Favorable-Risk mRCC: When to Initiate Therapy

Martin H. Voss, MD: We’ll switch gears a little and talk about the more controversial lot: patients with IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] favorable-risk disease. It’s challenging in that none of the trials we just reviewed that have shaped our frontline landscape of regimens available to us was set up to look specifically at favorable-risk patients. CheckMate 214 was specifically set up to look at intermediate vs poor risk, and then all the others looked at an ITT [intent-to-treat] population without specific focus. Nonetheless, we come across these patients.

Amishi, maybe you can speak a little to this. It’s relevant to note that we don’t have to treat all these patients. We can cautiously select patients with favorable-risk disease. This has been a practice for decades. They can be considered for other treatment approaches than just systemic therapy. Before we speak to the subgroup data off the trials, maybe you can allude to that a little.

Amishi Y. Shah, MD: Absolutely. You’re right, this is a very controversial topic in the field. There’s a lot of nuance to decision-making in this because, in many ways, patients with favorable risk do well despite us and not because of us, so patient selection, as you mentioned, is critical. There’s no question that there’s such a broad spectrum of biology in clear cell RCC [renal cell carcinoma], so the biology of these favorable-risk tumors in many ways is different.

There’s been beautiful subtyping work from the IMmotion151 study from multiple other large phase 3 studies that show differences in angiogenesis-driven tumors vs immune-driven tumors. Of course, there’s heterogeneity in individual tumor biology, but these patients with favorable risk tend to have more of that angiogenesis-driven behavior. They have lower-volume disease. They have slower-growing disease. They’re typically susceptible to TKIs [tyrosine kinase inhibitors]. Whereas we see these intermediate-course patients come in with faster-growing disease and higher burden of disease, and clearly they derive much of the benefit from I/O [immuno-oncology]–based therapy.

To that point, there’s a clear subset of patients with favorable risk who benefit from active surveillance. These patients who have incredible indolent biology. They have a long time to recurrence. They’re relatively asymptomatic, with low-volume disease. They might have favorable sites of disease, such as pancreas metastases, thyroid metastases—areas that even if we do nothing, they’re going to have a prolonged control. I have patients in my own practice who are approaching the 10-year mark without having to initiate systemic therapy, which is such a quality-of-life advantage to be able to offer someone 10 years off systemic therapy. Important also, besides active surveillance of the metastasectomy-type of paradigm in these patients, these are patients for whom either I’ll go metastatic resection or radiation, which I’ll touch on in a second and is a really helpful tool to have.

We know that I/O–TKI improves overall survival in these patients with favorable risk. It is an important tool in the armamentarium for some of these, but 1 size doesn’t fit all. For example, you may have a 40-year-old patient who’s favorable risk or a 40-year-old with no other comorbidities. Are you going to go for the tail of the curve for that prolonged duration of response, or do you reach for an I/O–TKI? It’s a controversy.

Coming back to the mention I made of radiation a second ago, there was some really beautiful work presented at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting by Dr Guerrero’s group with oligometastatic radiation. Essentially, they took low-volume disease and did oligometastatic radiation and were able to buy time off systemic therapy. There’s been similar work for oligometastatic progression sites. Say a patient is responding to a particular therapy and you have 1 or 2 oligo-progressive lesions controlling those. Even though we’ve had this sense for many decades that renal cell is not as radiation sensitive, that’s being turned around. There’s a role to using SAbR [stereotactic ablative radiation therapy] for these oligo-progressive diseases.

Transcript Edited for Clarity