Jose Pacheco, MD, an assistant professor of Medicine-Medical Oncology at the University of Colorado Anschutz Medical Campus, discusses the mechanism of action of trastuzumab deruxtecan (Enhertu) in patients with HER2-overexpressing metastatic non–small cell lung cancer.

Trastuzumab deruxtecan consists of an antibody that targets HER2 proteins, Pacheco says. Eight topoisomerase I–inhibiting chemotherapy molecules are attached to the HER2 antibody via a cleavable linker, he continues.

The antibody-drug conjugate attaches to HER2 proteins on the outside of the cell and undergoes endocytosis, with the drug complex being taken into the cell. Within the cell's lysosome, cleavage from the linker occurs and the topoisomerase I inhibitor is released inside the cell, Pacheco says. However, the chemotherapy molecules are known to leave the cell and damage nearby cells that may not express HER2, Pacheco concludes.

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Jose Pacheco, MD, discusses the mechanism of action of trastuzumab deruxtecan in patients with HER2-overexpressing metastatic non–small cell lung cancer.

Dr. Pacheco on the Mechanism of Action of Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic NSCLC

Jose M. Pacheco, MD, an assistant professor of medicine/medical oncology at the Colorado University School of Medicine, discusses frontline therapy for patients with 

-mutant non—small cell lung cancer (NSCLC).

The established genetic alterations for which physicians have approved targeted therapies include 

 V600E mutations, says Pacheco. Data from the FLAURA study presented within the past year suggested that first-line osimertinib (Tagrisso) provides a progression-free survival (PFS) benefit for patients with traditional 

 activating mutations, such as exon 19 deletions and 

 L858R point mutations in exon 21. The PFS benefit for osimertinib compared with gefitinib (Iressa) or erlotinib (Tarceva) was 19 months versus 10 months, notes Pacheco.

From a population-based standpoint, it makes more sense to give osimertinib first as opposed to sequencing EGFR inhibitors. If 100 patients are treated with osimertinib, the median PFS could be 19 months based on the trial data. If 100 patients are treated with gefitinib or erlotinib, the median PFS would be approximately 10 months, and only 50% to 60% of those patients would be eligible for sequencing with osimertinib. As high as 40% of patients may not reach second-line therapy, so it is important to give patients the therapy with the most impact upfront, adds Pacheco.

Jose M. Pacheco, MD, an assistant professor of medicine/medical oncology at the Colorado University School of Medicine, discusses frontline therapy for patients with EGFR-mutant non–small cell lung cancer (NSCLC).

Dr. Pacheco on Frontline Therapy for Patients With EGFR-Mutant NSCLC

Jose M. Pacheco, MD, assistant professor, Medicine/Medical Oncology, Colorado University School of Medicine, discusses second-line therapy for patients with 

-positive non—small cell lung cancer (NSCLC).

Following progression on a second-generation ALK inhibitor, Pacheco advises enrolling patients on a clinical trial with second-line brigatinib (Alunbrig). In the trial, patients will get a biopsy to determine what molecular markers they have that may help predict benefit from brigatinib following alectinib (Alecensa) or another second-generation ALK inhibitor, says Pacheco.

Physicians are gaining more insight into the mechanisms of resistance to ALK inhibitors. Physicians know that following a first-generation ALK inhibitor such as crizotinib (Xalkori), roughly 20% to 25% of patients may develop mutations in the ALK protein itself. Following a second-generation ALK inhibitor like ceritinib (Zykadia), alectinib, or brigatinib roughly 50% of patients will develop a mutation in the ALK protein that leads to resistance, says Pacheco.

Preclinically, it looks like lorlatinib may work better for a particular 

 mutation, G1202R. A patient in the phase II study of brigatinib who had a G1202R mutation responded to the tyrosine kinase inhibitor, says Pacheco. However, there have also been a lot of patients with G1202R mutations who have not responded to brigatinib. Physicians have limited data from lorlatinib in patients with that particular

Jose M. Pacheco, MD, assistant professor, Medicine/Medical Oncology, Colorado University School of Medicine, discusses second-line therapy for patients with ALK-positive non–small cell lung cancer (NSCLC).

Jose M. Pacheco, MD

Articles

Dr. Pacheco on the Mechanism of Action of Trastuzumab Deruxtecan in HER2-Overexpressing Metastatic NSCLC

Dr. Pacheco on Frontline Therapy for Patients With EGFR-Mutant NSCLC

Dr. Pacheco on Second-Line Therapy for ALK+ NSCLC