Dr. Hammers:
Hello, everybody. Welcome to Optimizing Patient Selection and Outcomes in Post-IO Advanced Renal Cell Carcinoma, an ASCO Post Roundtable. My name is Dr. Han Hammers. I'm a Professor of Medicine and GU Medical Oncologist here at UT Southwestern in Dallas. And today I'm excited to be joined by two of my colleagues, Dr. Qin and Dr. Harrison, who will introduce themselves. Dr. Qin?
Dr. Qin:
Hi, it's wonderful to be here. I'm Dr. Qin. I'm one of the medical oncologists, with a focus on genitourinary cancers at UT Southwestern Dallas.
Dr. Hammers:
And Dr. Harrison.
Dr. Harrison:
Hey, everyone. I'm Mike Harrison. I'm a GU medical oncologist and Associate Professor of Medicine at the Duke Cancer Institute here in Durham, North Carolina, and I'm looking forward to the discussion.
Dr. Hammers:
Outstanding. Thank you so much for joining me. Thank you so much for your time. Our final case, we'll focus on the treatment of metastatic renal cell carcinoma with symptomatic disease progression after IO/IO. And Dr. Harrison, please go on with your case.
Dr. Harrison:
So this is a 67-year-old man with a history of stage III chronic kidney disease, type 2 diabetes, hypertension, and recently an unexplained PE. Now, during workup of the PE, a renal mass was found, and he eventually underwent left radical nephrectomy, tumor thrombectomy, and IVC repair. Pathology showed a 5.4-cm clear cell RCC, grade 3 stage pathologic T3b, N0 with nine lymph nodes removed. He was then subsequently observed without evidence of recurrence. Three years later, a CT chest, abdomen, pelvis showed two new lesions, a T11 and a T12 lytic bone metastasis. Now, these were asymptomatic at the time, and so you can see this on the bone scan here at the right. It was also confirmed on MRI, and eventually biopsied. Biopsy of the T11 was consistent with clear cell renal cell carcinoma. And here you can see on the CT scan, the T11 vertebral lesion and the T12 vertebral lesion highlighted by the yellow arrows.
So because the patient was asymptomatic, he initially underwent SRS to the thoracic spine lesions. However, 2 months later, he developed confluent retroperitoneal lymphadenopathy shown here in the two yellow arrows and a right adrenal metastasis. The thoracic spine lesions were stable. So the patient's general characteristics at this point, he's asymptomatic. He's IMDC favorable risk with zero risk factors. And so a goals of care discussion was had with the patient, and his preference was really to avoid TKI therapy.
So he was initially treated with four cycles of ipilimumab and nivolumab, and he tolerated the therapy very well. He only had a mild rash that was successfully treated with triamcinolone. And so unfortunately, though, on the 12-week restaging scans, you can see here at the right, the patient had similar retroperitoneal lymphadenopathy, but had a new celiac lymph node measuring about 2 cm, and that's highlighted by the yellow arrows, as well as increase in the size of the lytic thoracic vertebral lesions. And so you can see this here in the CT scans highlighted by the yellow arrows. Also, the patient developed new mild back pain at the midline below the lower ribs for which he had begun taking acetaminophen a few weeks prior to the restaging scans.
So this brings up a number of questions. So first, I'll ask for Janie and Hans, what are some important considerations and goals when you're choosing the next line of therapy in this particular patient?
Dr. Hammers:
So this is certainly a patient I'm more worried about, especially with a disease progression in the spine. Spine is always a difficult area. The bone compartment is a difficult area. And so I think it will be important to use a therapy that we feel we can rely upon. So it's probably going to be one of the more effective or broad-spectrum VEGF TKI therapies, for example.
Dr. Harrison:
How about you, Janie? What considerations are going through your mind?
Dr. Qin:
Yeah, I definitely agree that this patient needs something very active that can shrink the tumor burden faster. So someone like this would be who I would think about potentially combination therapy like lenvatinib/everolimus for the very high response rate. And with LITESPARK-O11, potentially we could be thinking about lenvatinib with belzutifan in this space, as well. So I think those would be some of my considerations. Alternatively, for VEGF-TKI single agent, I think it's also reasonable. Maybe cabozantinib we know has some bone effects. There's data showing that the efficacy of cabozantinib in bone metastasis is there. So that could be another potential option.
Dr. Hammers:
Yeah, I agree. So for the listeners, I would say that a lot of us would've chosen a drug like cabozantinib, really, which is the gorilla in the room for many of these more broad spectrum agents, et cetera. And I think I would say with the more recent datasets that we have from ESMO 2025, with the study out of MD Anderson and with lenvatinib/everolimus vs cabozantinib, lenvatinib/everolimus beat cabozantinib. I don’t remember if it was single-site, but it was led out of MD Anderson. And then certainly lenvatinib/belzutifan, which is now the big elephant in the room, if you will, with GU ASCO 2026 data. So these are all important things. I think the theme really is looking at something that's most likely going to be effective.
Dr. Harrison:
Great discussion. And so the patient for second-line therapy was treated with cabozantinib. He was started at a dose reduction of 20 mg daily due to his renal function. His serum creatinine was about 2.8, and this was added to the nivolumab. So the patient's pain improved over 1 or 2 months after starting cabozantinib. And at the restaging visit 3 months later, he developed grade 2 and 3 transaminitis with pancreatitis and pneumonitis. However, fortunately though, the CT of the chest, abdomen, and pelvis was stable and the bone scan had less uptake shown here at the right. So cabozantinib and nivolumab were held and he was started on a steroid taper. Six weeks later after these adverse events resolved, cabozantinib and nivolumab were resumed. However, about a year later, the patient remained with stable disease. And so the CONTACT-03 data came out. This was several years ago now that this patient was treated. The CONTACT-03 data came out and nivolumab was held and he was continued on cabozantinib alone.
So moving into the key clinical takeaways, and we talked a little bit about this. Symptomatic patients may require tailoring of the therapy to their goals and sites of disease. So certainly, we mentioned there's the idea that cabozantinib works relatively well in the bone. Let me ask Hans and Janie about that. Do you think that's true or do you think a drug like lenvatinib maybe with everolimus or belzutifan could work just as well in the bone?
Dr. Hammers:
I think the best therapy for bone-based disease is a therapy that's effective against the kidney cancer. I am less impressed with the efficacy of antiresorptive therapy, per se. I would say the data is a little bit mixed. And I would say particularly with cabozantinib, I'm more cautious because cabozantinib in itself actually has significant bone turnover efficacy. In fact, it's the single VEGF-TKI that has the highest chance for osteonecrosis of the jaw. And I tend to avoid, to be honest with you, antiresorptive therapy when I use cabozantinib. I remember the days when cabozantinib was tested in prostate cancer patients and all the bone scans turned negative, the thinking that they had a major effect against prostate cancer, but that was just because of the significant effect on bone turnover. So, you essentially have both antiresorptive therapy built in.
I still believe that if you have a more effective therapy such as lenvatinib/everolimus or lenvatinib/belzutifan, that you will have a more anticancer effect and then I think you will have a better bone protective effect. So that's the way I think about it. I think the most important thing is actually an effective anti-cancer therapy.
I think a lot of people try to read into some of the data with cabozantinib maybe a little bit too much that is a de facto agent for bone-based disease. I'm not sure that's true, but it is certainly, as a single agent, and effective therapy, and I would say until very recently was really, I would say, the standard of care in the setting.
Dr. Qin:
Yeah, I think I really agree with thought that the most effective therapy is the therapy of choice. And I think the question in post-IO is what is the effect therapy for what patient cohort? And to this patient who had cabozantinib added to nivolumab and then had immune-related adverse events from nivolumab, I think it follows our CONTACT-03 and TiNivo-2 data of, well, rechallenging with IO after IO, or at least with a PD-1 after progression on PD-1 is probably not very effective. And I think the question is, can we find more novel agents to make immunotherapy work again? Or is it a PDIGREE approach of adaptive immunotherapy inclusion in the treatment paradigm. I think those are questions that remain to be answered. I agree with you, though, for a patient like this, the most effective treatment is the treatment we should go for.
Dr. Harrison:
Yeah. And I'll just say I agree with you, Hans, about the antiresorptive therapy with cabozantinib. I think that's probably introducing a lot of risk, essentially, or especially in a patient like this who only has two bone metastases.
Dr. Hammers:
Yeah. The other thing I would say is you saw the liver toxicity with the cabozantinib, and that's probably the cabozantinib, as well, because it's probably the least combinable, one of the least combinable TKIs with immunotherapy. Obviously we use it, but that's one of the side effects that clearly stands out. And I think we probably all remember COSMIC-313 where the combination or the addition of cabozantinib to 40 mg to nivolumab/ipilimumab was simply disastrous, with a fivefold increase in high-grade hepatitis.
So, we will see what the right answer is. But thank you for showing this case, and especially also how much we have learned in that time started on this, because the field has learned a lot in the last 2 years, and I think this case nicely illustrates how the thinking also evolves, first adding on something on and then learning that continuing PD-1 is probably not important, and then moving on, or these days we may even have used other agents. So brings us to the end of this case, please see the other segments for further discussion about the latest research in renal cell carcinoma or visit ascopost.com. And thank you very much, Dr. Qin, and thank you very much, Dr. Harrison, for your contribution.
