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ESMO 2020 | PRS-343 in HER2-Positive Solid Tumors: A trial update

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Geoffrey Ku

Geoffrey Ku, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses the results of a trial (NCT03330561) which evaluates the use of PRS-343 as a therapeutic approach in multiple tumor types. PRS-343 is a bispecific molecule which binds to both 4-1BB and HER2 and enhances the recruitment of T-cells to the tumor microenvironment, which results in a localized immune response. PRS-343 was also studied in combination with Atezolizumab, which proved to be as safe as PRS-343 monotherapy, with the exception of a low grade infusion-related reaction and some mild gastric symptoms. He also explores data which supports the effectiveness of 4-1BB directed therapies, and outlines a follow-up trial which intends to use PRS-343 in combination with Paclitaxel as a gastric cancer therapy. This interview was recorded via an online conference call with The Video Journal of Oncology (VJOncology).

Transcript (edited for clarity)

PRS-343 is a bispecific construct. It’s technically not an antibody, but basically it’s a construct against HER2 and 4-1BB. So HER2 of course is well known and has been a therapeutic target for more than 20 years. 4-1BB is less well known, it’s an immune agonist molecule that spawn on excavated T cells. So essentially what this molecule does is that it brings together HER2 positive cancer cells with activated T cells, and therefore facilitates a recognition of the cancer cells by the T cells...

PRS-343 is a bispecific construct. It’s technically not an antibody, but basically it’s a construct against HER2 and 4-1BB. So HER2 of course is well known and has been a therapeutic target for more than 20 years. 4-1BB is less well known, it’s an immune agonist molecule that spawn on excavated T cells. So essentially what this molecule does is that it brings together HER2 positive cancer cells with activated T cells, and therefore facilitates a recognition of the cancer cells by the T cells. So 4-1BB antibodies actually have been looked at over the last five years and they clearly are active and are able to activate the immune system, but the major problem is that they actually have had too many side effects. Liver inflammation as a result of immune activation was a major problem with the naked 4-1BB antibodies.

So the idea behind PRS-343 is that rather than activating the immune system throughout the body, it’s really only activating the immune system around the tumor cells as well. So it was looked at in phase one studies both on its own, but also in combination with atezolizumab, which is a anti PD-L1 antibody with the idea then that we’re potentially activating the immune system through two kind of related, but separate mechanisms. So, overall I think certainly the most important take-home point is that the combination is… PRS-343 on its own, as well as the combination are pretty safe. The major toxicity that was seen with PRS-343 is an infusion-related reaction, but it’s great one to two in the majority of patients when it happens. So that was about 20%, both as monotherapy and in combination with atezolizumab beyond that there were mild constitutional symptoms and some mild gastrointestinal symptoms.

In terms of activity, I would still consider it largely to be anecdotal at this point, but certainly we’re seeing responses in patients without progression. On other HER2 therapies, most patients are heavily pretreated and when these responses occur, they’re durable. So I think it’s proof of concept that 4-1BB directed therapies can be effective and I think based on these data, the next series of studies will begin to look at specific diseases in a phase two way to try and get a stronger signal of activity. So specifically the follow-up study that’s planned will be in gastric cancer and will be in HER2 gastric cancer in the second-line setting, for which currently in the standard of care is [inaudible 00:02:50] Paclitaxel. So PRS-343 will be added to that combination to try to get a more specific assessment of its activity in that context.

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