Stopping Immunotherapy Doesn't Stop Benefit

Jeffrey S. Weber, MD, PhD


October 10, 2016

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Hello. This is Dr Jeffrey Weber. I am the deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center. Today we will be talking about a couple of very interesting abstracts, one of which was recently presented at the European Association of Dermato-Oncology (EADO) meeting in Vienna. The other was presented at the relatively recent American Society of Clinical Oncology (ASCO) meeting in Chicago. Both relate to what happens when patients stop immunotherapy. In longer-term follow-up, what is the likelihood that patients will progress and do poorly? The data are very interesting.

The first abstract [that I want to talk about] was presented by Dirk Schadendorf from Essen, Germany, at the EADO meeting.[1] He presented an assessment of a number of patients pooled from two randomized trials. One was the BMS069 trial, which was a trial of ipilimumab plus nivolumab versus ipilimumab alone. The other was the CheckMate 067 trial, in which patients were treated with either ipilimumab plus nivolumab or either drug alone.

Both were large, well-powered trials, and the pooled analysis related to the patients who had combination ipilimumab and nivolumab. A total of 176 patients stopped treatment because of immune-related adverse events, obviously a significant proportion of patients at well over 30%. What happened to those patients during follow-up? The follow-up was fairly long: 21.3 months on average. Of the 242 patients who did not stop because of toxicity, there were more patients who had elevated LDH, either above normal or above twice normal. Otherwise, the patients were fairly well balanced.

The amazing thing was that the patients who had stopped because of toxicity clearly did better in terms of response. We are talking about 68% versus a 50%-plus response rate, and a median progression-free survival of 16-plus months versus 10.8 months. For those two significant clinical parameters, those who stopped did better than those who did not.

It appears that if you stop because of toxicity, you are still going to do very well clinically.

In contrast, it appears that about 68% of those who stopped because of toxicity stayed in remission compared with a whopping 80% of those who did not. In the aggregate, it appears that if you stop because of toxicity, you are still going to do very well clinically. We will see the mature survival data next year, hopefully, but so far this is very promising. We can assure patients who stop early—and in this trial it was after only a median three doses of combination therapy—that if they have toxicity, they are still going to do very well compared with those who do not stop.

A somewhat similar abstract[2] was presented by Caroline Robert from the [Institut] Gustave Roussy in Paris at the 2016 ASCO meeting a couple of months ago. She looked at patients who actually had a complete response and stopped because of a planned discontinuation of therapy. There was also a small group of patients who stopped because of toxicity. This was a pembrolizumab-alone trial. Again, the likelihood of significant toxicity leading to discontinuation was low. In fact, there were only 16 patients in that trial who had a complete response (CR) and stopped because of toxicity or other reasons. About two thirds of them, just like in the pooled ipilimumab/nivolumab trial, stayed in remission, which is quite encouraging. A total of 61 patients had CRs in that study. Fifty-nine of them, with a median follow-up of more than 1.5 years, have remained in remission, which is very impressive and speaks well to those who have a CR to checkpoint inhibition, this time with single-agent pembrolizumab. It would suggest that those patients are going to do very well in the long term.

As we have discussed, maybe now for the first time we can begin to think of the "C" word, the cure for these patients. At any rate, we can certainly tell our patients that achieving a response in the face of therapy and then stopping would suggest that you are going to do very well. Although analyses have not shown an obvious relationship between any toxicity and doing well, stopping or going on immunomodulators does not compromise your ability to have a good response. If you get a CR to pembrolizumab or nivolumab or the combination, you are probably also going to do very well in the long term.

Please feel free to write in with questions. This is Dr Jeffrey Weber. Thank you for your attention.


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