Adjuvant therapy treatment approaches for patients with advanced clear cell RCC

Adjuvant therapy treatment approaches for patients with advanced clear cell RCC

Dr Nizar Tannir: We’re going to end our program with a discussion of the KEYNOTE-564 data, what it brings, and how we think about adjuvant therapy. Does 1 year of pembrolizumab for patients who qualified for that trial (pembrolizumab for 1 year instead of placebo) cure patients who otherwise would not have been cured had they not received adjuvant pembrolizumab for 1 year and would not have been saved by the doublet? ? or triplet later, when they were repeated? Or are we simply delaying the recurrence? This is a question I am still grappling with. I have that discussion with patients. Obviously, these are important data. There is a trend towards the operating system [overall survival] with pembrolizumab over placebo of the Kaplan-Meier curves, but I’d like to get your opinion on this, starting with Moshe. What do you think? How are you interpreting the data? What are you telling your patients?

Moshe Ornstein, MD, MA: It’s a great question. When it comes to adjuvant therapy in general, it’s a complicated issue because there are patients who are cured by surgery alone, even if they didn’t get any therapy, and we’re overtreating them by giving them therapy. On the other side of the spectrum, there are patients who are still going to have a recurrence possibly at the same time and still have the same endpoint in terms of survival, even if they receive adjuvant therapy. We are looking to see if we can isolate those patients for whom there is a tangible benefit not just in DFS [disease-free survival] but also in the operating system.

My approach since it was approved is that for high risk patients and M1 NED [no evidence of disease]Recognizing the relatively small numbers, these patients should receive or at least be seriously considered for adjuvant pembrolizumab. I’m giving it as a standard for those patients. Certainly, we are hopeful that the benefit of the operating system will go from being just a trend and translate into a significant benefit, although it will take time to mature. This is an I/O [immuno-oncology] and systemic therapies have improved over time, meaning it is more difficult to find endpoints for survival in an adjuvant setting where many patients are already cured.

For patients who are intermediate-high risk, who were not the majority of patients, I talk about the fact that there are those 2 ends of the spectrum. It is important to consider the patient’s perspective. Many patients think, “If I have a recurrence in 2 years and die of the disease without taking an approved immunotherapy in the adjuvant setting, how am I going to feel about myself as a patient and about the oncology team?” That’s a real consideration, because we don’t know, and there’s a chance that the OS benefit will work.

This is different from the S-TRAC study, where the curves completely overlapped. The long-term benefits of immunotherapy may take time to mature. Even in the high-intermediate risk group, most patients have chosen to receive adjuvant pembrolizumab regardless of their risk. I’ve been giving it to most patients. I will generally give it unless a patient is concerned about toxicities after we discuss them. I think the tag is very broad in terms of what they allow in the helper configuration. I don’t think it’s as specific as the inclusion criteria in KEYNOTE-564. I am concerned that there may be patients with [much] lower risk that they might receive adjuvant therapy due to a doctor’s temptation to do something and a patient’s temptation to receive something to feel like they are doing something. But in general, for patients who would have met the inclusion criteria for this trial, I offer it as an option, and most patients choose to receive it.

Dr Nizar Tannir: To follow up on that question, I have 2 questions for you, Moshe. What therapy will you give to that patient who accepts your recommendation to receive adjuvant therapy? If you give them pembrolizumab for 1 year and then they relapse, are you concerned you’re compromising their response to subsequent immune checkpoint therapy?

Moshe Ornstein, MD, MA: The short answer is that we don’t know the answer. Over time, we will get follow-up data from KEYNOTE-564 on subsequent therapies. In terms of my practice, I have not seen a patient with explosive disease while receiving pembrolizumab in the adjuvant setting, but the decision about what to do for subsequent treatment will depend on two main factors. One is the timing of recurrence: whether it’s immediate while they’re on therapy, shortly after stopping therapy after a year, or 3 or 4 years later. Those patients would be treated differently. Also, some of this has to do with the nature of the recurrence. Do they recur through a couple of small pulmonary nodules that suddenly meet the criteria for PE? [progressive disease]? Or are they recurring because they suddenly have a lot of bone metastases or new liver metastases? I would treat both differently. Frankly, I haven’t dealt with it much because it’s still relatively new, but the timing and nature of the progression will determine subsequent therapies in my clinic.

Transcript edited for clarity.

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