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Trastuzumab Deruxtecan Demonstrates Durable Responses in Patients with Previously Treated HER2-mutated Metastatic NSCLC

Primary results from DESTINY-Lung02 study
27 Sep 2023
Immunotherapy;  Molecular Oncology
Non-Small Cell Lung Cancer

DESTINY-Lung02 is the randomised, blinded phase II study assessing the efficacy and safety of trastuzumab deruxtecan 5.4 mg/kg and 6.4 mg/kg once every 3 weeks in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC). Trastuzumab deruxtecan demonstrated deep and durable antitumour responses at both doses. Responses were consistent regardless of HER2 mutation type and amplification status and presence or absence of baseline CNS metastases and prior treatment.

The safety profile was acceptable and generally manageable with both doses; however, a lower incidence of drug-related treatment-emergent adverse events (TEAEs) and interstitial lung disease (ILD) or pneumonitis was observed with the lower dose. The primary results are reported by Dr. Koichi Goto of the National Cancer Center Hospital East in Chiba, Japan, and colleagues on 11 September 2023 in the JCO.

The primary results of DESTINY-Lung02 with data cut-off of 23 December 2023 are generally consistent with the interim analysis of study with data cut-off on 24 March 2022 that led to the US Food and Drug Administration (FDA) approval of trastuzumab deruxtecan 5.4 mg/kg for previously treated HER2-mutated metastatic NSCLC and support the therapeutic benefit of trastuzumab deruxtecan in this patient population.

Interim analysis provided the first clinical data of trastuzumab deruxtecan 5.4 mg/kg in patients with HER2-mutated metastatic NSCLC and served as the basis for accelerated approval of trastuzumab deruxtecan 5.4 mg/kg in the US as the first HER2-directed treatment for patients with unresectable NSCLC or metastatic NSCLC with activating HER2 mutations, as detected by an FDA approved test and who have received a prior systemic therapy.

The authors wrote in the background that approximately 2-4% of non-squamous NSCLC is driven by HER2 mutations. Chemotherapy and immunotherapy have limited efficacy, and other HER2-targeted therapies have demonstrated inconsistent results in patients with HER2-mutated metastatic NSCLC in the second-line setting. The clinical benefit of trastuzumab deruxtecan 6.4 mg/kg was demonstrated in the phase II DESTINY-Lung01 study. However, the incidence of drug-related ILD or pneumonitis was 27.5% in the HER2-mutated cohort, warranting evaluation of a lower dose of trastuzumab deruxtecan in patients with HER2-mutated metastatic NSCLC.

DESTINY-Lung02 is a phase II study evaluating the efficacy and safety of trastuzumab deruxtecan 5.4 mg/kg and 6.4 mg/kg once every 3 weeks in patients with HER2-mutated (single-nucleotide variants and exon 20 insertions) metastatic NSCLC. It investigated trastuzumab deruxtecan 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with HER2-mutated metastatic NSCLC and further assessed trastuzumab deruxtecan 6.4 mg/kg once every 3 weeks in this population. The primary endpoint was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.

A total of 152 patients were randomly assigned 2:1 to trastuzumab deruxtecan 5.4 or 6.4 mg/kg once every 3 weeks. As of 23 December 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% confidence interval [CI] 39.0 to 59.1) and 56.0% (95% CI 41.3 to 70.0) and median duration of response was 16.8 months (95% CI 6.4 to not estimable [NE]) and NE (95% CI 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg.

Grade ≥ 3 drug-related TEAEs occurred in 39 of 101 patients (38.6%) and 29 of 50 patients (58.0%) with 5.4 and 6.4 mg/kg, respectively; 13 of 101 patients (12.9%) and 14 of 50 patients (28.0%) had adjudicated drug-related ILD (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.

The authors concluded that the more favourable benefit/risk profile observed with trastuzumab deruxtecan 5.4 mg/kg supports the use of this dose for patients with previously treated HER2-mutated metastatic NSCLC and reinforces trastuzumab deruxtecan as the standard of care in this population.

In an accompanied editorial, Drs. Hui Jing Hoe and Benjamin J. Solomon of the Department of Medical Oncology, Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia wrote that DESTINY-Lung02 study underscores the critical role of dose optimisation in the development of safe and effective anticancer therapies. This is particularly relevant for antibody drug conjugates where the therapeutic window may be relatively narrow. Well-designed dose-finding studies are required to adequately characterise exposure-safety and exposure-efficacy relationships to select doses for registration studies and postapproval use.

Even at the approved dose of 5.4 mg/kg once every 3 weeks, prescribers must remain vigilant for the risk of drug-related ILD or pneumonitis. Early detection of drug-related ILD or pneumonitis is imperative, and if detected, trastuzumab deruxtecan treatment must be interrupted and treatment with steroids and other supportive measures must be instituted. Trastuzumab deruxtecan rechallenge after resolution of grade 1 ILD or pneumonitis appears to be feasible. Trastuzumab deruxtecan should not be rechallenged if a patient experienced ILD of grade 2 or greater severity.

Ongoing studies are evaluating trastuzumab deruxtecan 5.4 mg/kg once every 3 weeks compared with chemotherapy plus pembrolizumab in the first-line setting for HER2-mutated NSCLC (DESTINY-Lung04) and in combination strategies with immunotherapy and chemotherapy. In these settings, dose optimisation and mitigation of toxicities including drug-induced ILD or pneumonitis and other cumulative low-grade toxicities that are impactful for patients will be essential to enable long-term delivery of this effective new class of therapeutics and maximise therapeutic outcomes according to the editorialists.

The study was supported by Daiichi Sankyo in collaboration with AstraZeneca. The authors acknowledged Jing Zhao of Daiichi Sankyo and Thermo Fisher Scientific for their assistance with the HER2 amplification analysis.


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