Transcript

Hello, I'm Dr. Hope Rugo from the University of California at San Francisco's Comprehensive Cancer Center, and I'm going to review for you today a few different abstracts that were presented as posters at this year's virtual ASCO 2020 in order to familiarize you with some of the, I think, more important data that we understand now, based on previous studies and further analyses, and also, looking at some of the ongoing studies that may help us understand this area better.

We saw with excitement that this year we've seen approval of 2 novel agents for the treatment of HER2-positive metastatic breast cancer.

One of these drugs, trastuzumab deruxtecan, was approved in patients who'd received prior treatment in the metastatic HER2-positive setting, based on a single-arm, phase 2 trial called DESTINY-Breast01 and an unmet need. Really, a very impressive response rate, with almost all patients responding, and a very long progression-free survival (PFS), something that we really haven't seen at 16 months median.

At this year's ASCO, Shanu Modi, who published the DESTINY-01 paper that led to the accelerated approval, looked at a subset analysis, both looking at clinical markers to see whether or not there were any differences, something we're always very interested in, and also, a biomarker analysis of the 184 patients who were treated with trastuzumab deruxtecan, so to speak, and had an overall response rate of 60.9% and a PFS of 16.4 months. The median duration of response was an impressive 14.8 months as well, so very impressive.

When they looked to see whether or not there was a difference based on prior lines of therapy, they actually had a fair number of patients who'd received ≥6 lines of prior therapy in any setting.

It wasn't just a metastatic setting, but they had 76 patients there. If you looked at the overall responses, they were actually quite similar and impressive, regardless of the line of therapy. That's actually quite encouraging for us as we start using this agent in patients who'd been heavily treated with HER2-targeted therapy and chemotherapy.

They also looked at a univariate analysis between clinical variables and overall response, duration of response, and PFS, and none of the standard clinical variables made any difference; everybody responded relatively similarly.

They looked at once interesting area, which I think is fascinating, which is the HER2-IHC status. What they saw was that the IHC status didn't make a big difference. Everybody, of course, had to have HER2-positive breast cancer.

They looked at the mutational landscape as well, which I don't think helps us too much in selecting therapy for the patients. They looked at the ERBB2 plasma copy number and the HER2 extracellular domain levels, and then looked at response.

What was interesting to see was that patients responded regardless. You might have guessed that this would be the case, because we have seen that this particular agent, trastuzumab deruxtecan, seems to have efficacy in a, again, single-arm, much smaller trial in patients who have so-called HER2-low disease.

So, IHC1 and 2 plus, but not amplified by FISH. There's an ongoing randomized phase 3 trial looking at this trial population now we're very excited about to try and expand the use of agents like this, using the so-called bystander effect.

This goes along with what they showed in the subset analysis, where the majority of patients responded, and it didn't really matter whether you had a lower copy number, a higher copy number, or different extracellular domain levels, which we looked at very early on in the development of HER2-targeted therapy with trastuzumab.

They also looked at a variety of gene alterations, which weren't particularly helpful. But I thought that the most interesting data this entire poster showed (because I did expect, based on the original data, that they wouldn't see a specific category of patients who did benefit more or less, and in fact, that's the case - everybody seemed to benefit) what they looked at was ERBB2 plasma copy number over time by patient response and PFS.

What they saw was fascinating, and it's worth taking a look at figure 6 in this poster, where you see this huge drop in the ERBB2 plasma copy number in almost all patients, and there was a small number of patients who had continued evidence of amplification at cycle 4, day 1.

What we learned was it didn't matter how much amplification you had on cycle 1, day 1. Most people responded, as you would expect in a trial where the majority of patients have a shrinkage of their tumor lesion. I think some tiny number of patients didn't have any shrinkage in the results from the DESTINY-01 trial. The people who did not (so, at cycle 4, day 1, the patients who had persistent ERBB2 plasma amplification) had a much worse PFS and a lower response, which is very, very interesting.

This is actually the first time we've seen this marker, almost like looking at ctDNA or CTC clearance, and that may be very useful for us while we're monitoring patients and thinking about other treatments or adding on other therapies as we move forward.

In any case, that's the first time we've seen that, and I think that that's really interesting data. We're looking forward to seeing the data from the registration trial, which would lead to final approval of trastuzumab deruxtecan, which is comparing TDM1 to trastuzumab deruxtecan in patients in the mostly second-line metastatic setting.

That trial has been accruing, and we hope to see results. I expect to see results in the next year or 2 at the longest, maybe next year. We'll see what happens with that very interesting data.