Promising Treatments for Glioblastoma Are Emerging

ABT-414, an antibody drug conjugate, showed promising results for patients with EGFR-amplified, recurrent glioblastoma (GBM), according to a phase 1 trial.

Lead author Martin van den Bent, M.D., Ph.D., of the Erasmus MC Cancer Center in Rotterdam, the Netherlands, is presenting the findings during the 21st Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology (SNO) being held Nov. 17-20, 2016, in Scottsdale, Arizona.

Can you provide some highlights of the ABT-424 trial that you are presenting at SNO?

In an interview with CURE, van den Bent discussed the trial’s significant findings, that agent’s toxicity profile, and what lies ahead for the investigational agent.ABT-414 is an antibody drug conjugate directed against the activated EGFR receptor, and attached to it is a very strong, very potent cytotoxic agent, monomethyl auristatin F (MMAF). This compound is not like what we have done in the past with Tarceva (erlotinib) or Iressa (gefitinib) to inhibit EGFR signaling, but rather, to use EGFR to activate the EGFR receptor to get a very strong potent toxic into the tumor cell.

What is the mechanism of action for this drug?

We have been conducting a phase 1 study as part of a larger effort to evaluate the activity of this compound. What we are now reporting is the expansion phase of a group of recurrent GBM patients all with EGFR amplification, so all with targets present. What we are showing here is that if you treat these patients at first, second, or third relapse, we get a six-month progression-free survival (PFS) rate, which is in the area of 35 percent, which is sizable, as we know that passing the 20 percent six-month PFS rate typically implies that you are looking at something that is active and worthwhile for further investigation.In the past we have been using drugs like Iressa, Tarceva or Rituxan (rituximab), which were either small-molecule inhibitors targeting kinase inhibitors or monoclonal antibodies directed against the receptor. What we tried to do with those approaches is to inhibit the signaling, the downstream signaling of the EGFR receptor. All the trials, however, have been negative and there is no reason to assume that any of the other EGFR-inhibiting agents will yield a different result.

What else have you learned from this trial?

It is important to realize that although a GBM patient often has EGFR abnormalities, amplification or mutations, these are all in the extracellular domain. And from the other tumor types we know that Tarceva, Iressa work, in particular, with a completely different type of mutation. So using these agents to downregulate EGFR pathway signaling is not going to work. We need another approach. ABT-414 is a different approach as we are using a sort of Trojan horse concept to use the receptor to get the cytotoxic inside a tumor cell.What we see in more detail is that we typically do not see a response rate in GBM. We don’t see a clear survival signal, which is not unanticipated as we know that only a minority of the patients seem to respond. But we do see a 25 percent six-month PFS rate, and that’s of pivotal relevance here. We did a phase 1 study, an expansion cohort of a phase 1 study, and it shows that the signal that we see in this expansion cohort warrants further investigation. And we are actually doing that.

What about the safety profile? Is it any different from other known drugs in this class?

Does the risk of this toxicity outweigh the benefits?

There is a trial ongoing in recurring GBM, and there is another trial ongoing in the frontline setting, in which the activity of ABT-414 is investigated in newly diagnosed patients. With these two studies together, we will get a clear readout of the activity of ABT-414 in this setting. But we have to be smart about giving it to EGFR-amplified patients. We have to understand which patients are responding to this treatment and who are resistant, since it is clear that not all patients are alike with this compound.The toxicity profile is definitely different. There is eye toxicity of a type that we in neuro-oncology have rarely seen. One-third of patients get ocular toxicities, which comes down to a keratitis, an irritation of the eye. It feels like dry and burning eyes for the patient, and if severe, may even decrease vision, a toxicity which does not appear to be specific to the ABT-414 construct. That is really an issue. We have to make this drug acceptable for patients. We have to find ways of modifying the ocular toxicities; outside that, however, it is a very well-tolerated drug.It would be better if we see less toxicities, so this is what we have to work on. The signal that we now see in patients with this drug clearly warrants further clinical investigation. And along those lines, other compounds with similar mode of action but less toxicity might be something that needs to be developed, but that is for the future.