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New Targeted Therapies for EGFR-mutated and HER2-positive NSCLC Have Emerged

By Conor Killmurray
PUBLISHED WEDNESDAY, DECEMBER 31, 1969
Targeted therapies have changed the landscape for patients with cancer, yet there remains a need for the development of even more novel agents. Specifically, a large need exists for patients with EGFR-mutated and HER2-positive non-small cell lung cancer (NSCLC) to help overcome resistance, according to Pasi A. Janne, MD, PhD.

“[In the case of these diseases], one of the challenges is that for our existing EGFR-targeted therapies, patients develop resistance, especially to drugs like osimertinib (Tagrisso),” said Janne, 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, both in Boston.

During the 2019 World Conference on Lung Cancer (WCLC) in Barcelona, Spain, Janne discussed multiple studies aimed to address the unmet medical needs of patients with these mutations. Three novel agents are currently being examined in clinical trials that target EGFR-mutant and HER2-positive lung cancers via antibody-drug conjugates (ADCs) and new developments in tyrosine kinase inhibitors (TKIs). In an interview with OncLive®, a sister publication of Oncology Nursing News®, he explained how they work in treating patients with NSCLC.

U3-1402 is an ADC that targets HER3—a protein that is expressed in the majority of EGFR-mutant lung cancers—and can initiate a response in patients resistant to TKIs. “U3-1402 binds to the HER3 present in the cells and then it gets internalized and enters the lysosomes,” Janne said. “Then, in the lysosomes, the conjugate part gets cleaved and chemotherapy that's linked to the antibody gets specifically released to the tumor cell.” Also exciting about this agent, he said, is that it’s not limited to one resistance mechanism and possibly could be part of a broad strategy to treat resistance to EGFR.

The anti-AXL ADC is being examined in patients with pretreated NSCLC as AXL overexpression is associated with resistance in lung cancer treatment. The ADC gives the AXL a pathway directly to the tumor. Although the clinical data presented looks promising, there is still room to improve as researchers must determine the correlation between the expression of the targeted tumor and the agent’s efficacy. Both U3-1402 and anti-AXL ADCs may prove active for patients with HER2-positive NSCLC, currently a tumor type with no approved targeted agent.

The third agent under review, TAK-788, is an EGFR/HER2 inhibitor that is being developed for patients with EGFR exon 20 insertion lung cancer, a subset that makes up 5%-7% of EGFR-mutant lung cancers. Currently approved EGFR inhibitors don’t work well with this population, which is where TAK-788 has come in. “TAK-788 is a next-generation inhibitor that had preclinical and now has clinical activity in this patient population […] people are benefitting from it and we are seeing responses that we didn't see with the prior generation of inhibitors,” he said.

All 3 of these agents remain under study and, in the meantime, patients with either of these diseases have to contend with the current targeted therapies where resistance is emerging.

“The goal will be to develop specific therapeutic approaches against specific resistance mechanisms, as opposed to using chemotherapy more broadly,” Janne said. “This is a population that continues to need new treatment options.”

A version of this article originally appeared on OncLive as “Expert Discusses Novel Agents in Development Targeting EGFR HER2+ NSCLC
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