In "The Future of Anti-EGFR Therapy - Part 1" we covered some of the major ways anti-EGFR therapeutic antibodies work (“blocking the gas pedal” and “flagging the immune system”) – but there are certainly areas for improvement! Since approximately half of Stage IV colorectal cancer (CRC) patients are currently considered eligible for anti-EGFR therapy by being KRAS-wild type, any future improvements in this line of attack could have a positive impact on many thousands of patients’ lives. Scientists know this and have been working hard! As a reminder from Part 1, some issues are:

• Resistance. Unfortunately, resistance eventually develops to cetuximab (Erbitux™) and panitumumab (Vectibix™). Can new “second-line” anti-EGFR drugs be discovered which are active in these patients?
• The immune component. Can new strategies be found to more fully utilize the immunotherapy aspects of anti-EGFR therapeutic antibodies?

I wanted to describe two different experimental clinical trials which are attempting to address each of those points. Even for an “old target”, improving anti-EGFR therapeutics is a very active area of research.

Trial:  Sym004

Instead Of Just Blocking EGFR… Let’s Destroy It An experimental next generation anti-EGFR therapeutic with the code name “Sym004” is currently in a randomized phase 2 clinical trial. (NCT02083653) Sym004 is unique in that it is actually a mixture of two different next generation anti-EGFR antibodies. This mixture, acting in concert, is essentially a turbo-charged anti-EGFR therapeutic. How turbo-charged? It not only blocks EGFR (like first generation drugs do) but it actually causes its mass destruction via the EGFR being sucked from the surface of the cancer cell into the cell where it is subsequently destroyed. In preclinical test tube and mouse studies, this aspect of Sym004 not only made it more potent but also made it remain active against some of the ways in which tumors develop resistance to first generation anti-EGFR drugs. Will this preclinical research profile translate into clinical success in patients that have become resistant to first generation drugs? Recently the Sym004 Phase 1 clinical trial results were published. There were responses seen in multiple heavily-pretreated patients who had previously been on, and become resistant to, first generation anti-EGFR drugs – but the trial was small so both its activity and safety profile need to be further confirmed. There is currently a next phase trial (NCT02083653) which is randomized to test Sym004 and confirm its safety profile and activity in a larger number of patients.

Imprime PGG

Giving the Immune System Prescription Glasses One of the ways that anti-EGFR antibodies fight tumors is by engaging the immune system as immunotherapies. Essentially, they bind to the cancer cell and act as flags to get the immune system’s attention. There is disagreement among scientists exactly how much of their overall anti-cancer effect is via this immune system engagement but what is agreed upon is that this aspect of the therapy has room for improvement! You see, the antibodies may raise the flag– but a lot of the immune system really has to squint hard to see it. An experimental combination clinical trial is in progress in an attempt to address this. A specific form of beta-glucan called “Imprime PGG” is currently in a randomized phase 3 trial (NCT01309126). This trial doses both Imprime PGG with cetuximab (the combination) in patients with KRAS-wild type metastatic CRC. Imprime PGG is not intended however to attack the tumor directly. Instead it is meant to bind to immune cells like a pair of prescription glasses. In that way these immune cells can better see the cetuximab flag waving and go on the attack! Recent preclinical studies have shown even more potential ways that Imprime PGG may help the immune system out. A preliminary trial showed signs of encouraging activity but it was a very small trial. A current large randomized Phase 3 trial (NCT01309126) hopes to demonstrate safety and improved activity in a larger number of patients. So there are two examples of experimental trials aiming to significantly improve upon the activity of current anti-EGFR therapeutic regimens – one via destroying the EGFR receptor and the other via better engagement of the immune system. If either (or both) strategies succeed – patients will be the winner! Dr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV colon cancer and also a Colon Club 2016 Colondar 2.0 model. As mentioned in his introductory post, he is a Ph.D. scientist and not an M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice. He is currently undergoing cetuximab therapy. Disclosure: Fight Colorectal Cancer has received funding from companies in the form of unrestricted educational grants, including targeted therapy manufacturers Bristol Myers-Squibb and Lilly – the producers of Erbitux and Amgen – the producer of Vectibix. We maintain ultimate authority over website content and the content written in this article.

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