Management Round-Up: Translocation, Chromophobe, RMC, and Other Subtypes

A roundtable discussion, moderated by Laurence Albiges, MD, PhD, discussed the risk stratification and management of metastatic non-clear cell renal cell carcinoma (nccRCC), along with recent advancements in targeted therapies and immuno-agents, treatment sequencing and combination approaches, and adjuvant therapy options. Dr. Albiges was joined by Renée Maria Saliby, MD, MSc; Tian Zhang, MD; and Shahla Bari, MD.

In the fourth segment of the roundtable series, the panel delves into the challenges and treatment approaches for various rare subtypes of nccRCC, including translocation RCC, chromophobe RCC, renal medullary cancer, collecting duct carcinoma, HLRCC, unclassified RCC, and sarcomatoid RCC, highlighting the roles of immunotherapy, targeted therapy, and cytotoxic chemotherapy.

View the next segment on Adjuvant Setting, Toxicity Considerations for Single-Agent, Combination nccRCC Therapy.

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Dr. Albiges: What about translocation RCC? When we talk about translocation, it could involve different partners. It also includes amplification of the TFE family. How do you treat them?

Dr. Zhang: It is harder to extrapolate because those are smaller cohorts in all of these trials, and sometimes they do not respond very well to immunotherapy-based combinations. We can use these combinations in those cohorts because lenvatinib and pembrolizumab have just gained approval for an expanded label for nccRCC. So, I think it is worth a try.

But at some point, there are some partners of TFE, those fusions and amplifications, that might be more susceptible to an mTOR inhibitor. So if your first-line immunotherapy-based combination, lenvatinib/pembrolizumab, does not work out, then perhaps in the second-line setting you are trying an mTOR inhibitor for those patients.

Dr. Albiges: Got it. One of the outliers in combination therapy is chromophobe RCC. They are also outliers for single-agent PD-1. So what is your take on chromophobe metastatic patients, Dr. Saliby?

Dr. Saliby: Unfortunately, patients with chromophobe RCC are not having great responses in most trials. We know from a lot of basic science work that the immune landscape of chromophobe RCC is very different from all subtypes. So, it does not respond as well to immune-based therapies.

In KEYNOTE-B61, we see that the subgroup of chromophobe RCC did respond less than the other subtypes, but we see around 28% to 30% objective response, which is more than any other treatment. So, that is really promising for this subtype. Additionally, patients with RCC have benefited from lenvatinib/everolimus, which is one of the basic treatments that we had in RCC, and it does work in this setting.

Dr. Albiges: We may want to go for a lenvatinib-based regimen combination in the absence of randomized data. Chromophobe is challenging, but we are getting some degree of response with combination-based strategies.

Let us move on to even rarer entities. What about renal medullary carcinoma?

Dr. Zhang: Renal medullary cancer is one of the hardest to treat. It is a very aggressive phenotype, often presenting with metastatic disease, and on the whole, a younger patient population. There is a propensity toward it with sickle cell trait, as we know. The MD Anderson group has done an amazing job of defining the biology behind renal medullary cancer and looking at SMARCB1 loss.

My practice is really cytotoxic chemotherapies for these patients. The best practice right now is still carboplatin and paclitaxel upfront. Then, second-line gemcitabine with doxorubicin, which are really hefty, old cytotoxic chemotherapies. These highly specialized centers, like our friends Drs. Pavlos Msaouel and Nizar Tannir at MD Anderson and the folks at Dana-Farber, are really drilling down to look at that patient subtype and this aggressive histology.

They have just opened their fourth trial dedicated to renal medullary carcinoma at MD Anderson. It is important to stabilize those patients because they often present with symptomatic disease. When we are able to stabilize those patients with our chemotherapies, they can then seek more advanced therapy and trials so that we learn more about these patients overall.

Dr. Albiges: Dr. Bari, could you speak to collecting duct carcinoma?

Dr.Bari: It is one of the rarest variant histologies. Collecting duct tumors were mostly treated with cytotoxic chemotherapy, gemcitabine-cisplatin. But then the BONSAI trial came in, where they accrued 25 patients and completed a phase 2 trial for cabozantinib, showing a 35% overall response rate and a median progression-free survival of 6 months. The trial met its endpoint. It is a small study, but it is a rare disease, so seeing that a single agent like cabozantinib works in this setting was a huge leap in science.

Dr. Albiges: It is good to know there may be a role for single-agent TKI such as cabozantinib.

We have not touched on HLRCC. Dr. Zhang, do you want to say a word about the work conducted here in the US?

Dr. Zhang: There has been a great amount of work mostly at the NCI, and Dr. Ram Srinivasan has really pioneered the data behind erlotinib with bevacizumab, for example, showing some disease activity for HLRCC. For a long time, we depended on surgery for these hereditary syndromes. Many patients were getting partial nephrectomies and recurrences. It is good now that we have some disease-stabilizing treatments so people can avoid becoming dialysis-dependent and anephric, and keep their renal function.

Dr. Albiges: Perhaps a quick comment word, Dr. Saliby, on unclassified RCC. Sometimes, despite staining and different markers, pathologists are unable to make the call. It is usually a rather aggressive disease, right? How do you treat and classify where they enroll in those studies?

Dr. Saliby: The name might be misleading because we are classifying this disease by default, but we are starting to see some patterns and recording it as unclassified. There is a lot of work going on in that space, and I think…

Dr. Albiges: We usually tend to go for combination therapy as well.

Dr. Saliby: Exactly.

Dr. Albiges: Within KEYNOTE-B61, it was not fair to have unclassified RCC, and they tend to respond like papillary RCC with about 50% response rate and progression-free survival in the range of a 1 to 1.5 years. So, even if you have a patient with unclassified, you want to go for combination therapy. At least, that is my take.

One word on sarcomatoid. It is not a specific entity; it can occur in anything. Dr. Zhang, how do you treat sarcomatoid RCC?

Dr. Zhang: Sarcomatoid RCC can occur as a dedifferentiated state across histologies. This subtype is very sensitive to immunotherapy. We have seen sarcomatoid within clear cell, and I think we can extrapolate that sarcomatoid dedifferentiation in non-clear cell. They tend to be more inflamed.

We saw a great talk at KCRS from Dr. Sabina Signoretti, whose lab has been defining the tumor microenvironment for sarcomatoid kidney cancers. They have more tumor-inflamed microenvironments and are a bit more immune responsive. So, I tend to go for an immune-based combination when I see sarcomatoid in my clinics.