Agarwal Addresses Sequencing Challenges in Kidney Cancer

Neeraj Agarwal, MD

The FDA approval of cabozantinib (Cabometyx) in December 2017 and the subsequent approval of nivolumab (Opdivo) and ipilimumab (Yervoy) in April 2018 for the frontline treatment of patients with renal cell carcinoma (RCC) has broadened available therapeutic options for patients.

The challenge, said Neeraj Agarwal, MD, is, “sequencing and using these agents in a timely fashion, so as to optimize benefit and minimize the risk of disease progression.”

OncLive: Can you speak to the importance of sequencing agents in kidney cancer?

What are the patient factors that you take into consideration in determining first- and second-line therapy?

What are some unanswered questions in kidney cancer?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Agarwal, associate professor, Division of Oncology, Department of Medicine, University of Utah School of Medicine, Huntsman Cancer Institute, discussed his preferred sequencing strategies for treating patients with kidney cancer, and ongoing immunotherapy research in the field.Agarwal: Over the last 10 years, especially the last 3 years, multiple agents have been approved in the treatment of patients with metastatic RCC. This is great news for patients, but it also creates a lot of challenges for clinicians and oncologists.The most important resource I use for treatment decision-making is the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors. In my view, those are presently the most commonly recognized risk factors for prognostication and drug selection. I use them for first line, second line, or later lines of therapy. Until last year, the first-line agents were sunitinib (Sutent) or pazopanib (Votrient) and, for some patients, the mTOR inhibitor temsirolimus. Within the last 5 months, the FDA approved the combination of ipilimumab and nivolumab, as well as cabozantinib as a single agent, in the first-line setting. Cabozantinib was previously approved in the second-line setting.

I wouldn't be surprised if bevacizumab (Avastin) in combination with atezolizumab (Tecentriq) gets approved in the next few months. This is just a start. We are going to have more approvals in the next 2 years by combining novel checkpoint inhibitors with VEGF tyrosine kinase inhibitors (TKIs).

How do you decide between nivolumab plus ipilimumab or cabozantinib in the first-line setting?

The field continues to evolve very quickly, which is great for patients. However, this leaves sequencing questions unanswered with so many new drugs in the first-line setting. If you look at cabozantinib, nivolumab, or axitinib (Inlyta), which are currently approved for use in the second-line setting, they have never been tested after disease progression on immunotherapy, for example. If patients get nivolumab and ipilimumab, or bevacizumab with atezolizumab in the first-line setting, we don't know what their efficacy is in the second-line setting. Not knowing how these agents will pan out in the second-line setting is a challenge we are facing. The combination of nivolumab and ipilimumab was superior to sunitinib in intermediate- and poor-risk patients with newly diagnosed metastatic RCC in a randomized phase III trial. There is stronger evidence favoring nivolumab and ipilimumab in these patients. However, if you delve deeper into the data, you’ll see that favorable-risk patients benefit more from sunitinib. Progression-free survival was highly superior to nivolumab and ipilimumab. For those patients, a VEGF TKI remains the drug of choice. Since cabozantinib beat sunitinib in a randomized phase II trial, cabozantinib is my drug of choice for those patients.

Let's go beyond the risk categorization. Most of the patients who had 1% or greater PD-L1 expression in their tumors seemed to derive the most benefit from the combination of nivolumab and ipilimumab.

The majority of patients’ tumors in that trial did not have high PD-L1 expression. Most of the benefit in the trial with nivolumab and ipilimumab seemed to be driven by PD-L1—expressing tumors. In some patients, whose tumors do not express PD-L1, I do not expect to see a progression-free survival benefit with [the immunotherapy combination]. I would strongly consider cabozantinib in those patients.

Can you highlight some of the emerging combinations?

What is a key challenge that remains?

Cabozantinib is already an established drug with superior efficacy to most contemporary drugs in patients with bone metastases. If I see a patient with bone metastasis, I likely give them cabozantinib. Within the next 2 years, we are going to see the efficacy and approval of newer combinations. Some of these include axitinib with pembrolizumab (Keytruda), in which the overall response rate has exceeded 70% or 75%. Lenvatinib (Lenvima) with pembrolizumab and axitinib with avelumab (Bavencio) are additional combinations [being explored]. We are also testing cabozantinib with atezolizumab. Dr Sumanta Kumar Pal is leading the trial, and we are fortunate to have that combination available for our patients in our clinic. We have so many drugs and good combinations that are increasing survival with each passing year. That is fantastic news for us and our patients, but the problem is the selection of these drugs for a given patient at a given time point. We can always compare the clinical data across trials. However, there are problems with cross-trial analyses because populations can be different.

What we really need are biomarkers. We need biomarkers to predict who is going to respond, and, more importantly, who is not going to respond to a given therapy. If we have them, and we will have them in the next few years, they will allow us to optimize personalized medicine in a better fashion.