Immuno-Oncology Determining Optimal Treatment Duration - Allison Betof Warner, MD

Balancing the challenge of determining the optimal duration of cancer immunotherapy, especially with durable responses, poses questions about when and how to discontinue treatment, exploring possibilities to avoid toxicity and healthcare costs, drawing insights from studies like Keynote 001, real-world analyses.


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By: Allison Betof Warner, MD, PhD, Stanford
Date: 11/13/2023


Immuno-Oncology Determining Optimal Treatment Duration


The question of how long to treat patients is one of the more challenging ones in our field. It's always wonderful when our patients are responding.  Classically in oncology, we kept patients on treatment indefinitely in the days of chemotherapy and even targeted therapy. Um, but we really feel that the immune system can learn to take care of a cancer itself from immunotherapy.

And all of the data have suggested that over the years. the question is, how do we pick which patient is the right patient to discontinue? Um, and at what time point? And so the earliest studies, you know, planned immunotherapy indefinitely, then many set a cutoff of two years as a stopping date. And that's really when, you know, where most of the data lie at a two year stopping date.

And what we've seen is that patients really do quite well, particularly the patients who have a complete response or a deep partial response. They really do quite well if they discontinue treatment after two years.  The question lies in can we stop earlier, right? Trying to avoid toxicity. Certainly trying to avoid the cost of treatment both for patients and for the healthcare system.

Um, you know, we are running into the issue of not enough treatment beds, not enough treatment chairs as a healthcare system. Um, certainly as well as the high dollar cost of these medicines. So if we could safely discontinue patients earlier that gets them back to their life. That, you know, reduces the risk that they will develop a new side effect late, although that is somewhat uncommon, but certainly saves us and the healthcare system a lot of money, um, time, hassle, time away from work, et cetera. 

Um, there are several studies trying to examine this question, but really right now we're very reliant on retrospective data looking at what's been done, you know, across systems. And so we've looked back at certainly those clinical trials that planned stopping at two years and we know, as I said earlier, that patients who have a complete response and even patients who have a deep partial response have excellent outcomes.

You know, two, three, five years later, um, But what is harder is in a real world population, in a population outside of a clinical trial who didn't have a perfectly prescribed course. So my group published on this a few years ago looking at 102 patients who had a complete response who were not treated for a planned two years, but that actually the vast majority of those patients discontinued treatment.

right after they had a complete response. Um, this was a single center series, and so it's certainly not comprehensive by any stretch of the imagination. But those patients did quite well long term as well, maybe not quite overall as well. But in a real world population, 75 ish percent of them still had not required additional treatment years down the road. 

Overall, we are looking at prospective clinical trials to try to answer this question. There's an ongoing trial called Pet Stop, uh, led by Jeff Gibney at Georgetown University. Um, that is doing a plan stopping of treatment at a one year. If patients have a negative. PET scan or a PET scan that's positive, but the biopsy shows no viable disease and then following outcomes and recurrence for those patients.

Um, and some randomized trials that are occurring internationally that I think will help us define this better. But at this point, I'm counseling my patients, you know. That all of the data suggests that if you're tolerating treatment well, we stay on somewhere between one and two years. And then we plan to stop at that point.

Can you provide insights into the challenges and decision making process in defining the duration of therapy, especially when faced with durable responses, as seen in the Keynote 001 study?  Yeah, so the keynote 001 study looked at single agent pembrolizumab for the treatment of advanced unresectable melanoma. 

And the vast majority of those patients were treated for about two years. The median duration on treatment was 23 months.  And what they saw was patients who had a complete response in that study, years later, 90 percent of them still had not required any additional treatment after stopping at that median of 23 months.

So that provided a lot of reassurance that at least some patients and our best responders can safely discontinue treatment. Your presentation highlighted the results of real world studies on the duration of PD 1 therapy for melanoma, showing a median time on treatment of 9. 4 months with a 3 year treatment free survival of 72.

1%. How do these findings align with or differ from expectations based on clinical trial data? Yeah, so... This was a single center study that I conducted when I was at Memorial Sloan Kettering, um, of 102 patients who had a complete response. And at that time, there was a big push to discontinue treatment as soon as possible.

Right, we'd swung from keep patients on treatment forever, or... You know, long periods of time to get them off treatment as soon as they're responding very well to try to avoid side effects and long term type and long term toxicity.  And so  the median time on treatment in those patients was actually about nine months.

So much less than clinical trials that pre specified patients would stay on for two years.  Um, and the median time on treatment after a complete response was actually zero months. So many patients stopping right around the time of their complete response. Now some of those patients stopped for toxicity, so that is unavoidable, but many opted to stop treatment because of that complete response at that time.

This was not a prospective study, this was just a retrospective look at those patients. Um, But overall, you know, at three years, 72 percent of those patients still had not required additional treatment. That is not the 90%,  for example, or 88 percent that we saw from Keynote 001, but still a really excellent percentage of patients who were spared quite a bit of treatment.

Um, One of the keys to understand, though, is that we don't know  if the difference is just a difference in the patients or a difference in the duration that they were treated, right? A real world population typically performs differently than a clinical trial, even if they got exactly the same treatment.

So these retrospective analyses, they're helpful and they're the best data that we have right now. But we can't just extrapolate from that and say, well, they got shorter duration of treatment and, you know, a higher percentage of them recurred. So longer is better. I think that's a really important point.

This, these are hypothesis generating. Then we need to do the prospective clinical trial that answers this question.  Could you provide more details on the PET STOP study, the key objectives, and any preliminary findings that may shed light on the optimal treatment duration in advanced melanoma? The PET STOP study is led by my colleague and friend, Jeff Gibney, at Georgetown University, but it's a cooperative group trial taking place across the United States.

This trial enrolls patients, um, who have had a... complete response at one year. So you get a PET scan. If the PET scan is absolutely negative, patients have a planned stop of treatment. If the PET scan is positive, you then do a biopsy. If the biopsy does not show any viable melanoma, those patients stop treatment.

If there is viable melanoma, the patients stay on treatment for another year.  It's a non randomized trial. It's a single arm. Um, and the, uh, end point here is progression free survival. This is, you know, Attempting to look at can we stop at one year, at least for these best responders, these complete responders, rather than keeping patients on for a total of two years.

I would say it's still too early to talk about results yet.  actively accruing and we are looking for more sites across the U. S. Really trying to get these patients so we can categorize and really know how to advise our colleagues and our patients about best discontinuation.  But at this point, still a bit too early to talk about data.

Your presentation touched on the other study and the prospective trial checkmate 1 53 in non small cell lung cancer. Can you discuss the challenges and insights gained from these different cancer types and the influence on immunotherapy duration in oncology? You know, the other study is a meta analysis.

It's a retrospective look at all of the studies that have been done across different cancers.  So, while these can be helpful, they're still limited by the fact that this was not a planned analysis. Um, and the biggest thing that we saw from the other study was there wasn't a strong, strong signal that staying on treatment was better for any cancer, um, you know, beyond at least the two year mark, which was the cutoff that was used in that study.

Other than that, I think it's really hard to draw conclusions. The confidence intervals are very large from that study and, you know, without a prospect  It's very difficult to really make clear treatment recommendations based on that. Checkmate  153 was a prospective randomized trial in non small cell lung cancer that randomized patients to getting treated for one year versus continuous treatment.

Um, In that study, patients who were treated for longer actually did better in terms of progression free survival and event free survival. Um,  can we take that as gospel across all cancers, even across non small cell lung cancer? Probably not, but it is the best prospective data we have that does certainly raise questions about whether one year is sufficient, at least in an all comers population.

Now, had we broken that down by just... complete responders and stopped at one year. Some of those subgroup analyses were done, but that was a relatively small trial, um, to do that. I think it also, you know, many of us have used a two year cutoff rather than a one year cutoff, um, and advise our patients who have excellent responses to do two years of treatment.

And so, you know, certainly that trial does not answer the two year versus one year. question. It was indefinite versus one year. Um, but I do think it is an example of the type of trial that we need to truly answer this question. But it's important to know that non small cell lung cancer may be different from melanoma, may be different from renal cell cancer, and we may truly need to do these trials across all of our tumor types to really understand how to best counsel our patients.