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

Nichole Tucker

Pasi A. Janne, MD, PhD, from Dana-Farber Cancer Institute

Pasi A. Janne, MD, PhD

In the treatment of non–small cell lung cancer (NSCLC), there remains a need for more targeted therapies for patients with EGFR-mutated and HER2-positive disease to fill areas of unmet medical need, including targeting uncommon mutations as well as mechanisms of resistance. At the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, one investigator spoke to and participated in several studies that aim to address these areas of unmet medical need with the use of novel agents.

“One of the challenges is that for our existing EGFR-targeted therapies, patients develop resistance, especially to drugs like osimertinib [Tagrisso]. There continues to be a need to develop new and novel therapies to overcome resistance,” said Pasi A. Janne, MD, PhD, director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School.

One such form of targeted therapy that has shown promise in treating patients with lung cancers are antibody–drug conjugates (ADCs). In EGFR-mutant NSCLC, the emergence of the ADC U3-1402 is causing excitement with early results due to its ability to target the HER3 protein and initiate a disease response in patients who are resistant to tyrosine kinase inhibitors (TKIs). An anti-AXL ADC is also generating interest in treating patients with pretreated NSCLC because AXL overexpression has been associated with resistance to common lung cancer treatments, and the ADC acts as a way to get the AXL directly to the tumor. ADCs may also be active in patients with HER2-positive NSCLC, a tumor type where no approved agent currently exists.

New TKIs in development also show promise for targeting areas of unmet need, including the investigational EGFR/HER2 inhibitor TAK-788. The inhibitor has shown promise in treating patients with EGFR exon 20 insertions, an uncommon EGFR mutation that has traditionally been difficult to treat.

In an interview with OncLive during WCLC, Janne discussed these 3 studies of novel agents for targeting EGFR-mutant and HER2-positive lung cancers and the next steps in getting the research to cancer clinics.

OncLive: What novel agents have been introduced recently that look promising for patients with EGFR-mutant or HER2-positive NSCLC?

Janne: One of the challenges is that for our existing EGFR-targeted therapies, patients develop resistance, especially to drugs like osimertinib. There continues to be a need to develop new and novel therapies to overcome resistance.

Some of the new agents that have entered the clinic include next-generation inhibitors, including ADCs like U3-1402. There are [also] other ADCs. The goal is to match the molecular determinant of resistance with a strategy to overcome resistance.

For the HER2 patient population, this is an area where we need a targeted therapy. We don't have an effective targeted therapy and we're hoping that there will be one that will come to the clinic. There are ones being evaluated, specifically HER2 ADCs, including DS-8201a.

What are the key takeaways from the presentation on the anti-AXL ADC?

AXL is a resistance mechanism that happens [with] EGFR kinase inhibitors as well as other targeted therapies. This trial, using an AXL ADC is trying to evaluate the strategy of using the expression of AXL as a means of delivering an ADC specifically to those tumors.

I think the early clinical data look encouraging. There has definitely been some activity there. The opportunity now is to figure out the correlation of the expression of the target and the efficacy. That will continue to happen through the clinical trial as it moves forward.

Are there any ongoing challenges or unmet needs in this patient population?

The same population that is resistant to targeted therapies is the same population being tested here. This is not just EGFR-mutant patients, but others as well. I think once we run out of our approved kinase inhibitors, we are challenged with the fact that resistance emerges and we need to develop a therapeutic approach. I think the goal will be to develop specific therapeutic approaches against specific resistance mechanisms, as opposed to using chemotherapy more broadly. This is a population that continues to need new treatment options.

Could you also discuss key takeaways from the presentation on TAK-788 in patients with NSCLC harboring an EGFR exon 20 insertion?

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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