Impact of adjuvant therapy on treatment choice in advanced RCC

Tian Zhang, MD: Dr. Braun, how has the use of adjuvant therapy influenced our treatment decisions and subsequent therapy, especially patients progressing after adjuvant pembrolizumab?

David Braun, MD, PhD: That’s an excellent question. To tell the truth, it is a difficult question. I don’t think we know the answer. There are a few general principles we can think about, but for someone who has progressed with adjuvant pembrolizumab, we don’t have the data to know what’s the best thing to do. I have spoken to many colleagues, and some invoke the platinum paradigm: platinum sensitive, platinum resistant, or platinum refractory depending on when progression occurs. I’m not sure that biologically there’s the same connection between immunotherapy and cytotoxic chemotherapy, but in the absence of a better paradigm, it’s a very reasonable approach.

[There are a couple of] factors that I would take into account. First, when did the progression occur? Is someone who is actively taking pembrolizumab and whose progression occurs during treatment? It’s a very different story than someone who received adjuvant pembrolizumab and then progressed 5 years later. These are very different stories that would factor differently in my mind as to how I view them as susceptible or resistant to anti-PD-1 therapy. Obviously, there is quite a spectrum between the two. The second part is, how fast is the progression? Is this a situation with a relatively modest progression? She was found radiographically but not symptomatically. Or is it symptomatic progression? There is an impending visceral crisis, where you must maximize a response. This might guide you to think about combination therapies as opposed to a single agent.

Another important patient-specific factor is, how did the patient tolerate the immunotherapy? How did the patient tolerate pembrolizumab? Was it a relatively easy treatment? Are there many adverse events related to the immune system? Some of them are substantial. This might help us think about how much we are pushing more immunotherapy and in what setting. These are the general principles I would use, and I don’t think there is a perfect answer. My thought process for today…is if anyone had this progression on pembrolizumab – it was during this one year treatment period and progressed – I would be more inclined to switch to TKI [tyrosine kinase inhibitor]– basic treatment, considering more progression on the equivalent of first-line anti-PD-1 monotherapy.

For patients who are the opposite – they received treatment with pembrolizumab, and years later they relapsed – I am more inclined to treat them the same way I would treat a naïve patient. I would be more inclined to use an initial combination based on immunotherapy. For those in between, that’s where the patient factors come in. Is something that requires rapid progression, so I have to put everything I can into it to try and maximize the chance of a response ? Is this a slow progression, for which I could think of an I/O combination [immuno-oncology]– therapies based on the possibility of a lasting response? We’ve seen it with something like nivolumab-ipilimumab. This is where these 3 factors – timing of progression, speed of progression and tolerance of previous treatment – will play a part.

Tian Zhang, MD: Perfect. It is comprehensive in terms of thinking about toxicities, timing of progression, and mechanisms. It was a wonderful discussion. Thank you so much.

This transcript has been edited for clarity.

Martin E. Berry