Trastuzumab deruxtecan showed therapeutic efficacy in HER2-mutant non-small cell lung cancer

1. Patients with refractory HER2-mutant non-small cell lung cancer (NSCLC) show clinical response to trastuzumab deruxtecan.

2. Safety profiles were generally acceptable; however, careful monitoring in patients developing interstitial lung disease is warranted.

Evidence Rating Level: 2 (Good)   

Study Rundown: Human epidermal growth factor receptor 2 (HER2) is a driver mutation that has been successfully targeted in breast and gastric cancers; however, the use of HER2 inhibitors has not been approved for patients with non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan is composed of an anti-HER2 monoclonal antibody linked to a chemotherapeutic drug. In this phase II clinical trial, NSCLC patients with HER2-overexpression or mutation who were refractory to previously administered chemotherapy regimens were given intravenous trastuzumab deruxtecan every 3 weeks. The objective of this study was to investigate the objective therapeutic response of trastuzumab deruxtecan and its safety profile. The results of this study found that most patients experienced partial disease control and reduction in tumor size with a median duration of response of 9.3 months. With respect to the safety profile, all patients experienced at least one adverse event, while 46% experienced a severe adverse event with neutropenia being the most common. 2 patients died as a result of treatment. Moreover, 26% of patients developed drug-related interstitial lung disease leading. Together, this study demonstrates the acceptable clinical efficacy and safety profile of trastuzumab deruxtecan in NSCLC patients with HER2 mutation and supports the further clinical investigation. The limitations of this study include the lack of a comparator group and exclude patients previously treated with HER2 targeting antibodies or antibody-drug conjugates.

Click to read the study in NEJM

Relevant Reading: DS-8201a, A Novel HER2-Targeting ADC with a Novel DNA Topoisomerase I Inhibitor, Demonstrates a Promising Antitumor Efficacy with Differentiation from T-DM1

In-Depth [prospective cohort]: In this multi-center, open-label phase II clinical trial named DESTINY-Lung01, 91 patients with previously-treated non-small cell lung cancer (NSCLC) with HER2 overexpression or mutation were treated intravenously with 6.4mg/kg of trastuzumab deruxtecan every 3 weeks. Eligible patients had to have at least one measurable lesion which was refractory to standard treatment and an ECOG score of 0-1. Patients previously treated with a HER2 antibody or antibody-drug conjugate were excluded. The primary outcome of this study was to assess objective clinical response determined by an independent central review. Secondary outcomes were to assess the duration of response, disease control, progression-free and overall survival. To assess safety profile, adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The study found that 55% of treated patients achieved an objective response, while 92% showed disease control and reduction in tumor size. The median duration of response was 9.3 months (95%CI [5.7-1.47]) including one patient who achieved complete response. All patients experienced at least one adverse event, 46% experienced a severe drug-related adverse event (Grade 3 or higher) with neutropenia being the most common, and 2 patients died due to treatment. 24 patients (26%) developed interstitial lung disease from treatment with a median time to onset of 141 days. At the time of data cut-off, 50% of these patients fully recovered from the disease. Taken together, this study supports the continued clinical investigation of trastuzumab deruxtecan in patients with NSCLC with an acceptable clinical efficacy and safety profile.

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