Treatment management of favourable risk and very favourable risk RCC patients
Dr Guillermo de Velasco - University Hospital 12 de Octubre, Madrid, Spain
Dr Marco Maruzzo - Istituto Oncologico Veneto, Padova, Italy
GdV: Welcome everyone to this webinar on treatment approaches for favourable and very favourable risk patients. I’m Guillermo de Velasco, I’m a medical oncologist at University Hospital 12 de Octubre and I’m delighted to share this webinar with Dr Marco Maruzzo, medical oncologist with a special focus in mRCC. So today Dr Maruzzo will delve into managing patients with favourable risk metastatic RCC, focussing on treatment strategies and the implication of IMDC with a couple of case studies illustrating treatment outcomes. Please, Marco.
MM: Thank you. Hello everyone, I’m very happy to be here. I’m Marco Maruzzo, I’m a medical oncologist working at the Istituto Oncologico Veneto in Padova in the north of Italy. So, as already said, I’m happy to share with you some information and some cases to discuss the favourable and very favourable risk patients with metastatic renal cell carcinoma. As you all know, the main point we have to discuss today is the IMDC risk classification for metastatic renal cell carcinoma. It’s how we can divide our patients between all three groups, which is the favourable group, the intermediate risk group and the poor risk group, based on some risk factors we can detect in our patients. We know that, more or less, about 75% of our patients for which we select the first line treatment for metastatic renal cell carcinoma have at least one of these risk factors. This has been real when we use TKI alone, it’s true today that we use a combo, IO combo, IO/IO combos and IO/TKI combos.
The role of the combo is at the moment really controversial in the favourable risk group. Recently a very favourable group has been described which are a subgroup of the patients of the favourable risk which have some characteristics, specifically a primary diagnosis to systemic therapy greater than three years, no brain, liver or bone metastasis and a Karnofsky Performance Status of 90% or 100%.
So these patients who belong to the favourable risk group can be classified as a very favourable group. Recently in ASCO 2024, Zarba et al presented at the Rapid Oral Abstract session the result of these real world evidence treatment methods in IO combos in those subgroups of patients. So all the patients included in the IMDC database between 2016 and 2023 were selected and divided between the favourable risk group and the very favourable risk group.
You can see that the very favourable risk group is a small subgroup, about 30%, 26.9% of all the favourable group patients. You can see in this slide, in this table, all the baseline characteristics of the patients which are quite well balanced between the whole group, favourable risk, and the very favourable risk group.
The main point is when we try to analyse some oncological outcomes such as overall survival, we can see using VEGF, IO/VEGF and ipi/nivo, which is the only IO combo we have, there is no really significant difference in terms of overall survival among the favourable risk group.
But when we split patients in the very favourable risk group we can start to see some differences and we can see that the patients receiving IO/TKI or TKI alone possibly have a better outcome compared to the ones who received ipi/nivo. This is for the overall survival with a clinical follow-up of 33 months.
If we go through the overall response rate, we can see, again, that the main point is that both the patients belonging to the favourable risk or the very favourable risk groups seem to have a better outcome in terms of overall response rate if they receive a VEGF inhibitor, so a TKI, either alone or in combo with immunotherapy. So the IO/VEGF and VEGF patients have a quite greater overall response rate compared to the patients receiving an IO/IO combo.
This data is quite interesting because the main conclusion is that among the all favourable risk patients we have no significant difference in overall survival between all the regimens with a slight trend of either overall response rate for the IO/VEGF regimen. Among the very favourable risk subgroup there was a trend for decreased 2-year overall survival and overall response rate for patients treated with IO/IO compared to the other regimens.
These data that have been presented at ASCO 2024 last year are quite significant and could open new future directions for other possible trials to confirm these findings and possibly helping us in order to find out ways to treat the patients which belong to the favourable risk group for which the result, at the moment, is quite controversial.
GdV: One question Dr Maruzzo. So if you think this data, which is obviously really interesting data, retrospective data, is something that we need to consider, but also we’ve seen data, for example, from Dr Atkins demonstrating promising activity with PD-1 monotherapy also, including those IMDC favourable risk category. So when you look at those data from the retrospective data, some phase II data, how do these findings align with the current understanding and when do you consider to use immunotherapy and when not?
MM: It’s quite controversial. I do not think there is really a correct answer to this question. We have accumulating data on the favourable risk patients with, IO/IO combo, IO/TKI, TKI alone.
We have no concordance and alignment among all the data we have. I think that in real practice at the moment we are waiting for possibly some prospective data, not retrospective, studying specifically this subset of patients. At this point the issue, the main issue, is what we want to do for our patients, what we are looking for our patients. Because most of the data we have shows that those patients could achieve no real difference in terms of overall survival either with a combo or TKI alone but, yes, there are some differences among overall response rate.
So the main issue is what we want to achieve for our patients – we would like to achieve overall survival, overall response rate, chance of complete response. We have to consider and balance the toxic effects, even the long-term toxic effects because most of these patients will receive treatment for a long period of time.
Then we can discuss our patients with favourable and very favourable risk and we’ll go through the cases to discuss and to see what we have done and what happened for those patients.
So, the first case I would like to share with you is the case of a patient, Maria, 54 years old, no comorbidities, good general well-being. In September 2020 she had back pain and she underwent a US scan and CT scan showing a great left mass in the left kidney. No other site of disease at this point and she underwent radical nephrectomy with our urologist. The pathology report was clear cell renal cell carcinoma, pT3a, N0, grade 3.
In October 2023, so more or less greater than three years later during follow-up we clinically detected some lymph nodes at the neck and then the patient underwent a CT scan which showed lesions in the latero-cervical lymph nodes and in the retroperitoneal lymph nodes. Since it was three years from the previous diagnosis of renal cancer, the patient underwent a biopsy of the lymph nodes and the pathology report was for poorly differentiated clear cell renal cell carcinoma.
At this time the patient was good, ECOG performance status was zero, she had no labs alteration at any point and the time from the initial diagnosis to the metastasis was greater than three years. She has no unfavourable site of disease – liver, bone or brain – and so she was an IMDC score favourable and if we looked at the subgroup, and we have already discussed, because of these characteristics the patient belonged to a very favourable subgroup.
So at this point we need to start a treatment since we have several metastases from renal cell carcinoma and we discussed about the different options we had in October 2023 with this lady. We started in November 2023 a first line treatment with lenvatinib and pembrolizumab. We chose an IO/TKI combo because the patient was good and we discussed about the possible results of the overall survival but we also discussed about the overall response rate. And possibly, since she has not a very great amount of disease, we want to try to achieve a partial response, a complete response possibly.
She started the treatment. We know that sometimes this treatment or the combination of IO/TKI has different toxicities and different adverse events and sometimes we have to manage or reduce the dose of the TKI in combination with IO. She had some asthenia and fatigue, some, as expected, hypothyroidism and diarrhoea.
She continued on the treatment and in February 2024 the CT scan showed a partial response. And the last CT scan for this patient last month, in January 2025, was stable. So she maintained the response up to this point.
She was a very favourable subgroup so she could receive more or less everything we have.
GdV: So I guess there are three questions here but the most important one, in my opinion, is always what to choose and why. So for this type of patient the first question would be, would you consider in any of these kinds of patients with very favourable group to start only with a tyrosine kinase inhibitor? If the answer is yes, why, or if it’s no, the same. So what is your impression for this kind of patient?
MM: She asked about all the different options and we have considered the option to start a TKI alone. I’m pretty sure she could perform well with a TKI alone, especially in terms of overall survival. We have no really great differences from TKI alone, TKI and immunotherapy, for this lady in terms of overall survival. The other point we discussed with this lady, she wants to reduce the disease. She is young, she is very active, so try to achieve a complete response. So we discussed about the combination of immunotherapy and a TKI, that’s the main reason. So for this lady we do not want to really move nothing in terms of overall survival, possibly the survival is long and should be the same with all the treatments we have for first line metastatic renal cell carcinoma but we chose IO/TKI in the attempt to achieve durable partial response or possibly a complete response at some point. That was what we have discussed with the lady.
GdV: Marco, the second question is about quality of life. So I guess for this type of specific patient where we know that the PFS will be quite long for most of our patients with favourable and very favourable subgroup, so my question here is how do you see the quality of life of these patients having IO and tyrosine kinase inhibitor versus tyrosine kinase inhibitor? Do you think there are major differences?
MM: The final question there the answer is yes. She is highly motivated to receive the treatment. So this possibly has an impact in terms of quality of life. We know that we have to take into account that this lady will receive treatment for a long period of time. At this point, most of the side effects the patient is experiencing is due to the tyrosine kinase inhibitors. So she possibly should have experienced if she had received TKI alone or the combo IO/TKI.
So the second case we go back in time. Paola was 48 years old in November 2014 when for the same reasons that usually happen, back pain, she had an ultrasound scan, CT scan, left great mass in the kidney. The pathological record was clear cell renal cell carcinoma, pT2N0, grade 2. At that time, it was eleven years ago, she started follow-up. Five years later, so it was August 2019, during follow-up a CT scan showed multiple liver lesions, at least six lesion.
Again, it was quite a long period of time, we want to recharacterize the disease and we performed a liver biopsy for this patient. The pathology record was de-differentiated renal cell carcinoma. The patient was ECOG one, no labs alteration, time to mets was very long – five years. She has one unfavourable site, as we know that’s liver metastasis as quite an unfavourable site of disease, so she belongs to the favourable risk group according to the IMDC score. Because of the performance status and the site of disease we cannot reclassify her today in a very favourable subgroup risk.
In September 2019 she started a first-line treatment with sunitinib with classical schedule – four weeks on, two weeks off. The first CT scan showed stable disease. The patient continued on sunitinib, some side effects, some hand-foot skin reaction and no real changes in the dose of the treatment with sunitinib. She continued on the treatment and some months later after two other CT scans, in August 2020, the scan showed liver disease progression as you can see in the imaging from the CT scan of the patient. So for liver disease progression we have to stop sunitinib. At this time we tried to change mechanism of action – we have nivolumab available as a second-line treatment option, as an immunotherapy option for these patients. So she started with nivolumab in August 2020.
GdV: So Marco, looking at this case, one of the most important questions that we have for starting treatment for these patients, how big is the difference between using just a tyrosine kinase inhibitor followed by immunotherapy compared with a combination from the very beginning? Here the question is how many of your patients or the percentage of patients that you maybe losing during the path because they don’t get to the second line in this specific population?
MM: In general, in the favourable risk patients we have a small amount of patients we lose from first to second line. This is more true in some ways for poor risk patients and unfavourable risk patients. For the favourable risk patients we know that after starting the first line we usually can also do, the patient can also receive a second-line treatment. So for this subgroup of patients, and in fact our patient, the last one, had received nivolumab in August 2020. To be honest, she performed quite well for quite a long period of time receiving nivolumab and then she also received a third line. So the favourable risk patients are patients that we can decide what we want to do, having in mind possibly we have to think about a possible sequence of the treatment because those patients will usually receive more than one line and possibly more than two lines of treatment. So we have to make our choice of treatment thinking about the future of our patients and what we can offer them in the future.
GdV: Do you think that one of the factors to think about using IO plus tyrosine kinase inhibitor combinations from the very beginning in this specific population with favourable risk, even very favourable risk, may be that in those cases where you achieve a partial response you may try to go for either surgery or radiotherapy of their residual lesions?
MM: Yes, we have some patients in our experience, for those we go through local regional treatment – surgery, radiotherapy, ablative radiotherapy, stereotactic radiotherapy and so on – in order to try to obtain a multimodal complete response. When we have a great partial response we want to chose residual sites of disease, try to ablate all the sites and try to give the patient the chance to have a multimodal complete response. We have, to be honest, no real prospective data and so a big amount of data for those patients saying that this will impact on overall survival. But, of course, it will impact on treatment, it will impact on quality of life for those patients so, yes, it is something we have to discuss with the patient.
GdV: And I guess we are talking about favourable and very favourable patients, we need to talk about active surveillance. Do you have some patients on active surveillance these days with so many drugs available?
MM: We tend to continue to put on active surveillance patients with only lung metastasis or thyroid metastasis or pancreatic metastasis. For those patients when we detect a metastasis for the first time we usually put them on active surveillance and we decide to start the treatment only if there is a disease progression of the site or new lesions in other organs, in other parts of the body. This is a good way to manage patients with very favourable sites of disease belonging to the favourable or very favourable risk group. We know that we can start treatment once we see the disease progressing and sometimes in some patients we have some experience of patients staying on active surveillance for months or even for years before starting a treatment. We have given those patients quality of life, active surveillance, the patient should be aware that this is a personalised approach and this is something where there is the need of a great compliance from the patient with the surveillance programme.
GdV: Thank you, Marco. I think the field of renal cell carcinoma is constantly evolving and we hope that the discussions, including Dr Maruzzo’s insightful presentations are a change, have provided you with valuable insights to the management of this specific favourable risk metastatic renal cell carcinoma. Thank you very much.
MM: Thank you.
