Understanding patient expectations and clinician's goals in favourable risk aRCC patients

Dr Yann-Alexandre Vano (YAV)

Prof Daniele Santini (DS)

YAV:   Good afternoon, I’m Dr Yann-Alexandre Vano and I am with Professor Daniele Santini and we will talk today about understanding the patient expectations and clinician goals in favourable risk advanced RCC patients.

DS:     Hello, I’m Dr Daniele Santini, I’m the Director of Medical Oncology in Policlinico Umberto I, Rome, Sapienza University. My expertise is in genitourinary cancer and I will be talking with Yann on the very interesting topic in favourable risk renal cancer, metastatic renal cancer patients. Please, Yann, you can start.

YAV:   Thank you, this is our disclosures. So we will follow this plan, we will see the patient expectation, we will see again a reminder of the International mRCC Database Consortium prognostic group and the available options, and the treatment objectives for IMDC favourable risk RCC patients.

The first point, before focussing on favourable risk group patients, in RCC, as in other cancers, we are to focus on the patient’s expectations and to understand the difference between the patient’s and the doctor’s expectations. Clearly at the beginning of the disease, even more at the metastatic phase, we have to early align our patient’s goal with the physician goals to enable informed and shared decision making. We have to know what patients expect from the treatment. It’s very important to think about that and to discuss it with the patients at the very beginning of the treatment.

DS:     I have a question that is very important in this topic. According to the KCCure that you will show that is a survey, very interesting survey, what indication or indicators of treatment success do patients prioritise and how does this expectation differ from clinical goals?

YAV:   This is a great question, this is the point I would like to stress. In this Kidney Cancer Research Alliance survey which was presented in 2023 at the ASCO meeting, they asked nearly a thousand patients with RCC, among them 300-400 who had metastatic disease. When we ask what do you want from your treatment, what are the indicators of success of the treatment for your disease, the vast majority of patients said that they want to eliminate all evidence of the disease and this elimination of the disease would be durable. So in a very summarised way of things, it’s a chance they would like to achieve absence of detectable disease for a very long term.

The first element, the most important element for the patient, is to be with no detectable disease – you see 55% of patients said that at the first place they want to eliminate all the disease that, in terms of medical terms, to have a complete response. The patients would like to achieve a complete response, they want to get rid of their disease, this is something that we have to understand, and for a very long period of time. This is very important for them.

We have another survey performed earlier in 2019 because most of the clinicians, other clinicians, most of the time are asking if I can protect the patient from too much toxicity from the treatment. When we asked the patients if they would be willing to switch to a less effective treatment if the side effects would be more tolerable we see that only 12% of patients would agree to switch to a less effective targeted therapy and the vast majority of patients would like to have the most effective treatment even if it increases or it is linked to more side effects. I think it’s very important because of course quality of life is one of our goals but patients must have and would have a very effective treatment. This is the first objective for them.

Because we will focus particularly on the IMDC favourable risk group, just a reminder of the IMDC prognostic groups. Everyone knows these prognostic classificators, this is very important, to know that there are six factors to distinguish patients and to classify them into three groups. Today we will focus on the favourable risk group, that’s the patients that have no poor prognostic factors among the six factors. We’ve known for a long period of time that this classification is highly prognostic, it’s not predictive of response but it’s highly prognostic in the TKI era. I put here the publication, the original publication came from 2009 and then an update in 2013. In the TKI era we see that patients with IMDC favourable risk group had a prolonged survival than patients in the intermediate or poor risk groups. What is very important is to see that these prognosticators are also applicable to the combo era.

DS:     A question to you in this setting. In my clinical practice I use IMDC prognostic group, this is very important, but how important do you think the inflammatory prognosis group is in your clinical experience?

YAV:   Clearly the IMDC prognostic groups are still prognostic and this is the definition of prognostic factors. We keep this prognostic ability to predict survival and always this is prognostic for overall survival, not for progression free survival or for response rate but for survival. In the TKI/IO combination you can see the Kaplan-Meier at the left and we can see that we keep these prognostic indicators and with double IO, ipi/nivo, we can see also that we keep this prognostication. This is not a predictive factor, again, but it is very important to know if this is a natural history of the disease and we can see the natural history of the disease thanks to these kinds of prognosticators and it could have an impact on the choice of therapy regarding the guidelines. We will see later on the recommendations, European recommendations, based on the IMDC prognostic group. But, again, this is not something predictive, it’s something very prognostic and very important to have in mind in terms of the natural history of the disease, whatever the treatment that we will give.

Now, if we focus on the topic today, on the IMDC favourable risk group. Clearly, if we pool all the data from the randomised phase III trial, this is the FDA analysis on about 3,000 patients. We do not have a benefit in terms of overall survival of sunitinib – if we pool all the IO/TKI combinations over sunitinib we don’t have any benefit. We have a clear benefit in the intermediate and poor risk groups, clearly, but we don’t have an overall survival. The hazard ratio is 1.24. But we do not prolong overall survival with this combination, that is the first point.

We can see across all the three randomised phase III studies. Here you can see the overall survival in the CLEAR study, pembrolizumab and lenvatinib versus sunitinib, no benefit in overall survival over sunitinib. We can see it with KEYNOTE-426 with pembrolizumab axitinib, no benefit in overall survival in this particular group of favourable risk. And the CheckMate-9ER study with cabozantinib and nivolumab no benefit over sunitinib each time. So it is something very consistent. Last, for the double IO it’s important to note that even in the favourable risk group no benefit, again, for the double IO versus sunitinib in terms of overall survival in the favourable risk group.

So let’s move on to the progression free survival because overall survival is very important but we will see that other outcomes are very important in these patients. Progression free survival with double IO we do not see any benefit of the double IO over sunitinib and that’s why the European and USA do not recommend double IO in this favourable risk group because we do not improve survival, we do not improve progression free survival and we do not improve response rate.

But if we look at the other combination, IO/TKI, again the meta-analysis of the FDA in terms of progression free survival when we combine all the trials, we see a benefit in progression free survival of IO/TKI versus TKI with a hazard ratio of 0.63. This is exploratory data of course because we have pooled all the data together but it is very important to see the magnitude of the benefit in these patients, IMDC favourable risk group. When we look at each trial separately in the CLEAR trial we see a benefit of pembrolizumab and lenvatinib over sunitinib, hazard ratio of 0.5, a clear benefit. In the KEYNOTE-426 with pembrolizumab + axitinib the same picture – a benefit in progression free survival with a hazard ratio of 0.76. And in the CheckMate-9ER, cabo/nivo versus sunitinib, a clear benefit in progression free survival of 0.67. So all the three trials demonstrate a benefit in progression free survival over sunitinib in this particular group.

What is quite interesting, below the median progression free survival is long-term progression free survival, the durable response. This analysis looked at very long-term progression free survival, 24 months and 36 months, and what came out is that we have some long-term patients in the long term, at two years or three years, patients that are alive and did not progress. This is very consistent across the trials and very interesting to look at that. I think we have to fight for the patients for that kind of data to prolong and to reduce the risk of progression and death for a long period of time. That is quite the expectation of the patients.

DS:     Can I do a question to you? In the very favourable risk sunitinib performed very well, in a heterogenous way but very well. In your clinical practice what do you use in very favourable risk? Do you use sunitinib or a combo IO/TKI?

YAV:   Thank you for this question. You’re right, what is very interesting in the IMDC favourable disease is that obviously it’s an heterogeneous group of patients. Because if we look at the pivotal trials, so the three trials that I mentioned earlier, the four trials, we see that with the comparator arm with sunitinib the progression free survival ranged from 12.8 months to 28.9 months in the same group of IMDC favourable risk group. So we understand that there is something beyond this IMDC favourable risk group, that’s why some investigators showed in 2021 that there is a very favourable risk group, as you mentioned, which are patients that a primary diagnosis to systemic therapy, the delay between the two events are more than three years. Patients that have no brain, liver or bone metastases, patients that have a very good performance, Karnofsky Performance Score, these patients belong to the very favourable risk group. So your question is linked to is sunitinib sufficient in these patients, do we need IO/TKI in these patients?

The IMDC consortium made an analysis on favourable risk patients and very favourable risk patients. If we look at the very favourable risk patients in terms of treatment duration or time to next treatment, you can see on the Kaplan-Meier curves in the red curves the IO/TKI performed better and prolonged the treatment duration – you can see 32.1 months versus TKI alone 19 months. In terms of time to next treatment, which is quite a surrogate of progression free survival when we look at the data retrospectively, again we prolong very importantly this outcome – 48.3 months versus 23.2 months with TKI alone. So probably we are able even in this very favourable risk group, probably this disease is mainly driven by an angiogenic profile, even in this group IO/TKI seem to perform to improve the outcomes in this very, very favourable risk group.

So, to answer your question, honestly I do not use any more sunitinib because clearly we have a huge benefit in many outcomes, not in overall survival, that’s right, but all the other outcomes are improved with an IO/TKI. Even in the patients with very indolent disease I think it’s better to give IO/TKI and we used to manage it for a long period of time.

YAV:   So now I’ll show you the European guidelines, they are very consistent between the ESMO guidelines and the European Association of Urology guidelines. When we look at the IMDC favourable risk disease we have many options; we have all IO/TKI options that we mentioned before. In the European Urology guidelines also we have all the IO/TKI recommendations in the IMDC favourable risk group. You can see that we have the double IO but we know that double IO are not approved by the EMA and not also by the FDA so we can’t use it for the favourable risk group.  But you can see the level of evidence with 1a is better for IO/TKI than for sunitinib 1c and here 2b for the European guidelines we have a better level of proof of evidence with IO/TKI. So it’s OK to follow the guidelines and to use IO/TKI in these patients.

Now, if we come back to the patients’ expectations, I’ll remind that they want to eliminate all evidence of the disease for a long period of time. If we look at the response rate, because we need response to eliminate the disease, we need to decrease the disease as much as possible, I mentioned earlier the FDA analysis, pooled FDA analysis, and overall all the IO/TKI combination arms versus sunitinib provided a response rate of 68.2% versus 49.9%. So an improvement in overall response rate for the combination arm and clearly the randomised phase III trial found a complete response rate higher with the combination arm than in the sunitinib arm. I think it’s quite important, this point of complete response and very profound and depth of response because many patients are not symptomatic in these categories of IMDC favourable risk group.

This is even more important in the very favourable risk group but not obviously symptomatic but most of the patients are a low tumour burden. A low tumour burden is linked to the depth of response – the less you have tumours in the patient, the more you can achieve a profound response. The depth of response is correlated with the duration of response and the duration of response is correlated with overall survival. I think all these pictures make sense and the depth of response is important also because it will lead to an oligometastatic disease that’s something to say that if you have one to five metastatic disease we can use focal therapy and you can achieve complete remission using focal therapy and it will lead to a duration of response and overall survival. I think it’s important to keep this in mind.

DS:     In your clinical experience does the depth of response correlate with symptom reduction in this setting of patients?

YAV:   Yes, of course if we have a lot of tumours, a huge burden of tumours, if you can reduce it you will reduce and relieve the symptoms. Again, it’s not the majority of the patients because the majority of the patients in this particular group of IMDC favourable group have a low tumour burden and we can see, for example in this slide, that when you have a low tumour burden the depth of response is higher. So you have more complete response if you have a low tumour burden and this is the case of these favourable risk patients. But if you have symptoms you need to relieve these symptoms most efficiently with a very effective treatment and treatment that decreases the tumours. So clearly the depth of response is correlated with the relief of symptoms, a reduction of the symptoms, even in the favourable risk group, as it is the same in the intermediate and poor risk group, clearly.

So just to make the link between the depth of response and duration of response, I took this example from the CLEAR trial. When we see that patients with complete response the median duration of objective response is quite long – 43.7 months. If you have a partial response with a huge tumour shrinkage, more than 75%, you have a duration of objective response which is quite long but a little bit shorter than patients with complete response, 30 months. With the other partial response you have a little bit shorter again duration of response so more the response is important and the depth of response is clearly correlated with the duration of response. This is very important. So I think achieving a very profound response must be our goal to improve the duration of response.

DS:     I agree with you, Yann, but if you have a long-lasting response during the therapy on TKI but you have oligoprogression during the therapy is it important to treat the oligoprogression with local therapies?

YAV:   Yes, I think it’s a very important point. In this favourable risk group patients will be treated for a very long period of time and we need to keep the line as long as possible. When we have oligoprogression, another way to say it is that you control a part of the disease but some parts of the disease are not controlled and you have some progression at some sites. I think it’s very important to think about focal therapy, metastasis-directed therapy, radiotherapy, surgery, to control this oligoprogression which could be another clone of the disease and to keep on this line. It’s not the same picture in the poor risk group, I think it’s something very different because in the poor risk group you have a very explosive disease but here it is not the case. So I think it’s a very important thing to discuss in the multidisciplinary meeting to control the site at progress and to keep on the first line and it’s the same thing in the second line. I think it’s very important to keep the first line as long as possible to control the majority of the disease.

DS:     Thank you very much.

YAV:   Coming back to the depth of response, I mentioned it earlier, the depth of response in all the trials is correlated with overall survival. You can see here an example in the CLEAR trial with pembrolizumab/lenvatinib, if you have a complete response, it is the blue curve here, you do not have survival events and if you have a worse response or stable disease you have a shorter survival. This is quite intuitive but it has been shown in all the trials. You can see here with the double IO the patients with complete response have very prolonged survival, partial response have prolonged survival but a little shorter than complete responders, and stable disease is worse and so on.

You can see here it’s the same example for the pembrolizumab/axitinib in the KEYNOTE-426 – complete response very high survival rate and partial response a little bit inferior to complete responders. So, again, complete response is one of our goals and one of the patient expectations. We have the same picture with the CheckMate-9ER, nivo/cabo, complete responders a very prolonged survival.

So we have this continuum with depth of response, duration of response and overall survival. This is why depth of response, in my opinion, is so important and is achievable. Complete response is really achievable in this favourable risk group, more than in other groups with a worse prognosis. More than that, we do not have always complete responders but the French team in Strasbourg showed in a very elegant paper that a patient with stable disease or partial response, it’s not oligoprogressive disease but patients that are already responders are not progressive and they complete the treatment by focal therapy. Thanks to this focal therapy, it could be a nephrectomy, it could be surgery, lung resection, liver radio ablation and so on, with the help of these techniques we can increase the complete response rate that we have with systemic therapy. So in the series they moved from 11% of complete response to 24% of complete response, thanks to this focal therapy. This is something very interesting to look at.

DS:     The last question, only to close our discussion. So you underlined the importance of local therapy to obtain a complete response after a major response, also in the good risk patients.

YAV:   Yes, to increase the response it’s following this slide highlight the previous one and this is from the CARMENA trial. This is only TKI and when we look at the arm of sunitinib alone, I’ll remind that CARMENA compared in a randomised phase III trial surgery followed by sunitinib versus sunitinib alone in patients, this is intermediate and poor risk group patients, this is not IMDC favourable risk group but it’s just to exemplify what I said. The patients in the sunitinib alone group may have a nephrectomy because they have a very good partial response and sometimes there is just the primary tumours that are residual and all the disease is controlled but not the primary tumours, which is very frequently the case. We look at these patients that have delayed nephrectomy, when we compare them with those with no surgery, and we have a huge benefit in terms of survival. So to answer your question, treating residual disease with local therapy is a way to achieve complete remission at the end of the day for our patients and maybe then we will have to discuss that for the continuation of the systemic treatment for these patients that we have a lot of research programmes that are launched in the US, in France, in Europe, to know if we can randomise patients that have just their primary tumour in place or one or two metastases, if we have to follow treatment and no focal therapy or if we can treat this residual disease and what to do after treating this residual disease when we have no evidence of disease for our patients that would be metastatic at the beginning. We don’t know how to do it but I think it’s very important to treat this residual disease and I think there is a window of opportunity in this place.

So, just to summarise, I think complete response is very important in these patients, that if we can achieve no evidence of disease by systemic therapy, by treating residual disease with focal therapy, with no evidence of disease I think we will achieve an improvement in quality of life. So if we focus on the efficacy first we will achieve then the improvement of quality of life. I prefer this way to think versus the contrary, the inverse, of improvement of quality of life is at the centre of the strategy but you take the risk to not treat with effective optimal treatment if you use TKI alone, for example. The expectations of the patients are not aligned with that because they would like the most effective treatment as we saw earlier.

So, to summarise all this data, the long-term disease control is one of patients’ key expectations, clearly. It must be shared with physicians, this objective. It may be achievable in this IMDC favourable disease, it’s not always the case with poor risk disease. It may be achievable with a combination of treatment, better than TKI, and consolidating with focal therapy may support this strategy and improve quality of life, clearly.

DS:     Thank you very much Dr Vano for this very interesting discussion. I think that the topic is very interesting and I hope that all the colleagues will listen to this podcast and enjoy it. Thank you very much to you all.

YAV:   Thank you very much.