Dr. Yasir Elamin reviews key considerations for treating patients with HER2-mutated lung cancer, including the high frequency of CNS metastases and the importance of selecting therapies with demonstrated intracranial activity. He emphasizes comprehensive next-generation sequencing for all patients with lung cancer so actionable HER2 mutations can be identified and incorporated into treatment decisions. He also examines emerging sequencing strategies among HER2-directed TKIs and T-DXd, including evidence that agents with different mechanisms of action may retain activity after prior HER2-directed therapy. Dr. Elamin highlights the need for stronger data when sequencing therapies with similar mechanisms, while supporting T-DXd as a reasonable option after prior TKI treatment.
Transcript:
Dr. Elamin: My name is Yasir Elamin, I’m an associate professor of thoracic medical oncology at MD Anderson Cancer Center in Houston, Texas.
How should clinicians weigh the available CNS data when choosing a HER2-targeted therapy?
Dr. Elamin: Around maybe 20 to 30% of our two mutated lung cancer patients would have CNS metastasis at baseline, and CNS is a common site of disease progression and treatment failure. So it’s extremely important to take that into consideration when selecting treatment for our patients. We have seen some data around the efficacy of both zongertinib and sevabertinib in the in the brain. The drugs are clearly active. The response rates ranging from 55% to 60%. We have less robust data with T-DXd in that context. But I do believe that’s going to be an important consideration when recommending these drugs.
What testing approach best identifies HER2 tyrosine kinase domain activating mutations and avoids missing eligible patients?
Dr. Elamin: The first thing that I want to say, testing is the most important thing. So testing, testing, testing. All lung cancer patients must be tested, irrespective of their stage, given the different approvals that we have now. I think the practical thing would be to use a next-generation sequencing panel that includes all the relevant mutations in lung cancer.
All those DNA-based should be good in detecting HER2, exon 20 and exon 19 or all the tyrosine kinase, domain mutation testing. In an ideal world, it should include DNA and RNA-based, although RNA is less relevant to HER2 mutations. But the majority of wide-based testing would detect these mutations, and the most important thing when we get the results is to act on them
When a patient progresses on one HER2-directed therapy, what do we know about sequencing, and what evidence is still needed?
Dr. Elamin: I think we’ve seen across all these trials, there is very nice data from patients who have progressed on T-DXd that both sevabertinib and zongertinib, retain their activity and also the other way around. While the data is less robust in the situation where the mechanism of action is the same, so when patients had, for example, zongertinib, then switching them to sevabertinib.
We don’t have much robust data there. But I do think that for patients who are treated with a TKI, it’s very reasonable to treat them with T-DXd in the second line space.
