Selecting Frontline Therapy for mRCC

Robert Motzer, MD: There has been rapid transition and progress in our first-line therapy for clear cell carcinoma. Before the advent of tyrosine kinase inhibitors [TKIs], there was very little to offer patients with metastatic renal cancer. The median overall survival was less than a year. For many years, there were very few options, but that really changed as a result of a better understanding of tumor biology and the importance of the VHL gene and its mutation. There was also the development of drugs that targeted the downstream effects of that mutated gene. 

There have been a number of different tyrosine kinase inhibitors and mTOR inhibitors that were developed and revolutionized treatment, improved prognosis, expanded our therapeutic armamentarium. That development was beginning in 2005, with the regulatory approval for sorafenib. Recently, the last of these tyrosine kinase inhibitors to get approved in the United States was the lenvatinib plus everolimus combination. Even more recently, we’ve now included immunotherapy [IO] in the first line-treatment for RCC [renal cell carcinoma] with even more gains in efficacy. There has been a series of phase 3 trials that have compared these immunotherapy combinations to TKIs, and these trials have shown a benefit and received regulatory approval. 

For the most part, the 2 treatments that are used are ipilimumab/nivolumab and axitinib plus pembrolizumab. In deciding first-line treatment for patients, one question is, does that patient need systemic therapy immediately? 

There are a number of patients who present with small, asymptomatic metastasis. One of the features of RCC, historically, has been that the tumor can either progress rapidly or the tumors can be very indolent and slow growing. It is an unpredictable pattern of progression. For some patients, the best treatment is no treatment. We simply follow those patients with scans, and if it looks like there is a change in the progression pattern, then we implement systemic therapy. 

For other patients who need treatments, the best path is to look to see into what risk category those patients fit. For patients who have favorable-risk tumors, then there are different options. There’s tyrosine kinase inhibitor single therapy; there is a TKI/IO combination, pembrolizumab/axitinib; and there is IO/IO combination, ipilimumab/nivolumab. It is not that one shoe fits all. There are different pros and cons of each of those programs. These need to be taken care of while having discussions with patient, considering their individualized needs and recognizing the comorbid conditions. The patients who have intermediate- or poor-risk tumors may need therapy soon, although some intermediate-risk patients can likewise be followed for long periods. Following nephrectomy with metastasis, some of those patients do well for a long time. 

Again, the best path may be surveillance until therapy is needed. For intermediate- and poor-risk patients, when a systemic therapy is required, the options right now are either IO/IO therapy or IO/TKI therapy. There are some pros for one and cons for another, so it is really an individual decision by the physician that will best meet the needs of the patient. One of the factors that is involved here is that the different and new IO first-line programs have all been developed in parallel. They were all compared to sunitinib. We can make some cross-study comparisons and say, this looks better in this population and that looks better in that population, but since they were all developed in parallel, we really haven’t been able to compare them. They haven’t been compared to each other, which does cause a bit of a disadvantage when claiming one therapy is better than another.

Robert Alter, MD: When we sit and talk to our patient, we have already talked about their CT scans. We have talked about their cell type and possibly their surgical intervention prior to our visit. We then have to think about how we are going to approach our patients, whether we treat them using first-line therapy or active surveillance, which is sometimes an appropriate conversation. We talk about disease burden as well.

The first thing we have to try to do is have the physician undergo risk categorizations with our patients. Defining their risk is quite important. We have to take the patient, recognizing the concerns of the tumor itself. Is this a newly diagnosed disease? Is this fast-growing? Is the patient having symptoms? Is the patient’s functional performance status affected by this? We need to think about the emotional support the patient may have, patient compliance, if using oral therapies, and travel, depending upon the patient to come into our office for intravenous therapies, or even receiving oral therapies that require laboratory assessment or visits. Winter does bring some restrictions for some of our patients.

Some of our patients require family support for their transportation, so a defined patient quality is truly an important factor when it comes to assessing not only the treatment but also the patient themselves. The most important thing is discussing the patient’s performance status, symptoms, tumor burden, and extent of disease, which may define the patient’s treatment, visceral involvement, and which area is treated.

Does this patient have a small pulmonary nodules that may have been present for some time? Does this patient have liver involvement or bone pain? Every patient is different, so you cannot walk in with a cookie-cutter mindset that every patient who comes to your office who has a symptom gets a certain regimen. We have to be open-minded about not only the variety of therapies we have but the conversations you have with the patient as well. Including them in the conversation, defining their goals of therapy, and allowing them to recognize their therapies may be chronic is necessary. Alternatively, we can be a lot more aggressive and treat them with an immunotherapy combination that enables the patients to have fewer toxicities, or possibly durable remissions, where they can be observed off therapy.

The conversation regarding active surveillance is always important. Our patient populations who have nominal symptoms and have undergone a nephrectomy can have discussions about active surveillance. As a medical oncologist who takes care of patients with renal cell cancer, it is the hardest conversation to have when trying to convince a patient to opt for surveillance when they come to you saying, “I have an advanced or metastatic disease, and I was told to start therapy.”

This goes back to defining our goals. It is important that we have communication and a sense of appreciation to have a patient be educated. We now let them know how we think, and we have also started recognizing how, in the patient’s eyes, they want to have their therapies be as aggressive as possible for the elimination of disease with excellent quality of life.

Transcript edited for clarity.