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Expert Discusses Novel Agents in Development Targeting EGFR, HER2+ NSCLC

Nichole Tucker
Published: Sunday, Sep 08, 2019

TAK-788 is an EGFR/HER2 inhibitor that's specifically being developed for the patients with EGFR exon 20 insertion lung cancer. This is a subset of EGFR-mutant lung cancer [that accounts for] 5% to 7% of EGFR-mutant lung cancers, where our existing approved EGFR inhibitors don't work very well. TAK-788 is a next-generation inhibitor that had preclinical and now has clinical activity in this patient population.

In this WCLC meeting, we are presenting the updated poster from the ASCO Annual Meeting on TAK-788. It continues to show activity with a good response rate and the study is moving forward. It now has an expansion cohort ongoing to further enroll patients and to characterize the efficacy in this patient population. So far, it looks encouraging.

Could you discuss the safety profile for TAK-788?

As an EGFR inhibitor, this has [adverse events] that we typically associate with EGFR inhibitors. That can include some degree of skin rash and gastrointestinal toxicity, namely diarrhea. We're continuing to develop strategies to treat those symptoms at the earliest sign of their development to make the agent tolerable, because people are benefitting from it and we are seeing responses that we didn't see with the prior generation of inhibitors.

Are there any next steps with this research?

This trial has continued to accrue and there is an expansion cohort that is currently being filled. We hope to continue to see the activity that we've seen to date with this agent, and we'll see what happens from there. Again, it's been encouraging to see clinical activity in a population where we previously didn't have targeted therapies available.

Could you provide background on the phase I study exploring U3-1402 in patients with EGFR-mutant NSCLC who are resistant to EGFR TKIs?

U3-1402 is an ADC and it's specifically targeting a protein called HER3. HER3 is a protein that is expressed in the vast majority of EGFR-mutant lung cancers and it's not a mechanism that's associated with resistance to EGFR inhibitors. U3-1402 binds to the HER3 present in the cells and then it gets internalized and enters the lysosomes. Then, in the lysosomes, the conjugate part gets cleaved and chemotherapy that's linked to the antibody gets specifically released to the tumor cell. It's a selective way of delivering therapy for EGFR-mutant cancers, including those that express HER3.

At WCLC, there will be an updated presentation by Dr. Helena Yu that will describe additional patients that have been enrolled in this trial since the ASCO presentation. There will be further molecular characterization of the resistance mechanisms to EGFR inhibitors. At ASCO, we saw that the activity was not limited to one particular resistance mechanisms and we're particularly excited about that because this could be a broad-based strategy to treat a common problem, which is resistance to EGFR.

What other emerging targeted agents are you excited about for treating patients with molecularly driven NSCLC?

In the targeted therapy space, I think these are good examples because they either deal with an unmet medical need, like TAK-788, or they're novel against cancers where we commonly use targeted therapies. We historically use a targeted therapy, like a kinase inhibitor, then when a patient develops resistance, we use another one and another one. I think we need to develop complementary approaches that can treat cancers, but in a different way and by a different mechanism than that of existing inhibitors, and a lot of these agents can do that.

It's an exciting area because not only will they be effective as single agents but can also be further developed into rational combination strategies.

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