Deciding on the Ideal First-Line Treatment for Rare and Advanced Kidney Cancers

Gennady Bratslavsky, MD

Gennady Bratslavsky, MD

There is an ongoing controversary around which treatment is optimal for treating patients with rare and advanced kidney cancers in the first-line setting. During a debate at the 18th International Kidney Cancer Symposium (IKCS), 5 physicians raised their opinions on the subject.

Based on the debate between his peers, Gennady Bratslavsky, MD, explained that although there are multiple options for this patient population, cabozantinib (Cabometyx) may be the ideal first line therapy. Several ongoing clinical trials show the potential of this agent alone and in combination with other agents.

The phase II CABOSUN trial (NCT01835158), which evaluated progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety in patients with advanced, poor-risk disease, for example, showed that cabozantinib prolonged PFS and improved ORR compared with sunitinib (Sutent). In 62 patients withMET-positive renal cell carcinoma (RCC), the PFS was 13.8 months with cabozantinib versus 3 months with sunitinib. In the 69 patients withMET-negative disease, the PFS was 6.9 months with cabozantinib versus 6.1 months with sunitinib. The highest ORR was seen inMET-positive patients, and in this subgroup, cabozantinib showed a higher ORR than sunitinib (34% vs 10%).¹

Despite the superiority seen with cabozantinib compared with sunitinib, Bratslavsky stated that there is still space for sunitinib in the treatment landscape for non—clear cell RCC (nccRCC). In many cases, surgery is also still necessary to treat patients with nccRCC.

“As of today, it appears that while immunotherapy is promising, cabozantinib may be the [standard] first line based on the clinical trials that are coming out. Sunitinib is still an option, and there are also subsets of patients that may benefit from checkpoint inhibitors, although we don't have robust data regarding checkpoint inhibitors,” said Bratslavsky, professor and chair of the Department of Urology at Upstate Medical University.

In an interview withTargeted Oncologyat the IKCS meeting, Bratslavsky provided his expert opinion on the optimal first-line therapy for non—clear cell RCC, a topic he debated on with peers at IKCS.

TARGETED ONCOLOGY: In your opinion, what is the optimal first-line therapy for rare kidney cancer variants (such as non—clear cell RCC), and why?

Bratslavsky: If we can resect something, we should. I say that with the slight bias of a surgeon. However, when something is advanced, the story is very different.

There are a few studies that have looked specifically at the successes of varying histology treatments in the metastatic setting. As of today, it appears that while immunotherapy is promising, cabozantinib may be the first line based on the clinical trials that are coming out. Sunitinib is still an option, and there are also subsets of patients that may benefit from checkpoint inhibitors, although we don't have robust data regarding checkpoint inhibitors.

TARGETED ONCOLOGY: Can you give an overview of your presentation at IKCS?

Bratslavsky: My task was to discuss surgical insights into the management of the varying histologies, which is essentially non-clear histology. There are many types of non-clear kidney cancer and I focused on several aspects. I focused on the fact that once we deal with non-clear histology, we have numerous implications that we have to deal with. Number 1, I would say that it's important to understand how to surveil these patients because the tumors have different growth rates and certainly grow differently from their clear counterparts. Number 2, it's important which modality we use. While ultrasounds may be used for some of the other cancers, it's a modality that should be used carefully in non—clear cell carcinomas.

I talked about the role of surgery, the particular type of surgery when we do a partial nephrectomy, and I touched on the role of a nucleated resection. Essentially, this is a question of should we or should we not hug the tumor or tumoral pseudocapsule when we remove a tumor from the patient in an attempt to preserve the kidney.

I have presented data suggesting that some patients may not have a well-preserved pseudocapsule and pseudocapsules may be invaded in non-clear carcinomas compared to clear cell carcinomas. Perhaps considering removing some of these tumors with a healthier margin would be important. I also focused on the fact that some of these patients with non-clear histology may be aggressive, but some may be safely observed because of the metastatic potential of some of the tumors, such as chromophobe RCC. Watching the chromophobe RCC until it becomes 6 or 7 cm will put patients at the same risk as watching patients with clear cell RCC until it reaches 3 cm. Not all kidney tumors are created equally.

I also touched on the fact that sometimes we can predict who has what type of cancer based on the epidemiologic data. For example, African Americans are more likely to have papillary RCC. Young women are more likely to have chromophobe RCC and unlike papillary, that would be most commonly associated with non—clear cell RCC.

My final touchpoint was on the role of lymph node dissection for the renal masses. While it is not routinely performed, some cancers have a predilection to spread to the retroperitoneal. FH-deficient tumors are one example. In those cases, if we know that these are the types of tumors that we are dealing with or the patient has a family history, then the patient should be offered retroperitoneal lymph node dissection because we often can render them disease-free and identify micrometastatic disease early, even if we don't see an image.

TARGETED ONCOLOGY: What is the key takeaway from your presentation?

Bratslavsky: I stress the fact that non—clear cell RCC is very heterogeneous. I also stress the fact that knowing when we deal with varying histology surveillance is important, the type of imaging, the type of surgery, the role of retroperitoneal lymph node dissection, and metastatic potential.

TARGETED ONCOLOGY: Can you discuss the role of genomic profiling for understanding disease biology and ultimately selecting the best therapy for the patient?

Bratslavsky: Genomic profiling has been a topic of study for many years. We first focused on genomic profiling back at the National Cancer Institute over 10 years ago. But genomic profiling remains an integral part of separating RCC into different types and classifying them not only by how they are made genetically, but also how they will look under the microscope or histologically and how they will behave.

It's also important for us to learn what type of genomic profiling a patient has because their response to systemic therapy may be very different.

Genomic profiling has entered routine care for many patients with a disease such as RCC and is now an integral part of managing disease in these patients.

TARGETED ONCOLOGY: Which gene alterations benefit most from targeted therapies?

Bratslavsky: Certain mutations are known as phantom mutations and those are the ones that are known to have a high response to VEGF-targeted therapy or those that attack the von Hippel-Lindau (VHL) pathway. At the same time, there are different types of either germline or somatic mutations that may make said patients much more sensitive to AMP-2 inhibitors, for example. If these patients have a mutation in PSE-1 or PSE-2, which are tuberous sclerosis genes that are part of the M4 pathway. Those that have been found to havePBRM1mutations and those patients appear to be more sensitive to immune checkpoint inhibitors.

Understanding what type of mutations we deal with may help us in the indication of next-line therapy. As of today, it is not the first step in the management of patients. But for those that fail, it's now a standard of therapy and it's becoming the first step prior to the initiation of therapy that will help us guide what to do next.

Reference:

George DJ, Hessel C, Halabi S, et al. Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial. The Oncologist 2019; 24: 1497-1501 doi:10.1038/nm.4118.