Combination therapeutic strategies for aRCC patients with bone metastases

Dr Stefanie Zschäbitz – Heidelberg University Hospital, Heidelberg, Germany

Prof Stéphane Oudard – Hôpital Européen Georges-Pompidou, Paris, France

SO:  Hello everybody, my name is Stéphane Oudard. It’s a pleasure for me to share this session with Stefanie Zschäbitz to speak about combination therapy strategies for metastatic RCC patients with bone metastases. As you know, in metastatic RCC, we have four different combinations to use and specifically for patients having bone metastases who are usually having symptomatic disease, fracture, hypercalcaemia, we need to find out what is the standard of care treatment option to go for in order to treat those patients in the best way. So Stefanie could you maybe speak about two cases that you have prepared about how to treat those patients practically?

SZ:   Yes, I brought two cases out of my practice and the first one that I’d like to discuss with you and where I would like to get your feedback on is this patient. She’s female, she’s 62 years old and she has had the diagnosis of clear cell renal cell carcinoma in 2017. She has had a nephrectomy, also an adrenalectomy but she was non-metastatic at the time of first diagnosis. Then four years later she had a fracture of her humerus and that was operated on and the histology came back as a metastasis of clear cell renal cell carcinoma.

We obviously did some staging here in this patient and it turned out that she had a multifocal recurrence with lesions to different organ sites, among them pancreas, thyroid gland and the muscles and she had an IMDC score of 0. I’d like to know from you, I’ll discuss with you what your therapeutic regimen would be that you would use in this patient knowing that she has the scar that I just showed you and she probably also needs some radiation. So if you have a patient like this in your practice how would you decide? Is it for you TKI/IO? Is it ipi/nivo because of the wound healing? Or would you in this patient, as she is a favourable risk patient, also discuss TKI monotherapy?

SO:  Thank you. So it’s a typical case of a patient having bone metastasis and other metastases as well. As you said, it’s a favourable risk group. Usually for those patients we don’t allow it to go for IO/IO but we need to go for TKI plus IO. About TKI monotherapy, I think it’s now a too old treatment such as sunitinib that we had ten years ago. So I think that I will focus on TKI plus immunotherapy. So now the goal is to know which one to use between cabo/nivo, pembro/lenvatinib or pembro plus axitinib. So based on that I think that we have the choice but I won’t go for IO/IO because I think that in the US you can use it if you want but in Europe it’s impossible.

SZ:   So we would have to ask the insurance company, at least, if they would reimburse it. So there is no standard reimbursement for those patients. Yes, I absolutely agree with you. I would use a combination therapy as well. So it’s probably not a patient where we should use TKI monotherapy because she has high risk, given her many sites of lesions. We will discuss a little bit later also the results of the studies.

I just brought to you also a second case of mine. This is just recently, so this patient has had the clear cell renal cell carcinoma diagnosis in autumn of last year. He has received a nephrectomy and he has a single synchronous singular bone lesion. So the question here is if you only have that single lesion is this a patient where you would recommend also surgery or radiation and how would you proceed in this case? So he has synchronous disease which makes him IMDC risk group intermediate. We operated on him and also the discussion is to go with further radiation but then he has no lesion anymore. In this case would you use pembrolizumab adjuvant? Would you use IO/IO because now we would be in label? Would you use in this patient where all metastatic lesions are treated a TKI/IO or is that too much for this patient? How would you decide in such a patient where no lesion is left but has a high risk of probably having micrometastases as well.

SO:  It’s a difficult case because you know that you have performed local therapy and I understood that, in fact, the patient has no more metastasis in fact, no more disease. So, in fact, we are in the case of adjuvant therapy but we know that bone metastases are bad prognostic metastases, in other words it means that those patients may relapse really quite rapidly with all the metastasis, either at the bone level or in other sites of the body. But since you have performed a surgery, and I would go for radiation therapy later on to have this combination between surgery and radiation therapy in order to have the highest effect regarding the local dorsal metastasis.

I’m not sure that I would go for any further treatment. We know that for pembrolizumab it’s approved in M1 disease, no more disease, at the metastatic level in the KEYNOTE 564 study but here maybe it’s different. It has not been removed, still the metastasis is here. So now about TKI or plus immunotherapy or IO/IO, maybe you have different choices, maybe you can wait and see and perform regular imaging. Maybe, it would be my choice.

SZ:   So that’s exactly how we decided. So this is really a fresh case. I think he has a very, very high risk, the lesion is still there, it’s just irradiated with a high dose. I opted for having a CT scan really quick just to see if more lesions evolve and then I obviously would go with a TKI/IO too. It’s not like the situation as in KEYNOTE-564 where the lesions were removed surgically in total and it’s M1 no evidence of disease. In my assumption pembro adjuvant would be probably a little bit under-treatment as well in this patient.

So I brought you this information, again, on the distribution of metastatic lesions and I think we sometimes think that bone lesions only make up for a small proportion of patients. This is a very old analysis but it shows that among the three top lesions it’s lung, bone and lymph node. Approximately one third of all patients will develop bone metastases so actually it’s not a rare situation at all. As you pointed out, those patients do not have a very, very good prognosis. My question next would be how do you stage patients with bone mets in your daily practice? So there is this analysis, or consensus manuscript, from Germany with Viktor Grünwald. They just depicted there is a low sensitivity of bone scans and they have an example as well and I just brought you on the right side an example of my patient. It’s a patient within a clinical trial as well and we are forced to do the bone scans on a very regular basis because this is part of the study protocol. But actually we only see those osteolytic lesions within the CT scans. So the patient obviously asks me why do I have to perform the bone scans and my question to you would be obviously if we do not see the osteolytic lesions very well in bone scans what is your way to go? How do you stage those patients?

SO:  I think that bone scan is really not a good imaging to perform in kidney cancer; I think we should go for CT scan or MRI maybe if you have symptomatic pains regarding a bone, a specific bone. But I think that bone scan is really not useful outside a clinical trial where we need to go for a bone scan. But outside a clinical trial I won’t go for a bone scan.

SZ:   I have the panel recommendation from the Grünwald manuscript. They have the same opinion as you – they say bone scintigraphy and PET scans should not be routinely used, that probably could change with the carbonic anhydrase-IX PET scans in the future but for now in asymptomatic patients we should use just the standard CT scan and then, as you said, MRI in certain cases, especially when we have to evaluate epidural disease and soft tissue lesions in the spine.

So the next is how would we treat those patients and we have discussed it a little bit before. There is not so much regarding bone lesions within the guidelines, to be honest, I’ve just copied what I found in the EAU and ESMO Guideline. They say we should use stereotactic radiotherapy for clinically relevant bone or brain metastases for local control and symptomatic relief. They also point out that we can use the adjuvant pembrolizumab if oligometastatic disease has been removed and patients should be discussed multidisciplinary; I think that’s very important too. Then they also point out zoledronic acid or denosumab is a bone protecting agent. 

I found this picture which I liked about the oligometastatic disease and my question here would be how do you decide if a patient has one or two bone lesions who is involved? Do you have an orthopaedic surgeon in the tumour board and how do you do it in France? So what is your standard?

SO:  We have a multidisciplinary team where we always speak about those patients because we need to have the orthopaedics, we need to have the radiation therapists, oncologists as well. We need to have different persons who can take care of the patient because, as you said, bone metastasis usually induces symptomatic disease – fracture, epiduritis, hypercalcemia and so on. So really we need to be as preventive as we can regarding those specific metastases. As it’s shown here, we need to take into account patient characteristics, the extent of the disease, either it’s de novo disease or a metachrone disease. Do we have, in terms of tumour biology, sarcomatoid differentiation or whatever? Is it oligometastasis with only bone metastasis or full of metastasis everywhere? So, based on that, either you go for local treatment, as you said, with surgery and maybe radiation therapy or you go for systematic therapy.

On top of that, as you just said before about the protective bone agents, it’s always a question regarding the use of these drugs with TKIs because maybe it could increase the efficacy but also it could increase toxicity in terms of osteonecrosis of the jaw. So I usually use protective bone agents in case of IO/IO therapy but not for TKI plus immunotherapy.

SZ:   And if you use it, given the fact that our patients are longer on treatment now, they survive 1-2 years etc., do you use the monthly interval or do you extend if you use it? Like in breast cancer they state, and myeloma, that you can use it q3month – what is your schedule for bone protecting agents?

SO:  I think there is no study so far which compares monthly versus every three months but, based on the risk of toxicity, I think every three months could be good enough. But there is no rationale and no study which tells us this point.

SZ:   So this imaging also shows that they would recommend local therapy to peripheral location of metastases only. So what does this mean to you, that if it is in your humerus, the lesion, or it’s in the femur that you would operate versus if it’s in the spine? Are there specific lesions where you would rather radiotherapy to perform local therapy?

SO:  If you can go for surgery, I think that we need to go for surgery. If it’s impossible or it’s too risky I will go for, as you said, embolization, radiation therapy as well. Always you need to look at the specific bone metastasis and according to that to propose the best treatment.

SZ:   Then sometimes we have oligometastatic or oligoprogressive disease, what do your radio-oncologists tell you? Should you stop TKIs while they do radiotherapy? Because obviously immunotherapy has a long half-life and you give it only every q4weeks or 6 weeks. But do you stop the TKI in those patients?

SO:  Usually we stop the TKI, especially cabozantinib because it has a long half-life, which is not the case for axitinib, for instance. So, based on the half-life, we either continue on the treatment, for instance with axitinib, but for cabo we stop the treatment during the radiation therapy period.

SZ:   This is just an algorithm that Viktor Grünwald proposed regarding local therapy, when to use definitive therapy in bone metastatic lesions. I think this is probably that which we have discussed or reflects what we have discussed too. Then maybe let’s talk a little bit about the different treatment options that we have in first-line therapy. So I have copied the ESMO Guideline here and, as you already discussed, there are options outside of Europe that we do not have. So the guidelines list a lot more agents than we are capable of using, at least in label and with reimbursement.

So you were talking about we have four combination therapies and that is what we can find in the EAU Guideline which is maybe a little bit more done to daily life. So we have those four combination options here and we have the CLEAR study which is one of the four combinations with lenvatinib and pembrolizumab. When you compare those studies, which you’re not allowed to do but I think I’m allowed to talk about prevalences here, so the amount of patients with bone lesions is pretty much the same throughout the studies, which is something that we should note here. It’s always between 20% and 24% so it’s in the same range, actually.

This is a post-hoc subgroup analysis with a two-year follow-up and you can see the PFS for patients with different sites of metastasis at baseline. We can see here that for bone lesions it is 24 months versus 5.6 months in favour for the combination, also for the bone metastatic group. It’s better for lung and, as you can see here, for patients with liver metastases the PFS is a little bit shorter. So did these data change your daily practice of prescribing when you saw that?

SO:  Yes, I think that this sub-analysis regarding by type of metastasis, liver, bone and lung, reassured me regarding the fact that if you have bone metastasis you can go for pembro/lenva and it’s useful, it prolongs the PFS as well as the objective response rate, which is around 65%. We have here not obtained in terms of follow-up for median overall survival. So I think that you can be reassured about the fact that it works really well for patients having bone metastases.

SZ:   So we have here the analysis for the four year post follow-up. It’s pretty much the same, I think you just can see that patients with brain metastases that obviously were able to be in a clinical trial, which are patients that have a very good performance status, and those patients have still a not so good prognosis with 9 months versus 6 months. So this is really something that is of note here.

Then the outcome by metastatic site has been published as well, again by Viktor Grünwald. Again for all sites of metastasis we do see a huge percentage change in sum of diameters of target lesions and also in bone lesions, which I thought is not what I expected because the lymph nodes, they get smaller and smaller, the liver lesions get smaller and smaller but the bone lesions, it’s not so easy for them to get smaller. But still you can see a huge difference compared to sunitinib here.  How would you interpret this data?

SO:  Yes, it’s always difficult to measure the bone metastasis, looking at the RECIST criteria, because it’s much more difficult than lung or liver mets. But maybe you need to focus on recalcification and so on, which is quite difficult to look at because, as we said just before, bone scans are not all that useful for those patients and we need to go for MRI or CT scan to see how it goes on. But as you have shown here, we have some tumour shrinkage, even at the bone level, bone metastatic level. So that’s fine.

SZ:   So what we do not know is if the target lesions were in the bone. So this could be patients with bone mets and the target lesions would be in the liver or in the lymph nodes or in the lung. But still I think it’s a very positive result. Then the safety data, any comments here or is it no difference?

SO:  No, I think it’s not dependant on the type of metastasis. We know well now for lenva/pembro or the other combos the types of toxicities so I think we need to handle those patients with supportive care treatment and so on and so on. But it is not dependent on type of metastasis.

SZ:   So these are the data of CheckMate 9ER. As I pointed out before, it’s around 20-24% of patients with bone mets here. They did the same, they also showed us the data by target lesion or by baseline existence of lesions and here you can see that the median PFS was 13.8 months versus 5.3 months and the median OS 34.8 months versus 20.7 months for sunitinib. They also did an analysis of patients and depth of response in patients with bone target lesions at baseline. So they really said it’s target lesions, what we just discussed before with the CLEAR study. As you can see here too, it’s a better result with cabo/nivo compared to sunitinib. And you also see that some patients have primary progressive disease on sunitinib as well.

Then we have the CheckMate-214 study and again here 20-22% of patients with bone lesions. They had also this discussion on what is the PFS by baseline bone lesions or baseline liver lesions and lung lesions. What were your thoughts when you saw these data?

SO:  I think that the new IO/IO regimen is not very good for bone metastases, and as it’s shown here, because you don’t have such a difference in terms of PFS, in terms of median OS and in terms of objective response rates. So I think that is not a good combo to go for in the case of bone metastasis and we should maybe go to focus on TKI plus immunotherapy.

SZ:   Yes, so there is a biological rationale for that as well as those patients have more pro-angiogenic signatures when they have bone lesions.  You probably also have some patients that have IO/IO with bone lesions and they respond but if you have the choice between different drugs probably the decision is more towards TKI/IO in those patients, right?

I have also brought two images of the pathophysiology of bone metastatic lesions because I think it’s a very specific niche that we have here and we have an addition like the osteoblasts and the osteoclasts. You were also discussing RANKL ligand and denosumab. So we have just one more player here with all those osteoclasts, osteoblasts etc. There is some differentiation.

SO:  It’s promotion of the vicious circle of osteoblasts leading to the destruction of the bone. Also you’re targeting c-Met at this level and it induces the release of a lot of cytokines which leads to osteolysis of the bone. Therefore, it could be a nice niche for cancer cells to be at the bone level and to induce fractures and so on. So there is a physiopathology towards bone metastasis regarding the kidney cancer cells, leading to this type of metastasis.

SZ:   And that is why you would use a specific TKI in this case like those which target c-Met and FGFR.

SO:  Yes, I think that if you dose the cytokine in the blood from those patients you will find out a lot of high levels of VEGF or FGF and so on, leading to the production of this type of metastasis. So I think that the rationale to go for a TKI is really great in this situation.

SZ:   So I think that is probably what we wanted to discuss, is there anything that we have missed or we should also talk about?

SO:  I think that it’s a really great presentation and thank you for your cases which allowed us to speak about this specific type of metastasis in kidney cancer and how to choose one combo versus another. So there is, in fact, no recommendation of one combo which would be the best compared to another. But maybe you can give the summary of this presentation?

SZ:   So, to summarise, I think we should be aware of how to stage our patients. It’s not a rare site of metastasis, approximately one third of our patients will develop lesions. We best see them within CAT scans and sometimes we will need MRIs, I think that is very important. Then we have the high response rates of IO/TKI combos in those patients with bone lesions, probably because the tumours that metastasise to bones have a pro-angiogenic signature which makes those combos maybe the combos of choice. Then we have only a touched a little bit on the adverse events but you have pointed out that it’s not specific to the site of metastasis where you would use different management of those patients because bone lesions… this could be different for brain metastases but for bone metastasis it doesn’t play a role in most cases.

SO:  Thank you Stefanie, I think that is the end of this presentation so we tried to overview bone metastasis in kidney cancer. So go for a combination and go for maybe a TKI plus immunotherapy drugs. We would like to thank you for your attention, Stefanie and myself, have a good day.