Pooled Analysis of Neoadjuvant Therapy

Transcript: Jeffrey S. Weber, MD, PhD: And there was actually a compilation done, meaning a whole series of studies, and I think that’s an oral presentation. Hussein, what do we know about this compilation from this large group of neoadjuvant investigators?

Hussein A. Tawbi, MD, PhD: Actually, let me just back up a little bit. Again, remember what Vernon said. Those are patients who come to us with bulky nodal disease that’s either clinically detectable or on CT [computed tomography] scans, and those are patients with an extremely high risk of recurrence. And suddenly in melanoma we have the opportunity of having effective therapies in our hands, and so multiple institutions across multiple countries started some of these neoadjuvant trials. Again, we, at The University of Texas MD Anderson Cancer Center, did the neoadjuvant dabrafenib-trametinib trial, or we compared it with actual surgery and proved that there’s a 60-fold improvement in the relapsed-free survival.

Other collaborators have done immunotherapy-based trials, either of single-agent pembrolizumab, single-agent nivolumab, or ipilimumab-nivolumab, so we all actually collaborated on a 1-on-1 basis together, and at some point we realized that we actually can all come together and think about what would be the best way to conduct those trials and actually standardize the ways we conduct those trials. We even assess the pathologic complete response [CR] rate. This International Neoadjuvant Melanoma Consortium was formed a couple of years ago to kind of think through those issues and kind of help the field harmonize the approach. One of the first outcomes was actually a white paper describing for pathologists exactly how you classify a pathologic complete response, how you actually take the tumor, cut it and look at the slides and say, “This is what a pathologic CR looks like. This is what a partial response looks like.”

The other piece of this was the fact that all these different institutions have conducted their individual trials, but there were quite a few, or a lot of similarities in how we did it. So you know how many weeks you treated ahead of time and how long you followed the patients after. We felt actually compelled to pull all that data together. And in fact at this ASCO [American Society of Clinical Oncology] Annual Meeting, 184 patients who were treated in all these individual trials were pooled together and looked at as an aggregate. And it was really fascinating to see because there was a pathologic complete rate of actually about 40% across the board.

This is actually also with a reasonable follow-up of around 15.2 months, which for this population you would expect a loft of the events to happen. And it actually allowed us to look at maybe the differences between targeted therapy versus immunotherapy. And it was really remarkable to see that patients who achieved the pathologic CR in general, whether with immunotherapy or targeted, did really well and had very few events of relapsed-free survival. And then if you looked at the pathologic CR from immunotherapy alone, 51 patients actually had a pathologic CR from immunotherapy alone. Not a single 1 of them has recurred.

Jeffrey S. Weber, MD, PhD: What kind of follow-up are we talking about?

Hussein A. Tawbi, MD, PhD: It was 15.2 months, which again, for this population, is a perfectly appropriate time to see relapses. With targeted therapy, the patients who did that had a pathologic CR rate and really did pretty well for this particular population, but there were some relapses, actually about 7 of 17 patients. So a little less kind of robust. And then when you compared the nonpathologic CR again, the patients who did not achieve a pathologic CR with targeted therapy kind of did the worst essentially.

Jeffrey S. Weber, MD, PhD: The last thing we’ll hear about is there are even neoadjuvant T-VECs [talimogene laherparepvec therapies]. Just in a few words, Jason, can you tell us about the T-VEC neoadjuvant study.

Jason J. Luke, MD, FACP: Yes. So just remember that talimogene laherparepvec, or T-VEC, is the oncolytic virus that we directly inject into tumors. It is currently approved in the advanced disease setting. An obvious thing to do with that would be to say, “Oh, well, there’s a bulky melanoma. Why don’t we inject it before the surgery to shrink it?” And so, similar to these neoadjuvant studies, T-VEC has been explored in that area. There is an updated abstract in that scenario. Again, a few doses before going to surgery does suggest that you can improve relapse-free survival, but I think with the caveat that not nearly as robustly as we are hearing about with the targeted agents or with immunotherapies.

It was interesting to note that there were actually substantially fewer patients who made it to surgery. It was 75% versus 96%. So 75% of the patients who got the T-VEC made it, which kind of sounds good until you realize that everyone should have had surgery. So that was a little bit of an outlier. And then instead of hearing about 70% at 1-year relapse-free survival, now we’re talking about 50%. I really think that while it’s an interesting agent, that theoretically it could be used this way. If we’re going to consider neoadjuvant therapy, I really think we should think about using the active agents that are systemic agents that we know can be effective.

Transcript Edited for Clarity