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, Professor of Medicine, Surgery, and Urology at the Duke University Medical Center. And joining me today are two of my colleagues that will introduce themselves. First, Dr. Harrison?
Dr. Mike Harrison:
Hi, I am Mike Harrison. I am a GU medical oncologist and Associate Professor of Medicine at the Duke Cancer Institute
Dr. Daniel George:
And Dr. Fahey.
Dr. Catherine Fahey:
Hi, I am Dr. Catherine Fahey. I'm an Assistant Pprofessor of Medicine in the Division of Oncology at the University of North Carolina at Chapel Hill.
Dr. Daniel George:
Well welcome Catherine and Mike. Happy to have you on the roundtable with us today. And we're going to be discussing the treatment and management of advanced renal cell carcinoma with three patients. Our final installment here will focus on the treatment of recurrent chromophobe cell carcinoma in a 67-year-old man.
So Mr. Ml is a 67-year-old man who presents back in October 2017 with flank pain. A CT reveals a 15-cm right renal mass, status post nephrectomy, which reveals actually turns out to be a 19-cm chromophobe renal cell carcinoma. This is a rare form of kidney cancer. It's grade 2 pathologic stage IIIa, no nodes or metastasis known at the time and he's followed. And in many of these patients, despite being stage III, will not recur, but unfortunately he does. And in June of 2020, he's found to have now an 8.8-cm retroperitoneal mass.
A CT-guided biopsy confirms the recurrence of his renal cell carcinoma and in July of 2020 undergoes an exploratory laparotomy which reveals at the time of surgery multiple liver metastases studding on his liver. A biopsy intraoperatively confirms this, and the resection is aborted. In August of 2020, an MRI reveals now five new lesions in his liver ranging from 1 to 2 cm in size. And he's referred to Duke and sees me to discuss treatment options. So Mike, I'll start with you. What would you consider in a patient like this now with recurrent liver metastasis, retroperitoneal mass, chromophobe carcinoma?
Dr. Mike Harrison:
Sure. So I think this is a patient who needs systemic therapy and the question is which systemic therapy. This is an area where there's not a lot of data, and in 2022 the data was even more limited. Some of the first trials were comparing mTOR inhibitors to sunitinib. And what I think was interesting as we were talking about before the call actually is that this is one of those non–clear cell kidney cancers where everolimus actually had a superior response rate and also overall survival in small numbers compared with sunitinib. So I think everolimus is definitely an option. TKIs are also an option, so either sunitinib or newer TKIs, like for example, cabozantinib, lenvatinib. And then of course lenvatinib has been tested also with everolimus as well. So I think you have a lot of different options.
Dr. Daniel George:
Excellent, excellent. So by the time he comes to see me, he's already started on cabozantinib, it's 60 mg a day and he comes to see me and at this point we have new data in 2020 on the combination of cabozantinib and nivolumab. So I talked to him about adding an IO agent, to your point, not having a lot of clinical data in chromophobe, we switch him from 60 mg of cabozantinib to 40 mg plus nivolumab and that's in October of 2020. By December, a CT scan shows stable liver lesions, but he's got increasing retroperitoneal mass and a brain MRI shows a single new brain metastasis. He undergoes SRS therapy, stereotactic radio treatment to his single brain metastasis in January, and he's got this persistent pain, so with his retroperitoneal mass. So I work him up here with our surgeons and we involve our colorectal surgeons because his tumor is abutting his colon and we're able to end block resect this retroperitoneal mass and do a right hemicolectomy and that's in May of 2021. By July of 2021, he's back in my clinic and we're discussing what other treatment options we can consider. So I offer him axitinib and pembrolizumab and we started that in July of 2021. By September of 2021, just 2 months later, he's got grade 3/4 hepatotoxicity. He's got new onset type 1 diabetes and we immediately get him on steroids and hold his axitinib and pembrolizumab. Catherine, what went wrong?
Dr. Catherine Fahey:
I mean “What went wrong” is such a harsh way to phrase that. I'm certainly concerned about an immune-related adverse event, ICI toxicity. It can be tricky with a lot of these to figure out was it the TKI, was it the immunotherapy? The combination of the hepatotoxicity and the diabetes is making you lean toward immunotherapy, but calling it going wrong I think is doing a disservice to our immunotherapy drugs. We know these things can happen and I would suspect that's what's going on here.
Dr. Daniel George:
I agree and I think we do see, again, different side effects with different combinations. This can happen with cabozantinib and nivolumab. It didn't. It certainly can happen with axitinib and pembrolizumab and it did. So just recognizing that these are things that can happen and they can happen early within the first 2 or 3 months. So that is certainly the window to be looking for. So the patient’s treated with high-dose prednisone, we, actually our specialists, our liver specialist is involved and he gets started on mycophenolate as well. And it's on, we get our endocrinologist involved. He started on insulin and we get control. He actually has evidence of response in his liver with decrease in his liver metastases and nodes in October. But by March off of all therapy now his CT is starting to show progression with increasing in new liver metastases in his renal bed as well. And shown here on the right are some of those liver metastases. So Mike, what would you think about his prognosis now and goals of care and what would you consider for treatment next?
Dr. Mike Harrison:
Yeah, so I mean this has all kind of happened over a couple of years now. I mean certainly we know that chromophobe classically can be indolent, but then it can metastasize, it can then become aggressive or it can still be indolent when it's metastasized. I mean concerning is that it's in the liver. I think that across all renal cell, that's a concerning metastatic site. So I'm thinking this is a patient that needs systemic therapy. His prognosis is going to be measured in a year, a few years. And so I think you're back in kind of the same boat of thinking about systemic therapies. It's a little bit later down the line. We have a little bit more evidence now. So I think certainly he's had cabozantinib, he's had axitinib/pembrolizumab, he's had nivolumab. So thinking about lenvatinib, I think there's reasonable data for lenvatinib with everolimus around this time coming out. I think everolimus alone wouldn't be wrong necessarily, but you're definitely shifting into controlling disease and balancing that with quality of life at this stage of the game.
Dr. Daniel George:
Yeah, that's great. That's great. Yeah, and that's exactly what we felt as well, that this patient was motivated to be aggressive. He wanted to do everything he could. He had grandchildren, life ahead of him. He's got a boat so he's ready to use it. So we went with a combination of lenvatinib and everolimus and that was started in May of 2022. And at first he just basically had stable disease and then over time his disease began to decrease and over the course of the next year he had further and further decreases in his liver metastases and renal bed until sort of towards the end of 2023. Now about a year and a half on this regimen still with stable disease, but now he's developing proteinuria and multiple grams of protein in his urine. He's had some weight loss and we're really concerned about this toxicity. Catherine, what do you think this toxicity is due from this proteinuria that we're seeing?
Dr. Catherine Fahey:
Very common with the lenvatinib. I feel like in my anecdata, lenvatinib is one of our TKIs that is the worst for this. You all may have the actual data to support that, but I would almost certainly say the lenvatinib.
Dr. Daniel George:
Yeah, I think that's right. And I think in particular in this combination we see this and we lowered his dose of lenvatinib over this 18 months. I think he was down to like 10 mg, still having some hypertension, but certainly having the proteinuria. And when we stopped it over the course of about 2 to 3 months, the proteinuria resolved, to your point, kept the everolimus going. That was clearly the cause and his disease remained stable. And on everolimus alone for another 6 months he was stable. But by August of last year, his MRI shows a new L4 lesion and he's got a couple of pelvic nodes. So at this point in time he's got basically oligoprogression of disease. It's 2 plus years since starting lenvatinib-everolimus. Catherine, what would you consider next for him with this kind of presentation?
Dr. Catherine Fahey:
I think anytime you're looking at oligoprogression, you should consider is there anything I can do to the sites that are growing? Is there some sort of local intervention that is an option for him at this point? So I'd be probably talking to my colleagues in radiation oncology to figure out if there's anything in particular we can do for these individual spots that have grown.
Dr. Daniel George:
That's exactly right, and that's exactly what we did. And so we did SBRT stereotactic body radiotherapy to his L4 and to the pelvic nodes. A couple months later he is having an increase in his largest liver lesion and some new implants on that same right side along the iliacus and psoas muscles and he gets radiation. He actually ends up getting proton beam radiation to his three liver lesions as well as the iliacus and psoas muscles. And this is down at Atlanta closer to where he lives and he tolerates this pretty well. It has a flare effect. His largest lesion actually flares up to 5 cm. But on his April MRI scan now it's got a lot of loss of vascularity. You can see that we've really had a treatment effect in that area larger than the actual tumor. He is shown decrease in his other areas and he's just got a couple of lesions that are over 1 cm.
Liver, everything else is tiny or has been radiated. And so the plan is to do cryoablation now on his remaining two liver lesions that are over a centimeter. So it is really kind of an example of how we can utilize tumor-directed therapies to again minimize the tumor burden in the setting of systemic therapy that's stabilizing that maybe isn't curative, but is delaying the progression of disease; in this case, years. And by decreasing that tumor burden between surgery, radiation, and ablative therapies, really giving us an option to extend the survival of what this patient might've experienced otherwise with no further systemic therapy.
So I think there are key takeaways from this case are that number one, chromophobe renal cell carcinoma is rarely aggressive. Rarely aggressive, and that's important. This is an atypical case, but even in these aggressive, recurrent cases, as Mike said, they can still follow an indolent course. And interestingly everolimus, a drug that we don't use much anymore, certainly by itself or just in combination with lenvatinib now, but it can result in long-term disease control rates and that the disease burden can be controlled with both TKIs as well as tumor-directed therapies. But there's one more option. And Catherine, there's a new study result suggesting that maybe immunotherapy is not over for this disease. Can you update us on that?
Dr. Catherine Fahey:
Think you're talking about the SUNNIFORECAST trial.
Dr. Daniel George:
I am, yes indeed.
Dr. Catherine Fahey:
So in SUNNIFORECAST, it was actually a randomized trial in rare subtypes of renal cell carcinoma, which just by itself needs to be commended, but they took patients with non–clear cell renal cell and randomized them to either get ipilimumab/nivolumab or standard of care. Now in the standard of care option, a fair number of patients did receive TKI monotherapy. So this isn't a direct comparison of IO/IO vs IO/TKI, but they did show that some patients did have response to ipilimumab/nivolumab, I believe it didn't actually meet a PFS benefit, but its pre-specified endpoint was 12-month OS. And at 12 months there was an overall survival benefit compared to the standard of care. The chromophobe group was small within that study. So how much our chromophobe patients really benefit from this combination, hard to say, but it is a new option with new randomized data to actually support it.
Dr. Daniel George:
That's great. And I think this is where we are in the field of rare tumors. It is going to be small data sets, but it gives us something to consider in the future. If everolimus stops working at some point, certainly an option to turn to.
So this brings us to the end of this case, and I would encourage you if you have time, please see the other segments for further discussion about the latest research in advances in renal cell carcinoma or visit our ascopost.com website. Thank you so much for your attention.
