ASCO 2021 | First-in-human trial of an EGFR/TGFβ fusion protein for advanced solid tumors

This is an abstract, number 3074, and we will be reporting the very first data of the compound BCA101, as we pointed out, which actually hit the clinic quite recently, I mean, just really a few months ago, back in 2020. So it’s quite exciting that we generated enough data to present that at ASCO this year.

So BCA101 is actually bifunctional EGFR/TGF beta fusion protein. So, I mean, if I try to kind of explain how does it work, so it’s essentially a construct which is like a EGFR antibody. They just attach to the TGF beta trap. So, by having these two functionalities, it’s expected to inhibit EGFR, as you would anticipate from EGFR antibody, but at the same time, it’s also actually expected to inhibit TGF beta.

There are multiple reasons why this one might be important, including the data which actually suggests that some of the resistance to EGFR targeting might be actually mediated through TGF beta. So that was one of the many rationales why to put these things together. In addition to that, there is clearly demand for having better way, or more efficacious way, of EGFR targeting, given the fact that EGFR antibodies by themselves are not necessarily always very effective.

So the BCA101 actually hit the clinic, as I pointed out, a few months ago in 2020. To date, we have accumulated data on actually quite few patients, so we are presenting the data on about 33 patients, which mostly received the single agent, but some of them also actually received a combination with PD-1 antibody, pembrolizumab.

The safety profile is, so far, as we would expect with the drugs which have mechanism including EGFR/TGF beta targeting. TGF beta is usually associated with very few side effects. EGFR targeting has typically dermatitis, or skin rash if you will, which is usually acne form. And that’s actually what we have been seeing. That being said, I mean, this is typically grade one and grade two. In fact, the grade three AEs were actually very infrequent. We had one episode of grade three hypophosphatemia, which was deemed to be potentially related to the studied drug.

The pharmacokinetic data are, so far, very predictable. The drug is behaving in a way we would anticipate, so we see overall dose-proportional increase of its half-life, which is, again, relatively long, which we would anticipate for this type of agent, which is probably somewhere close to 90 hours.

So, as far as the efficacy is concerned, when it comes to the single agent, we have a broad spectrum of patients, which includes mainly colorectal cancer patients and head and neck squamous cell cancer patients. And the best response in the single agent was really a stable disease, which in several patients was maintained for more than hundred days. And some of them actually stayed on therapy for… As we speak. When it comes to the combination arm, I mean we present three patients who received combination with pembrolizumab, and one of them actually developed a confirmed partial response. It was a patient with squamous stem cell cancer, but that patient actually did not have prior PD-1 antibody tracing, it’s probably important to mention.

And we have, also, quite a extensive translational effort to look at pharmacodynamic endpoints and look at the target engagement. And so far, the data are showing what we would like to see. So, I mean, we do actually see complete sequestered response, not only TGF beta, which is encouraging, can suggest things that we do have a desired effect on TGF beta.

In addition to that, we also actually see changes in immune populations, with those proportional increase in CD3, CD4 and CD8 cells, and decrease in some of the myeloid cells, such as MDSCs, which is again what we would anticipate to see this type of approach. We also look at actually the tissue biopsies to look at the tumor of the surrogate of TGF beta targeting, and we did find that phospho-smad2, which can be used as a readout for TGF beta targeting, did actually decrease those, suggesting the desired target engagement.

So it’s all early data, obviously, but the drug already appear to be safe. I mean, we continue with the dose escalation. We haven’t reached any dose limiting problems, so the dose escalation continues. We should be pretty much close or within the active range at this point. And at the same time, we opened actually deescalation for patients taking this combination with pembrolizumab.