Dramatic Changes in the RCC Landscape Underscore Importance of Molecular Profiling

Alexander Helfand, MD

In recent years, clinical trials have demonstrated prolonged survival and improved responseswith tyrosine kinase inhibitor and immuno-oncology (IO) combination regimens, according to Alexander Helfand, MD.

Namely, the CheckMate 9ER (NCT03141177) and CLEAR (NCT02811861) studies, have shown promise using the combinations of nivolumab (Opdivo) plus cabozantinib (Cabometyx) andlenvatinib (Lenvima) plus pembrolizumab (Keytruda). However, knowledge of whether these regimens will be practice-changing will come with additional follow-up, Helfand, medical oncologist at Allegheny Health Network and assistant professor of Medicine at Drexel University College of Medicine told Targeted Oncology™, in an interview.

“It will be interesting to see what happens with some of the trials of doublets in the adjuvant setting, like pembrolizumab plus belzutifan [Welireg]. But I think that time will tell as to overall survival benefits from the use of pembrolizumab, and I think that we need to be cautious given the history of limited survival benefit with adjuvant therapies in the past. I would say that we should proceed eagerly with putting patients on trials, but with caution, given the history of trials over the past 10 years. Certainly, pembrolizumab is a very exciting option going forward. We'll have to see if novel combinations can build on that success,” said Helfand.

In the interview, Helfand discussed the current standard practice for testing patients with renal cell carcinoma (RCC) and administering immunotherapy or targeted therapy.

TARGETED ONCOLOGY: What testing should oncologists be doing for patients with RCC? Which biomarkers are important to identify?

Helfand: The landscape of RCC has changed recently with new targeted markers based on germline von Hippel-Lindau [VHL] mutations. Certainly, in the setting of locally advanced or metastatic renal cell carcinoma, we want to consider doing testing toidentify those patients with VHL mutations. What we know is that belzutifan, which is approved now for treatment of renal cell carcinomas in patients with a germline VHL mutation as well as for cerebellar hemangioblastomas and pancreatic neuroendocrine tumors associated with VHL mutations has improved outcomes. The key is to try to identify those patients.

In terms of testing, there are criteria for whom to test for VHL mutations and those you know, those criteria are going to include both patients who are diagnosed with any RCC, particularly clear cell RCC, below the age of 47. But also, the criteria includes patients who have bilateral or multifocal disease, and patients with a family of first- or second-degree family history of renal cell carcinoma. Patients who have multiple papillary tumors, anybody who has a diagnosis of rare tumors like hereditary leiomyomatosis [HL]RCC, Birt-Hogg Dube, or other significant family history or tumor findings, that would prompt germline testing. As a general matter, I have a low threshold to send the patient to genetic counseling and water germline testing and to be able to treat patients appropriately. Now, there have not been any published trials looking at belzutifan compared with immunotherapy or TKI and IO based combination therapy in these patients, but most of the data on belzutifan is going to be in later lines. We also know that these patients should enroll in studies so that we can investigate the use of these agents earlier, especially whereby the mechanism that we know they tend to be quite effective.

Can you discuss the role of immunotherapy in RCC right now? Which therapies are most promising?

In general, role of immunotherapy in RCC is either in the adjuvant setting or in the setting of high-risk disease, in the locally advanced or metastatic setting with the use of doublet immunotherapy with ipilimumab [Yervoy] and nivolumab [Opdivo], or with the use of multiple TKI and IO combinations. The data from CheckMate 214 [NCT02231749] have the longest follow-up time and we you know; the use of doublet immunotherapy essentially changed the landscape of renal cell carcinoma in terms of achieving durable responses in a certain subset of patients. The TKI/IO combinations are also excellent with good survival data. In terms of which is superior, it depends on the toxicity profile, patient preference, and often clinician preference, but we do not have any great biomarkers to identify which will be superior and in terms of IO development going forward.

The question becomes, are there ways to try to improve on IO? There are a number of studies going on thatlooking at combinations with interleukin [IL]-1 or high-dose IL-2, and some of those I think will be promising, especially seeing whether, in the second-line, we can overcome immunotherapy resistance.

What is the role of targeted therapy in RCC, and which therapies have the most promise?

There are many ongoing trials looking at various options for treatment. One is looking at a combination with a histone deacetylase inhibitor, another trial is looking at the combination of pembrolizumab and a histone deacetylase inhibitor, and there are combinations of belzutifan being used. Essentially, those are combinations of belzutifan and pembrolizumab, and lenvatinib and pembrolizumab. These are in various stages of development.

There's also a trial looking at the combination of belzutifan and palbociclib [Ibrance] compared with belzutifan alone. In terms of targeted therapy, that's essentially where we stand. There are a number of phase 1 trials also looking at novel agents. But again, we'll have to see what those results show.

Recent clinical trial updates in first-line RCC have mainly come from the CheckMate 9ER. What can you about this study and its impact?

The data are very promising from CheckMate 9ER. It showed a 49.5-month survival with an excellent overall response rate of up 56%. In terms of the overall response rate, this is certainly comparable with data from CheckMate 214. Cabozantinib and nivolumab have a fairly tolerable toxicity profile, as well as excellent survival data.

I don't think that this honestly changes the landscape dramatically in terms of the choice of cabozantinib vs lenvatinib/pembrolizumab combinations or axitinib [Inlyta]/pembrolizumab combinations. Again, I think it's also a question of long-term follow-up. I think the choice is based on toxicity profile, and I don't think that the results necessarily suggest that 1 agent is superior to the other. But it is reinforcing the efficacy of these extremely important IO/TKI combinations.

In advanced RCC, recent findings from CLEAR appear exciting. What are your thoughts on this study?

The CLEAR trial has about 34 months of follow-up, overall survival data are not reached in terms of median overall survival, and the PFS data are very reassuring with about 23 months vs about 9 months in the control arm. Again, I think these data are compelling. Longer-term follow-up will be necessary in order to tease out the exact overall survival benefits.

The question for all these studies is looking at the complete response rate compared with that of doublet IO. I think the complete response rate with doublet IO has been reported as high as 16%, but closer to 10% in longer-term follow-up.

I think that it's difficult to make decisions about each agent. Sometimes this is simply guided by the underlying hypertension, underlying vascular disease, and tolerance of various, cutaneous, and gastrointestinal complications.

A few other studies are looking at the role of adjuvant therapy. Is there any adjuvant research that appears interesting?

It will be interesting to see what happens with some of the trials of doublets in the adjuvant setting, like pembrolizumab plus belzutifan. I think that time will tell as to overall survival benefits from the use of pembrolizumab, and I think that we need to be cautious given the history of limited survival benefit with adjuvant therapies in the past. I would say that we should proceed eagerly with putting patients on trials, but with caution, given the history of trials over the past 10 years. Certainly, pembrolizumab is a very exciting option going forward, and we'll have to see if novel combinations can build on that success.

Based on all the research happening now and recent data you have seen, what key advice do you have for other oncologists on treating RCC?

My advice would be that the landscape of RCC has changed dramatically in recent years and there is tremendous nuance in treating this group of patients and that whenever possible, I advise obtaining molecular profiling of these tumors. With a low threshold for germline testing as well, I think that trying to enroll patients on clinical trials is essential if we are to make progress in this disease. I think that it's an excellent opportunity to improve on known success with the various agents we have now. The management of toxicity is important, but with good close attentive patient care, we can keep patients on these regimens for a long time. We know with the TKI-IO combinations, we want to try to keep patients consistently on the TKI. Even with dose reductions, if we can try to maintain that continued level of therapy, then that portends well for the patient. Particularly in the second-line and later, I think looking at new ways to try to overcome immunotherapy resistance is going to be the wave of the future and trying to find ways to either do that with existing agents.