Advanced RCC Treatment Selection

Robert Alter, MD: Going back to our case, we described a patient who initially was diagnosed with stage III disease and, within 9 months, developed metastatic disease. When deciding how to approach our patient, in terms of treatment options, we did identify that the patient’s functional performance status did go from an ECOG of 0 to a 1. We did discuss that the patient had disease recurrence within 1 year. Those 2 parameters now categorize him as being an intermediate-risk patient.

Things that we always think about when exploring treatment options include, obviously, important factors that are not on that list. We do discuss performance status. I think that we have to recognize that even though it’s part of risk categorization, this is very subjective by the physician. We have to ask more questions to identify the risk of the patient’s functional performance status. We do recognize that functional performance status can predict the patient’s tolerance to therapy and longevity of being on a therapy. Based on the patient’s tolerability, the patient can potentially benefit from long exposure to these therapies.

Other items that are not usually considered in risk stratification include sites of disease, number of metastases, the disease burden. I think that when we talk about what therapies may be of quicker onset of action, what therapies may be better tolerated, we have to consider the visceral involvement of the patient, sites of disease. Sometimes, despite the fact that the patient may have a large volume of disease, the patient may be asymptomatic. This may be helpful when deciding what treatment options are available to give.

Therapies include oral tyrosine kinase inhibitors [TKIs]. These have significant benefits. Patients can take these drugs away from the office. Patients may have different types of toxicities to oral tyrosine kinase inhibitors. They may have GI [gastrointestinal] toxicities, fatigue, hypertension, rashes, wound healing issues.

Despite the fact that these therapies are potentially toxic, they are adjustable. You can actually lower the dose of an oral therapy, allowing it to be more tolerable so the patient can remain on therapy.

VEGF inhibition seems to be a very strong component and action against renal cell carcinoma, as it has antiangiogenic properties to a very vascular disease. Patients tend to respond well to oral tyrosine kinase inhibitor therapy.

The newest form of therapy is immunotherapy, and we have several agents available. Initially, we were utilizing nivolumab as a single agent for second-line therapy following November of 2015. And now, we see the evolution of these therapies into the first line, either in combinations of immunotherapy—ipilimumab and nivolumab—or oral tyrosine kinase inhibitor therapy combined with immunotherapy. We’re definitely deriving benefits. Though we are utilizing the 2 mechanisms, we are definitely seeing durable response rates, and more importantly, complete remissions.

As first-line therapy for patients, again we have to talk about categorizing these patients as favorable risk, intermediate risk, and poor risk. For patients who are considered favorable risk, one has the opportunity to treat with oral tyrosine kinase inhibition, either sunitinib or pazopanib. However, based upon the KEYNOTE-426 clinical trial, patients categorized as favorable risk who receive axitinib and pembrolizumab do have benefit. For patients categorized as intermediate or poor risk, we also have axitinib and pembrolizumab, as well as axitinib and nivolumab, single-agent cabozantinib, and then based upon CheckMate 214, the combination of ipilimumab and nivolumab.

In patients who have progressed after first-line therapy, when deciding on second-line therapy, there are several factors one must consider. Of course, we are concerned about functional performance status and tolerability to first-line therapy. I do believe response to first-line therapy may predict response to second-line therapy. That really comes down to, when do we utilize immunotherapy as a second-line therapy? Do we do so if they received prior immunotherapies? Do we continue with the same mechanism of action? Do we switch mechanism of action? The sequencing has been studied, and I think that beyond the patient’s ability to tolerate systemic therapy, patients have to be able to recognize the potential long-term benefits we see with second-line therapy.

Transcript edited for clarity.

Case: A 58-Year-Old Man With Advanced Renal Cell Carcinoma

• August 2018: A 58-year-old man complained of fatigue and anorexia; after appropriate workup the patient was diagnosed with clear cell renal cell carcinoma
  • He underwent left total nephrectomy
• March 2019: He developed metastatic disease to the lungs bilaterally (30 x 35 mm), mediastinum and soft tissue metastatic deposits
  • MSKCC risk status: intermediate
  • ECOG 1
  • He was started on pembrolizumab 200 mg IV every 21 days + axitinib 5 mg PO q2Days
• September 2019: He developed progressive disease (45 x 50 mm); pulmonary lymph nodes increased in size and new mediastinal and hilar lymphadenopathy was noted
  • He was started on lenvatinib 18 mg PO qDay + everolimus 5 mg PO qDay
• October 2019: Due to grade 1 diarrhea, reduced dose of lenvatinib to 14 mg PO qDay + everolimus 5 mg PO qDay
• December 2019: Lesions reduced to 20 x 20 mm from September 2019; achieved partial response
• January 2020: He remained on therapy with lenvatinib + everolimus