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Choosing Newer Agents in RCC
How I Choose Newer Agents for Patients With Advanced Renal Cell Carcinoma

Released: February 27, 2017

Expiration: February 26, 2018

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Patient Case
A 57-year-old male with renal cell carcinoma (RCC) who initially received a nephrectomy developed multiple metastatic lung nodules up to 1.5 cm in diameter with enlarged adenopathy in his abdomen. He was started on sunitinib and initially achieved a PR, but his disease progressed after 1 year on sunitinib. He remained asymptomatic, but he experienced enlarging disease primarily in the lung nodules and somewhat in the retroperitoneum.

As with all my patients, I discussed the different treatment options available for metastatic RCC after progression on first-line therapy with tyrosine kinase inhibitors (TKIs). For this patient, I recommended nivolumab. He was familiar with immune checkpoint inhibitors from the media and was very interested in beginning treatment with nivolumab. After initiating treatment with nivolumab, a subsequent CT scan showed some regression of both the lung nodules and the retroperitoneal adenopathy. He continues to receive nivolumab and came to see me recently for follow-up. There was continued regression of his lung nodules, but his retroperitoneal lymph nodes were larger than before. When he was receiving sunitinib, he was troubled by fatigue and moderate to severe hand–foot syndrome, which required dose reduction down to 37.5 mg/day. However, after switching to nivolumab, he commented that he feels very well with few or no adverse events.

Based on his current physical appearance, I elected to continue treatment with nivolumab and ordered a repeat scan in 6 weeks to monitor the enlarging nodule in his retroperitoneum.

Selecting Treatment After Disease Progression
In the first-line RCC setting, pazopanib or sunitinib are both effective options, with slightly different adverse event profiles. Once patients progress, several drugs have been approved based on high-level evidence in clinical trials: axitinib, cabozantinib, nivolumab, and lenvatinib plus everolimus. Pazopanib can be used following progression on sunitinib, and vice versa, but there is less evidence to support it. In any case, none of these treatments appear to be preferable to the others based on any given disease site or previous response. I typically choose nivolumab in the second-line setting based on the favorable safety profile and the improved quality of life seen compared with everolimus in the phase III Checkmate 025 clinical trial. I would consider one of the TKIs instead if a patient has a contraindication, such as an uncontrolled autoimmune disorder. 

Of note, educated patients increasingly desire immunotherapies. Many patients with RCC already know they want nivolumab at the initial visit. Although this is typically my recommendation as well, my approach is to outline all of the potential options for patients and give pros and cons for each. If a patient prefers an option that falls within clinical practice or standard guidelines, then I go with the patient’s choice.

Regarding the other new second-line agents for RCC, I participated in early-phase clinical trials (10-15 patients/trial) of both cabozantinib and lenvatinib plus everolimus. Building experience with each of these new treatment options is key for optimal treatment outcomes for patients, whether clinicians choose to use nivolumab, cabozantinib, or everolimus with or without lenvatinib. For my patients who progress on nivolumab, both cabozantinib and lenvatinib plus everolimus produce good responses, but I don’t have enough experience yet to determine if one of those approaches is preferable.

For heavily pretreated patients progressing on later lines of therapy (eg, after axitinib or nivolumab), cabozantinib or lenvatinib plus everolimus can produce good results in terms of responses or stable disease. However, the optimal sequence has yet to be determined and the safety profiles for both are reasonable and similar to the other TKIs in this setting.

To help with treatment decisions for your patients with RCC, my colleagues (Thomas E. Hutson, DO, PharmD, FACP; Won Kim, MD; Elizabeth R. Plimack, MD, MS; and Brian Rini, MD, FACP) and I are updating an Interactive Treatment Decision Tool along with several more commentaries on managing patients with RCC. The tool is designed to help you rapidly select individualized treatment options based on your patient’s specific characteristics by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool. An older version of this tool is available here. An updated version will be published on the CCO Web site shortly, so please check this page again soon.

Understanding How to Integrate New Agents Into the Clinic
Patients with RCC receive sequenced therapy, so whether an agent is given as second-line or third-line treatment may not be critical. What is important for keeping our patients doing well and to extend their lives is access to multiple drugs used in a sequential fashion with appropriate dosing, good compliance, and adequate management of toxicities to ensure maximal benefit over time. It is therefore very important for clinicians to gain experience with these new agents and understand not only the improved efficacy but also the potential adverse events, so that they are comfortable making dose modifications and managing toxicities associated with these agents. A good nursing team, both for standard treatment and clinical trials, should be very familiar with the adverse events of newer agents (eg, diarrhea with axitinib or pazopanib, hand–foot syndrome with cabozantinib or sunitinib, immune-related reactions with nivolumab). In addition, there needs to be close coordination between the doctor, nurse, and patient, so that the patient knows to report adverse events and the toxicities are managed appropriately.

Are you using these newer agents in your clinical practice? Share your experience in the comment box below.