In the interest of time, I’m going to move on to our second case, and we’re going to talk briefly about non-clear cell [cancer].

This is a 42-year-old woman who presents to clinic with new onset gross hematuria, fatigue, and flank pain. Past medical history is just well-controlled hypertension and occasional smoking for her social history. On CT scan imaging, she has a nearly 8-cm infiltrated left renal mass and some small nonpathologically enlarged retroperitoneal nodes. [She has] normal labs and a performance status of one. This patient undergoes a left radial nephrectomy, which confirms renal cell carcinoma [RCC], but it’s a fumarate hydratase or FH-deficient tumor. So non-clear cell, a relatively rare tumor. It’s grade 3, no sarcomatoid features, pathologic stage T3aN0. And she’s referred appropriately for genetic testing given her age and her histology, and is actually found to have a germline pathogenic variant, which is then confirmed to be present in family members. So, unfortunately, [this patient doesn’t] get adjuvant therapy; this is non-clear cell disease, this patient undergoes imaging post nephrectomy 6 months and has, unfortunately, recurrent metastatic disease, mediastinal lymph nodes, and hepatic metastasis. So [Dr Jonasch], I’m going to start with you, FH-deficient kidney cancer. Do you see a lot of this? I don’t.

I have several, I have a number of cases, and my go-to treatment for these patients is bevacizumab-erlotinib, based on the NCI [National Cancer Institute] data. And I’ve had some pretty dramatic and sustained responses with that combination.

[Dr Berg], any experience here? Maybe just [with] non-clear cell in general. We’re talking about germline variant, so I don’t want to get too down the rabbit hole here. But either this or just non-clear cell, a papillary patient who comes in, which is obviously far more common.

 Variant histology is always challenging. The [PAPMET] data that [Sumanta “Monty” K. Pal, MD] started through SWOG was, I think it did establish cabozantinib...for papillary was the best. And we know about chromophobe not really reacting to immunotherapy, medullary cancer. We know it doesn’t really react in normal kidney cancer types. But I think it is something where I’m a go-to of cabozantinib for a lot of the variants. And sometimes now we have a lot of doublets that I’ve been looking at for pap.

That was going to be my next question. There are some phase 2 data of IO-TKI [immuno-oncology/tyrosine kinase inhibitor] combinations. Some presented at ASCO [American Society of Clinical Oncology annual meeting] and if people know numbers, feel free to chime in, but there’s clear activity to IO-TKI combinations. To me it looks like more activity than TKI monotherapy, separate trials of course. Do you give TKI monotherapy or IO-TKI or both, or how do you decide?

 Since with everything coming out now, I’ve switched to just treating [non-clear cell] like a clear cell to actually giving a doublet therapy.

 Yes. FH-deficient [cancer] obviously is very rare, and I agree with the bevacizumab [plus] erlotinib, but I think there’s that proper classification, once we know it’s a variant histology, is so important, and getting pathology review and getting second opinions, sequencing, things like that are giving us what these unclassifieds used to be and giving us an in to them. Because I think, we always see these trials, like what are these unclassifieds? What does that even mean anymore? We really need to start defining these, and there’s even, in the WHO [World Health Organization] classification, there are new entities that are coming out that have different variants.

They seem to come out with another 12 classifications.

 Yes, exactly. So having that pathology is really important.

Academic center pathology review, hugely important. You mentioned genetics and genomics in these, and I couldn’t agree more. [Dr Plimack], what’s your approach? You can either comment on this or just on non-clear stuff in general.

 My comment on this is kudos to whoever picked up the FH deficiency, because it’s not necessarily apparent on pathology. You do need to send them for germline testing. I think the teaching point here is that any papillary that’s young, it’s a good idea to send them because [of] that match to bevacizumab [plus] erlotinib. I have a handful of patients too, and some of the best responses of any of my patients have occurred with that combination in these FH-deficient patients. So that’s something. And then to [Dr Berg’s] point, I think there’s chromophobe, which is treated one way, and papillary, that’s treated another. I tend to go to [lenvatinib plus pembrolizumab] based on the data at ESMO [European Society for Medical Oncology] that Laurence Albiges [MD, PhD] presented. And then there’s medullary, which is a chemotherapy-treated disease. If you can just separate those three out and consider them completely separate, that would be great. Unfortunately, the trials don’t do that for us, so we’re sort of subsetting those data.

 [A patient with] typical metastatic papillary [cancer] who comes in, what do you give them?

[Dr Bastos], what do you think, either this case or just more broadly, non-clear cell, papillary being the most common when [a case] comes in, what are you reaching to?

 I have a patient also with FH deficiency, and the erlotinib [plus] bevacizumab is the treatment that I’m using for this patient. They are responding very well, and there is a family history, but there is also some interesting discussion about how this was picked up, because there are data in undeveloped countries that don’t have access to NGS [next generation sequencing]. How to train the pathologist, how to triage which pathology cases: you should refer to NGS. They’re using AI [artificial intelligence] also on this pathology, to help this pathologist to triage better the NGS. That’s very important because as you see, there are two family members, and there is a 15% to 20% risk of developing RCC in this patient population. They need to be monitored very closely. So that’s very important. And then if it’s not a genetic-related tumor like this one, I think I’m tending to treat more like a clear cell now, with IO-TKI because just a TKI by itself [is] obsolete right now, and we should incorporate better strategies on this, definitely.

So it seems like in non-clear cell we go back and forth between, oh, we want special treatments [and] oh, we’ll just treat them like clear cell. They want special treatments, we treat them like clear cell. But I agree, I tend to do IO-TKI in your average papillary, whether it’s a cabozantinib [plus] nivolumab or lenvatinib [plus] pembrolizumab based on some recent ASCO data. Again, I think it’s the same as our discussion in clear cell, pick your favorite.

Videos

Focusing their discussion on a real-world patient scenario, expert panelists discuss treatment options in the setting of advanced non-clear cell renal cell carcinoma.

Discussant: Brian I. Rini, MD, Cleveland Clinic

Articles

Selecting Optimal Therapy for Advanced Non-Clear Cell RCC