Second-Line Treatment for HER2-Overexpressing Lung Cancer
Karen Yun, MD, University of California, San Diego, California, presents a case of HER2-overexpressing metastatic non-small cell lung cancer to illustrate second-line treatment selection following progression on chemoimmunotherapy.
The discussion reviews the role of trastuzumab deruxtecan in HER2-overexpressing NSCLC, emphasizing the importance of distinguishing HER2 overexpression from HER2 mutation and highlighting the efficacy and safety data supporting HER2-targeted therapy in previously treated disease.
Transcript:
My name is Karen Yun, I'm a head and neck and thoracic medical oncologist at UC San Diego, and today's case is a patient who is a 52-year-old male with metastatic lung adenocarcinoma with metastasis to the liver.
He did have a liver biopsy at one point that didn't show any actionable mutations and PD-L1 TPS was 10%. This patient was treated initially with the combination of carboplatin, pemetrexed, and pembrolizumab for 4 cycles, followed by pemetrexed and pembrolizumab maintenance, and he did have a partial response to his initial chemoimmunotherapy. However, after 10 months on treatment, the CT scans demonstrated disease progression in the liver, and further testing on his initial liver biopsy didn't show any c-Met overexpression but did show HER2 IHC 3+.
As far as what his next treatment options are, the answer to this case is trastuzumab deruxtecan, and I use this case to highlight how, as far as the landscape for treating lung cancer, it's certainly expanded such that we now have more and more therapies, more targeted therapies in our patients with lung cancer. But as far as the HER2 alterations in lung cancers, it's important to recognize that there are different HER2 alterations. When we're specifically talking about HER2-positive lung cancer, it's important to know that there's HER2 protein expression, which is detected or measured by immunohistochemistry, and that can occur in about 59% of patients with lung cancer. There's also HER2 amplification or gene amplification that can be detected by FISH or molecular testing or NGS, and that happens less frequently than overexpression but is found in 2% to 6% of patients with lung cancer. The other HER2 alteration is a HER2 mutation occurring in 1% to 5% of patients with lung cancer.
Now, as far as trastuzumab deruxtecan, it's an antibody-drug conjugate that targets HER2 and it's linked to a cytotoxic payload, and that cytotoxic payload is a topoisomerase inhibitor. Trastuzumab deruxtecan has its effect by killing the cells that it binds to, as well as has a bystander killing effect, so it can kill neighboring cells. Trastuzumab deruxtecan was initially approved in other cancer types, so it's used in breast cancer, gastric cancer, and more recently in lung cancer. But as far as its approval in lung cancer, it was first approved in patients who had HER2-mutated lung cancers, and trastuzumab was approved in the second-line setting in those patients. More recently, as far as the data that we have, trastuzumab deruxtecan was most recently approved for treatment of patients with advanced metastatic HER2 IHC 3+ positive solid tumors with prior treatment and no satisfactory alternatives.
As far as the data for trastuzumab deruxtecan and HER2 overexpressed lung cancer, some of the data that we first had in that particular patient population came from DESTINY-Lung01. And as far as the efficacy of trastuzumab deruxtecan in patients who had HER2-overexpressed lung cancers, in those patients who were previously treated, the overall response rate of trastuzumab deruxtecan in DESTINY-Lung01 was 53%, and the median duration of response was 6.9 months. It was actually data from 3 clinical trials that looked at trastuzumab deruxtecan in different cancer types that led to its approval, led to its tumor-agnostic approval, in patients with HER2-positive IHC 3+ positive tumors who were previously treated. There is data from DESTINY-Lung03, that was a Phase 1B study that looked at trastuzumab deruxtecan, specifically in patients with HER2-overexpressed non-small cell lung cancer, and these patients were previously treated with HER2-overexpressed non-small cell lung cancers with IHC 3+ or 2+. And specifically in those patients who were HER2 IHC 3+, trastuzumab deruxtecan demonstrated an overall response rate of 56%, a duration of response of 12.5 months, a median progression-free survival of 6.9 months, and a median overall survival of 16.4 months.
Given the data from DESTINY-Lung01 and DESTINY-Lung03, we certainly have data to show that trastuzumab deruxtecan does have efficacy in patients with HER2-overexpressed non-small cell lung cancer, and it was the data from DESTINY-Lung01 that led to its approval in these patients with HER2-overexpressed lung cancer.
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