Finally, an Effective Treatment Option for HER2-Mutant Lung Cancer

DESTINY-Lung01 phase II clinical trial results suggest that previously treated patients with metastatic (stage 4) HER2-mutant non-small cell lung cancer (NSCLC) may benefit significantly from the antibody-drug conjugate trastuzumab deruxtecan (Enhertu).

The New England Journal of Medicine published the study on 20 January 2022, reporting promising survival results with trastuzumab deruxtecan in this patient group. Median progression-free survival was reported as 8.2 months, and overall survival as 18 months.

These results could lead to a new standard of treatment for patients with HER2 mutation-positive non-small cell lung cancer (NSCLC). These significant survival benefits could even potentially be extended to patients who have not previously received systemic therapy (that is, first-line treatment).

About 3% of NSCLCs carry a mutation in the HER2 gene

About 3% of nonsquamous NSCLCs carry a mutation in the HER2 gene, which is associated with female sex, never-smoking status and poor prognosis (an unfavorable disease course).

HER2-targeted therapies – particularly trastuzumab deruxtecan – are FDA-approved for patients with breast and gastric cancer. However, such agents have not been approved for patients with HER2-mutant NSCLC.

Bob T. Li of Memorial Sloan Kettering Cancer Center in New York, one of the study’s authors, says the patients enrolled in this study had previously received standard chemotherapy or immunotherapy, which currently has “limited activity as second-line or later treatment.”

The Challenge of Targeting HER2 in Lung Cancer…

Previous studies evaluating HER2-targeted therapies in patients with advanced NSCLC have largely been unimpressive. One previous study found that trastuzumab alone or in combination with chemotherapy or pertuzumab “showed equally negative results in HER2-overexpressing NSCLC.” Another study reported that trastuzumab emtansine (Kadcyla) produced a response in only 20% of patients with advanced HER2-overexpressing NSCLC.

Note: HER2 overproduction (overexpression) or gene-copy increase (amplification) is an important biomarker in breast cancer, and many HER2-targeted drugs are currently used predominantly in breast cancer. However, studies show that mutations in the HER2 gene in patients with advanced NSCLC are more influential than gene overproduction or amplification. 1%-4% of people with lung cancer have a HER2 mutation, but so far no treatment has been accepted for use in this patient group. Developing targeted therapies for NSCLC patients with a HER2 mutation is therefore a major need. All 3 changes in the HER2 gene – overexpression, amplification or mutation – can stimulate cell growth and proliferation; however, different inhibitory drugs are needed for these 3 different conditions.

DESTINY-Lung01 Changes the Outlook for HER2-Mutant Lung Cancer

In contrast to previous unsatisfactory drug trials for HER2-mutant lung cancer, the new phase 2 results from DESTINY-Lung01 showed that trastuzumab deruxtecan is a promising treatment option in previously treated patients with metastatic HER2-mutant NSCLC. To investigate trastuzumab deruxtecan in NSCLC patients, the team conducted a multicenter, international study in patients with metastatic HER2-positive lung cancer resistant to standard treatment.

The researchers studied 91 patients between 30 May 2018 and 21 July 2020. Their median age was 60, and they had previously received a median of 2 lines of treatment, including platinum-based therapy in 95%, anti-programmed death 1 (PD1) or anti-programmed death ligand 1 (PD-L1) immunotherapies in 66%, and docetaxel in 20%. In this study, patients received intravenous trastuzumab deruxtecan at 6.4 mg per kilogram of body weight every 3 weeks. The median treatment duration with trastuzumab deruxtecan was 6.9 months, and the follow-up duration was 13.1 months. At data collection, 16% of patients were still receiving treatment.

The summary results

• showed that 55% of patients had a confirmed objective response to trastuzumab deruxtecan. Overall, the median response duration was 9.3 months, and responses were observed across all HER2 mutation subtypes.
• The researchers reported a median progression-free survival (PFS) of 8.2 months and an overall survival of 17.8 months.
• Among 33 patients with brain metastases, median PFS was 7.1 months and overall survival was 13.8 months.
• The safety profile of trastuzumab deruxtecan, with grade 3 serious drug-related side effects in 46% of patients and most commonly, in 19%, neutropenia, was “generally consistent” with previous studies. 26% of patients experienced interstitial lung disease, and 2 patients died. Because of this side effect, the drug was withdrawn in 16 patients and interrupted in 8. Editorialists Passaro and Peters describe this finding as “concerning,” noting that “the incidence of interstitial lung disease in lung cancer patients is significantly higher than in breast or gastric cancer patients, which may suggest that smoking-related damage is responsible”.

The editorialists also refer to DESTINY-Lung02, in which a reduced dose of trastuzumab deruxtecan is being evaluated, and emphasize the need to investigate its clinical effects. In addition, Passaro and Peters said that the ongoing DESTINY-Lung04 trial will compare trastuzumab deruxtecan with pembrolizumab plus platinum-pemetrexed chemotherapy, formally assessing whether trastuzumab deruxtecan is a more effective first-line treatment strategy than the current standard of care for patients with HER2-mutant NSCLC.