paper, it's going to be like 7 months on the median or something like that. But I might quote her 6 to 12 months, probably not a year. And then I think what's difficult here is her kind of textbook options are really like IO/IO so ipilimumab/nivolumab vs an IO/TKI. But you hit on a great point, Dan, that she's probably not going to tolerate a TKI very well with being in bed 12+ hours a day. So I think it's really important to have that goals-of-care discussion and kind of figure out what the patient values. And I think in the ipilimumab/nivolumab study, CheckMate 214, they did allow poor-risk patients. They allowed patients with six risk factors and I've had patients over the years who respond. So I think that is an option as well.
Dr. Daniel George:
Great, great. Yeah, and I think you touched on it. I mean she's very poor risk, recognizing that poor performance status and quality of life and life expectancy. Hospice is absolutely reasonable. We do that in some patients, but if she wants to try combination with ipilimumab and nivolumab, it's probably her best shot at a long-term change in prognosis. So that's exactly what she gets. She gets started and treated with ipilimumab/nivolumab, some of these patients will go downhill immediately and not even get through two cycles of therapy, but she's able to get through all four. In fact, at the end of those four cycles, her CT shows a mixed response, but some progression. She has this large renal mass that's largely still stable and she's got development of some newer left renal masses now. Her pancreatic mass actually increased slightly. Her nodes were stable, but she's had significant decrease in her pulmonary metastasis and a new mediastinal node. Her brain CT shows decreased enhancement in that bone lesion, which is great and stable adjacent dural thickening. And 3 weeks after her last infusion, she's feeling better. She's out of bed, she's got improved energy, she's gaining weight, her headaches have resolved, and now her performance status is probably closer to a 1 and she's planned to go on nivolumab alone, which is a reasonable standard of care. That's our NCCN guidelines. But what about adding a TKI or switching to a TKI? Is there any rationale to that? Mike, what was your thinking?
Dr. Mike Harrison:
Yeah, so my thinking here, I should say this was before CONTACT-03 and TiNivo-2 came out, which were of course studies that showed in certain situations, there's probably not a benefit from continuing the IO therapy PD-1 or PD-L1 inhibitor when you're adding a TKI either with cabozantinib or with tivozanib. In this setting, what I thought was interesting, and you didn't get to, I don't know if you got to this slide yet, but that she was feeling better. So she had some evidence of clinical benefit from the immunotherapy, whether or not that really showed up on the imaging yet was the question and she would've met probably RESIST criteria with the new lesions for progression. So that was the reason that I was thinking about adding cabozantinib. And of course that, a different question not in patients with progression is being answered in PEDIGREE study and those patients who don't have progression. So just to be clear, not like this patient don't have a great response but are kind of in that middle zone of like a stable disease or a partial response looking at that question. But my just simple thinking was essentially doubling down on what's working. And I had offered her cabozantinib/nivolumab at the start as one of the options.
Dr. Daniel George:
And that's great, and I think this is just a remarkable case. If you look on this next slide, she starts at cabozantinib 40 mg plus continues the nivolumab and after 9 weeks she's dose reduced because a hand-foot syndrome not uncommon to 20 mg, but after 12 weeks she's got decrease in all of her disease sites and moving on. She's continuing after a year, to continue to have responses where she's got a complete response in her bone, in her lung, in her lymph node, she's got a small pancreatic lesion visible and she's got the large renal mass and then the other opposite side, renal lesion. And so she's really minimized down to a minimal amount of disease outside of her kidneys. And so she's taken for radical nephrectomy and taking out that renal cell carcinoma on the right 10 cm. Turns out it's got a large component of necrosis.
It has sarcomatoid and rhabdoid features, which may explain this really nice response to immunotherapy. And her cabozantinib has continued and now after 2 years she's getting SBRT to a remaining lesion in her left kidney. She's really at a minimal disease burden.
So just to summarize, I think this has been an informative case to recognize that IMDC is poor risk designation for patients who are not treated or treated with TKI alone. But in the IO era, poor risk may not be the same as for patients treated with ipilimumab/nivolumab, some of these patients can get really outstanding responses. To consider these consolidative approaches in renal cell carcinoma as we see responses and durable responses to further lower that tumor burden and really to work towards a minimal residual disease.
Well, I hope you found this case informative. This brings us to an end to the case and please consider viewing other segments for further discussion about the latest research in advances in renal cell carcinoma or visit our website at ascopost.com. Thank you very much.
