Non-clear cell renal cell carcinoma: Updated classification with focus on papillary histology and international guidelines
Prof Camillo Porta - A. Moro University of Bari, Bari, Italy
Prof Laurence Albiges - Institut Gustave Roussy, Villejuif, France
CP: Hello everybody, my name is Camillo Porta. I’m a medical oncologist from Italy and today, together with Laurence Albiges from Paris, France, we are going to briefly discuss non-clear cell renal cell carcinomas and particularly the management of papillary renal cell carcinoma. And I want to start recalling you that the histopathological classification of renal cell carcinomas has greatly evolved over time. The very first classification dated back to 1997 and it included only a few histotypes – clear cell, papillary, chromophobe, collecting duct and the so-called unclassified carcinomas. This classification involved in 2004 and already in 2016 the first WHO/ISUP classification included a vast number of different histotypes. Of course, clear cell RCC is the commonest one but, as you can see, the number of different histotypes increased greatly.
Finally, we came to the present, 2022, histopathological classification that, as you can see here, includes a huge number of novel entities. Clear cell remains by far the most common histotype but we can see that we have different papillary renal tumours, oncocytic and chromophobe tumours, collecting duct, the so-called other family of renal cell tumours and, more importantly, that is a great novelty in the classification, molecularly defined renal cell carcinomas which are gaining increasing importance. Despite this, it is clear that the older four histotypes of clear cell, papillary, oncocytic and chromophobe remain the most common. But still the number of novel entities that are recognised in the 2024 histopathologic classifications need a great expertise from pathologists. This is so important to highlight because we better need the competence of dedicated pathologists in order to classify renal cancers.
This table comes from a paper that Laurence knows quite well because she was the first author of this paper and recalls us that different non-clear cell renal cell carcinoma subtypes have clearly distinct cytogenetic, molecular and genomic features. As we can see, papillary are characterised by molecular alterations that until recently allowed us to differentiate the two subtypes of papillary renal cell carcinomas, although in the latest classification this sub-classification between type 1 and type 2 has been changed and presently only papillary as a whole renal cell carcinoma is considered. Although the different genetic and molecular alterations still remain, irrespective of a specific definition of papillary renal cell carcinoma. Laurence, you published this paper earlier on, do you want to add something about how it evolved, all this classification based on cytogenetic, molecular and pathway deregulations?
LA: Yes, thank you Camillo. I think what is at stake here is the fact that it’s an evolving understanding of the non-clear cell entities. So you highlighted how the classification has evolved over time, it’s still a work in progress. We are understanding better the biology of each of these different entities and basically identifying new entities. So this table is a bit outdated, it’s great for our patients because we’re getting to a better understanding of the different biology. But I think one of the bottom lines is that those patients have a worse prognosis than the patients that we are treating with clear cell RCC.
CP: Exactly, and this slide records this point which is so important. This is a retrospective analysis of more than 4,000 patients treated with either antiangiogenic agents or mTOR inhibitors. It is clear that the progression free survival and, more importantly, the overall survival of non-clear cell kidney cancer patients is usually poorer as compared to that of their clear cell counterparts. Therefore we can clearly say, taking a look at these curves, that non-clear cell histologies are inured by a poorer prognosis as compared to clear cell histologies. This is something that we should keep in mind because we need active treatments in order to improve the prognosis of these patients.
So let’s move to papillary which is the most common subtype of non-clear cell renal cell carcinoma, representing roughly 10-20% of all RCCs. We have a clearly comprehensive molecular characterisation of these tumours. I want to, again, go back to Laurence in order to clearly define these cases.
LA: Thank you, Camillo. So let’s bring the focus on papillary RCC as it is the most common form of those non-clear cell entities. So any physician treating kidney cancer will at some point see patients with metastatic papillary RCC. So we have been better at characterising the biology but the question is how should we treat them. The first part is do we have a target that is specific to papillary RCC? A few years ago now from especially the TCGA work was identified MET alterations to be relevant in papillary RCC. So what is MET alteration? It could be either germline mutation but it also could be other abnormalities that would trigger a MET pathway activation which could be chromosome 7 gain or amplification as well as MET amplification, or the ligand itself, HGF. That accounts for about a third of papillary RCC.
The question would be can we target this? And there has been effort to develop biomarker-based strategies in papillary RCC. SAVOIR was a large randomised study which looked at patients with papillary RCC which had this biomarker identified, either MET mutation or chromosome 7 gain, so what we call MET-driven tumours that were screened and then the patients were randomised to receive either single agent MET inhibitor savolitinib versus sunitinib. So, to cut a long story short, it was a huge challenge to identify within the papillary those that had the biomarker. It took many centres to enrol about 60 patients that were having this biomarker identified.
The surprise in this study is although it was challenging to enrol there was a signal favouring the MET inhibitor over single-agent TKI sunitinib in both the blinded PFS as well as, more importantly, in the overall survival assessment. But the study was under-powered because the number of patients that could be randomised was lower than anticipated. So that did not lead to an approval, however, you can see savolitinib appearing at some point in the guidelines based on this data. So it’s much food for thought than changing your practice.
What was really important in the field of how we daily manage our patients is this study. It’s a small randomised study that was conducted in the US which looked at papillary all-comers, not biomarker selected. Here what the authors did was to randomised sunitinib versus different MET inhibitors, broad spectrum cabozantinib, which is a VEGFR and MET inhibitor, but also crizotinib and savolitinib. The two red arms on this graph were stopped for futility so we end up having a well-conducted randomised study between sunitinib and cabozantinib. If you look at those different results we can see a higher response rate favouring cabozantinib, a longer progression free survival and an overall survival which was not statistically significant but favouring as well cabozantinib. So the bottom line, the PAPMET study led to the fact that cabozantinib was integrated in our guidelines and was considered, based on the response rate and PFS, as the relevant treatment for patients with papillary RCC all-comers.
Of course as we’ve moved for clear cell we did the same for papillary and the question is should we go for IO/TKI in patients with papillary RCC. So there have been different studies, many of which were below 50 patients enrolled, and the largest will be discussing with lenvatinib pembrolizumab. All of these studies were not phase III, they were phase II, and not randomised studies but papillary being the most common form of non-clear cell. It was the more representative entity in those mixed non-clear cell trials.
What do we know? Cabozantinib + nivolumab, about 50 patients randomised, look at the response rate – 48% response rate in this study for cabozantinib + nivolumab. We’re having now the B61 study. Here again not a randomised study lenvatinib plus pembrolizumab. This study is important because of the numbers of patients that were enrolled – almost 100 papillary. Here the response rate, again, is above 50%. Very interestingly, both the PFS and the overall survival were giving a signal of activity of this lenvatinib + pembrolizumab combination strategy. So these data were published and that also explained why in the guidelines we now see combination regimens, both cabozantinib + nivolumab and here lenvatinib + pembrolizumab, being presented.
I think this is very interesting to see this deep response we’re having. On this slide the blue bars are the patients with papillary but you can also see the activity outside of papillary in the black bars for the chromophobe entity as well as in the purple one for the unclassified or the grey for the translocation.
These are the subgroups within this large phase II study; highlighted in red the papillary histology. As I mentioned, 54% objective response.
So what are the side effects? Whoever has used an IO/TKI regimen in clear cell is able to handle that in non-clear cell, so no new safety signal and it is true for lenvatinib plus pembrolizumab, the most common adverse event being high blood pressure and GI toxicities such as diarrhoea.
What about an IO/IO strategy? We learned at the last ESMO meeting that there could be a role for nivolumab plus ipilimumab also in non-clear cell. This is an academic study, SUNNIFORECAST, led by the German group. Here patients with non-clear cell entity first-line setting were randomised to receive either nivolumab plus ipilimumab or standard of care. In this study the most common standard of care used was single agent TKI. About 250 patients have been randomised in the study. The primary endpoint was very well picked because it was the rate of overall survival at 12 months, survival rate at 12 months. Interestingly, the study met its primary endpoint and within the non-clear cell papillary is again here the most common entity - about 70-80 patients in both arms. We have a response rate that for the IO/IO strategy is about 30%.
I just want to highlight here the curves for overall survival and the progression free survival. I told you that the study met its endpoint, primary endpoint. One challenge we’re facing, and we may have this discussion with Camillo in a minute, is how do we pick patients that we want to offer an IO/IO strategy? So this study is confirming the role of IO-based regimen strategy in non-clear cell but how should we decide within our patients? Many of our papillary patients have symptomatic disease and then we want to seek for the response rate. So in those patients I may look for an IO/TKI strategy until I am able to know which patients should be given, or should be offered an IO/IO strategy.
I’m going to finish now on the other combination strategies. There is one regimen that you may have heard of which is bevacizumab plus erlotinib. It has been tested in papillary RCC, both HLRCC, which is FH-altered tumours or sporadic papillary RCC. This study was conducted many years ago and has been presented. I think it is relevant for our clinic if you treat patients with FH-altered tumours, HLRCC, and that are germline usually mutations. In these patients we have some activity that is relevant. There are efforts to seek again in the MET inhibition pathway on top of an IO strategy, this is the CALYPSO study led by Chris Suárez. I think it is very interesting, we’re still working on the biomarker definition and combining with an immune checkpoint inhibitor. The study combined savolitinib with durvalumab with some degree of activity in the MET-driven patient population. This is not approved but it's again building around the biomarker-based strategy for the MET-altered tumours.
I’m going to summarise with the ESMO guidelines, for papillary RCC especially, what is within the guidelines, and both Camillo and myself are heavily involved there, is combination therapy which is lenvatinib plus pembrolizumab or cabozantinib plus nivolumab and IO/IO strategy, based on the data I have presented, or single-agent TKI.
Take home messages: please be sure that your pathologist is sure about the diagnosis. Make sure you can have a referral pathologist rule out HLRCC, FH-altered tumours, or translocation RCC. The prognosis is small and could be very heterogeneous, especially in high-grade tumours. MET represents a target in about a third of the patients and we’re getting to biomarker-guided trials here. As of now, I consider the standard of care is an IO/TKI combination and we need new mechanisms of action, especially for those patients that have aggressive tumours or if they are failing an IO/TKI strategy. So we need to have more and more trials.
CP: Absolutely. I think that you clearly demonstrated that, as in the past, we know that non-clear cell histologies may respond to the usual treatments, either monotherapies or combinations, but we should expect less survival, less responses, because, again, these tumours are endowed by a very poor prognosis. Nevertheless, we can achieve in some patients long disease control but overall I cannot but agree with you that we need novel agents and novel mechanisms of action because, as you mentioned, MET alterations are relatively common with just one third of papillary cancer patients and therefore we should look for something different that could offer improve our capability of taking control of these tumours.
LA: Thank you very much, Camillo, for the invitation.
CP: Thank you Laurence.
