Expert Highlights Breakthroughs and Next Steps in RCC Paradigm

Matthew T. Campbell, MD, MS

Single-agent immunotherapy and combination regimens have revolutionized the treatment paradigm for patients with renal cell carcinoma (RCC), explained Matthew T. Campbell, MD, MS.

The latest breakthroughs include the frontline IO/targeted regimens of pembrolizumab (Keytruda) or avelumab (Bavencio) in combination with axitinib (Inlyta) for the frontline treatment of patients with advanced RCC.

The avelumab approval came in May 2019 and was based on data from the pivotal phase III JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib (Sutent) in an intent-to-treat population of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

Campbell looks to these groundbreaking developments as a foundation for further advances.

“It is a very exciting time as we follow other fields in terms of various combinations and the development of CAR T-cell therapy, which appears to be promising for kidney cancer. We are seeing significant new roles for drugs that are targeting different mechanisms and pathways. HIF inhibitors also appear to be active and have a reasonable safety signal,” said Campbell. Campbell is also hopeful that these advances will reach all patients with RCC, including those with non-clear cell (NCC) disease.

In an interview with OncLive, Campbell, assistant professor in the Department of Genitourinary Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the evolving treatment options in the RCC paradigm.

OncLive: What treatments are currently available for patients with RCC?

Campbell: There are 3 classes of medicines that are currently available. One is immunotherapy-based and those are mostly now the immune checkpoint inhibitors that are designed to help the immune system fight against cancer recurrence. The second class is targeted therapies which are drugs mainly trying to block the blood vessel supply that the cancers are using to grow, such as VEGF targeting therapies. The last class is called mTOR inhibitors and these are targeted therapies, but they work slightly differently and have different adverse events. We are using a variety of these in different combinations and it has been exciting how quickly therapies are emerging and how they are benefiting our patients.

What is the current role of immunotherapy in RCC?

The first immunotherapy that was developed for RCC was cytokine therapies, such as high-dose interleukin-2. They were the first drugs ever shown to cure patients with metastatic RCC outside of surgery and potentially at times with radiation. Previously, they did not have the ability to cure patients with metastatic disease.

In 2016, we had the approval of nivolumab (Opdivo). That was the first drug that was tested and showed significant improvement in overall survival in the second-line setting. Shortly after, nivolumab was combined with ipilimumab (Yervoy) and was FDA approved as frontline therapy. Suddenly, we are seeing more patients having complete responses with therapy, suggesting that there is a good portion of patients remaining disease-free off of therapy, which is very exciting.

In 2019, we had the approval of drugs very similar to nivolumab with pembrolizumab and avelumab combined with axitinib. These combinations have shown that they have extremely high response rates and they are helping patients live longer when compared with older therapies. We are in a time of riches in terms of new therapy options for our patients.

Are there any combination therapies currently in the pipeline?

Right now, we are awaiting 2 studies that will probably be ready this year. One is known as the CLEAR study which combines lenvatinib (Lenvima) with pembrolizumab. They are also studying the combination of lenvatinib plus everolimus and comparing that to the old standard which is sunitinib (Sutent). We are hopeful that data has matured and will be presented this year.

The second trial is called the CheckMate-9ER study, which is cabozantinib (Cabometyx) plus nivolumab compared with sunitinib. I consider cabozantinib and lenvatinib as newer generation targeted therapies because they are hitting several different pathways older drugs were not hitting. They have also demonstrated significant activity in the second-line setting. We are anxious to see what those combinations are going to produce.

Could you talk about the findings from the study you conducted on nivolumab for the treatment of metastatic (NCC) RCC?

That effort was led by Jad Chahoud, MD, MPH, of Moffitt Cancer Center. We showed that both prospectively and retrospectively, patients that have capillary and unclassified kidney cancers appear to have very similar responses or slightly diminished as compared with clear-cell, but they do have significant activity in that setting. We also found that patients with chromophobe subtypes tended to have a lower response rate than what we see with other subtypes of kidney cancer. It is helping to inform our approach in terms of how we are going to incorporate immunotherapy for the NCC kidney cancer subtypes.

How are you choosing between regimens?

We are all struggling as a community to figure out optimal therapies. It is hard on a guideline level because there are extreme nuances in deciding what to provide for each patient. For example, when we are using classic risk criteria it would suggest that patients who have intermediate porous disease would benefit from combination therapy. We have to take into account that sometimes the risk categories are best for trials and not necessarily best for clinical applicability. They do not take into account some of the high-risk sites of disease such as patients who have liver, brain, or bone metastases. It also does not take into account financial considerations for the patient or if the patient can tolerate extreme toxicity from a given agent. We have to tailor to each patient.

What data have been released on the possible role of PARP inhibitors in RCC?

They have been finding that hypoxia can dampen homologous repair mechanisms. It appears to particularly dampen BRCA pathway repair and RAD51 repair. When this happens, it appears that patients with RCC may be more sensitive to PARP inhibitors. It is an area worth exploring and there are ongoing studies both with single-agent and combinations with immunotherapy.

What are some challenges in RCC and how are they being addressed?

Some of the challenges are that we are finding that it seems the best time to give immunotherapy for most patients is in the frontline. That seems to be our chance to get patients into a complete response. We are still struggling with later-line therapy and we do not have a lot of guidance in terms of optimal sequencing and a lack of biomarkers that are helping guide therapy.

What is your take-home message?

The key is you have to look at what data are available and really think about the patient that is in front of you. RCC remains one of the most important cancers to treat in a multidisciplinary fashion. If you have an opportunity to clear somebody of cancer with surgery that is still an important piece to consider. Not everybody requires treatment and some patients who have a very indolent disease can be safely monitored.

Then you have to think about the other complexities that are going on in a patient's life, including their drug copay, if they develop toxicity to therapy, and the community where they live. If you are trying to take a holistic approach, you are going to serve your patient the best.

Motzer RJ, Penkov K, Hannen JBAG, et al. JAVELIN Renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA6_PR.