Earlier this year, Razelle Kurzrock, MD, an oncologist and the chief of the Division of Hematology and Oncology at the University of California, San Diego, and Shumei Kato, MD, an oncologist also at UC San Diego and colleagues published a report analyzing potential genetic biomarkers of so-called “hyperprogressors”—cancer patients who had been treated with either an anti-PD1 or anti-PDL1 antibody, checkpoint inhibitors, and other types of immunotherapy, and had what the authors described as the unexpected result of faster tumor growth and worsening disease state following treatment. Similar observations of hyperprogression had been documented and published at the end of last year by clinical researchers at the Institut Gustave Roussy in Paris, France.
-Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: Dr. Kato, let’s start with you. Could you tell us your initial experience with this phenomenon of hyperprogression?
Dr. Kato: Yes, thank you. We had a couple cases where we were puzzled whether the patients were having rapid progression from immunotherapy or just regular progression or pseudo-progression. The first case was a 65-year-old woman with endometrial stromal sarcoma who had several lines of therapy and was having indolent disease with gradual progression. We gave her nivolumab because there was some [efficacy] data of the drug with sarcoma. About a month after initiation of nivolumab, which is an anti-PD1 antibody, she developed multiple new large masses in the abdomen and existing liver metastases were also rapidly growing. The second case was a 73-year-old man, a bladder cancer patient who actually had a marker for immunotherapy response (high tumor mutation burden). At that time, atezolizumab, an anti-PDL1 antibody, had just been approved for his type of cancer, so we initiated treatment for him with the drug. However, within a few months of therapy, the patient’s clinical condition rapidly declined and repeat scans including a CT scan showed, unfortunately, multiple emerging liver metastases. So those were our first experiences [with hyperprogression]. Back then we were not really sure what was going on with these patients.
OncoTherapy Network: Dr. Kurzrock, was there any pattern that was emerging as you saw a handful of patients that looked like their disease was getting worse, as Dr. Kato just described, following treatment with one of these checkpoint inhibitors?
Dr. Kurzrock: Yes, it is very interesting about the pattern and also how this whole phenomenon emerged to us. As Dr. Kato mentioned, there were initially two patients—Dr. Kato and I share patients in the rare tumor clinic—and these two patients had pretty slow-growing disease before getting a checkpoint inhibitor. But then their disease literally exploded when they were on the checkpoint inhibitor. It was very curious because this had not been reported before and Dr. Kato and I discussed whether this acceleration or fueling of disease was real. Then Dr. Kato came back to me and said “You know, Dr. Kurzrock, did you notice that they both have MDM2 amplification?” MDM2 amplification is a specific genomic abnormality that is found in only about 5% of patients. And I thought, well, that is a little strange, what a coincidence. And then, just to tell you how this evolved, I was talking to one of my colleagues at M.D. Anderson, a physician who has also treated a lot of patients with immunotherapy, and I asked him if he had ever seen patients that looked like they got worse on immunotherapy. He said, ”Oh yes, we definitely have seen that” and I said, ”Why didn’t you publish this?” His reply was, ”I don't think anyone would believe us.” I asked him whether he did the genomics on these patients, and he told me he had one patient that came to mind immediately who had had a genomics analysis. He sent me the analysis of the patient’s tumor and the patient also had an MDM2 amplification. At that point I thought that it could not be a coincidence because this only occurs in 5% of patients, total. That led to the study where Dr. Kato and I analyzed all of the patients that we had access to who had been treated with immunotherapy at [the UCSD] Moores Cancer Center and found that both MDM2 amplification and EGFR [epidermal growth factor receptor] alterations co-related with this phenomenon of hyperprogression.
OncoTherapy Network: Dr. Kurzrock, could you describe the study that you and Dr. Kato and colleagues did in a bit more detail? How many patients were there and did you look at other genetic alterations besides the two you just mentioned?
Dr. Kurzrock: There were about 150 patients total, and really, I want to give credit to Dr. Kato for doing the bulk of the work here. We started out looking at any patients that had progressed in less than 2 months, which would be considered rapid progression. We know that physicians don’t want to take patients off immunotherapy because there have been so many positive results, therefore was any patients that were taken off before 2 months of therapy had been completed, we suspected that the physician’s hands had probably been forced. Then we looked at all of the genomic alterations and we performed a multivariate analysis, which is a statistical methodology that allows you to pick out the variables that co-relate with the phenomenon that you are looking at, and what fell out of the multivariate analysis was MDM2 amplification. The other alteration that came from the multivariate analysis was an EGFR alteration. Dr. Kato then went back and pulled all of the films, so that we could examine these patients and the explosive growth of their tumors. We had very strict criteria because one of the things we expected people would say is “how do you know that these patients’ tumors weren’t growing very quickly even before the immunotherapy?” Therefore we elected not to include any patient unless we had films from 2 months before they started immunotherapy and at baseline so we could see that the rate of growth had indeed increased at least 2-fold, and in some patients, the growth had increased 35- to 40-fold.
OncoTherapy Network: Dr. Kato, anything else you would like to add about the major findings of the work?
Dr. Kato: I think one of the key things was to compare the images pre-immunotherapy, meaning not just the baseline scan. So we usually do a scan before and after treatment, but the key was to compare between 2 months before starting the immunotherapy to baseline and then after starting the immunotherapy to figure out the progression pace.
OncoTherapy Network: Finally, it seems that there are many unanswered questions. Are there any that you and your colleagues are currently addressing on this phenomenon of worsening disease following immunotherapy?
Dr. Kurzrock: Yes, so I think there are a few important things to mention. The first was that we were almost afraid to submit the report because, as our colleague at M.D. Anderson said, we also felt that it might not be believable. Then the Institut Gustave Roussy published their report—I want to give them credit for publishing that first report—and they found that 9% of their patients were showing hyperprogression, which we think is probably very similar to our patient group. What we added is that we had the genomic correlate. What was very interesting and encouraging is that there was an abstract at the recent ESMO [European Society of Medical Oncology] Congress that showed the exact same genomic correlates, MDM2 amplification and EGFR alteration, co-relate with this phenomenon of hyperprogression. So I think that there are a few very important unanswered questions. The first is that we don't understand the mechansims, and being scientists, we’d like to understand the mechanism. We found something that we think is very important for patients but we don’t understand how that occurs so we are working with our scientists to do some fundamental research to understand the mechanisms. The other unknown is whether this occurs in all patients that have these alterations. I think that patients with MDM amplification and EGFR abnormalities are at risk, but I wouldn’t say that we think that this is universal among these patients. Another unknown is whether there is a way to overcome this. For instance, could one give a checkpoint inhibitor together with an MDM2 inhibitor, as an example, and would that mitigate whatever effect the MDM2 amplification might have [on response to the checkpoint inhibitor]? So I think this raises a lot of new questions for us.
OncoTherapy Network: Thank you so much to both of you for joining us today.
Dr. Kurzrock: Thank you!
Dr. Kato: Thank you.