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Trastuzumab Deruxtecan Demonstrates Robust and Durable Activity in Previously Treated Metastatic NSCLC with HER2 mutations

The results from the DESTINY-Lung01 study
18 Sep 2021
Anticancer agents & Biologic therapy;  Lung and other thoracic tumours;  Personalised medicine

The DESTINY-Lung01 study assessed the efficacy and safety of HER2 antibody-drug conjugate trastuzumab deruxtecan in patients with metastatic non-small cell lung cancer (NSCLC) with HER2 mutations. Trastuzumab deruxtecan demonstrated robust and durable activity in this population, with a manageable safety profile. The results from this multicentre, international, phase II study were presented by Bob T. Li, MD, PhD, MPH, first author and medical oncologist, Thoracic Oncology and Early Drug Development Service; Physician Ambassador to China and Asia-Pacific; and Chief Scientific Officer, MSK Direct at Memorial Sloan Kettering Cancer Center (MSK) in New York, NY, USA at ESMO Congress 2021 (16-21 September) and simultaneously published in The New England Journal of Medicine.

HER2 mutations occur in approximately 3% of NSCLC. However, currently there are no approved HER2-targeted agents for the management of patients with NSCLC; thus, this setting represents a high unmet medical need. Patients included in the DESTINY-Lung01 study had HER2-mutated metastatic NSCLC refractory to standard treatment; all patients were treated with trastuzumab deruxtecan.

Primary study endpoint was objective response rate (ORR) assessed per RECIST v1.1 by independent central review. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory biomarkers of HER2 alterations were analyzed.

In total, 91 patients were enrolled. Data cut-off was 3 May 2021. Median follow-up was 13.1 months. Median age was 60 years. Among included patients, 93.4% had a HER2 kinase domain mutation. Furthermore, 36.3% had asymptomatic central nervous system (CNS) metastases not requiring ongoing treatment. Median number of prior therapy lines was 2 (range, 0-7), including platinum-based therapy in 94.5% patients and anti-PD-(L)1 therapy in 65.9% patients.

Centrally confirmed ORR was 54.9% (95% confidence interval [CI] 44.2-65.4) with 1 complete response (1.1%) and 49 partial responses (53.8%). Disease control rate was 92.3% (95% CI 84.8-96.9). Median DoR was 9.3 months (95% CI 5.7-14.7). Median PFS was 8.2 months (95% CI 6.0-11.9). Median OS was 17.8 months (95% CI 13.8-22.1).

Efficacy was consistent across subgroups, including patients previously treated with a HER2 tyrosine kinase inhibitor or with CNS metastases.

Treatment-related adverse events occurred in 96.7% patients. Drug-related interstitial lung disease (ILD) occurred in 24 patients of which 3 patients had grade 1, 15 grade 2, 4 grade 3, and 2 grade 5 ILD. Overall, the toxicity profile was consistent with previously reported studies and ILD remains an important risk that requires careful monitoring.

Dr. Li reported that additional biomarker analyses showed responses across different HER2-mutated subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification.

Dr. Li concluded that the DESTINY-Lung01 study results provide compelling evidence of positive benefit/risk balance and support trastuzumab deruxtecan as a potential new standard treatment in this patient population.

The study results are published simultaneously in The New England Journal of Medicine.

The study was funded by Daiichi Sankyo, Inc. and AstraZeneca.

Dr. Li has provided uncompensated advisory services to Daiichi Sankyo and AstraZeneca.

References

  1. LBA45 – Li BT, Smit EFF,Goto Y, et al. Primary data from DESTINY-Lung01: A phase II trial of trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC). ESMO Congress 2021 (16-21 September).
  2. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. NEJM; Published online 18 September 2021. DOI: 10.1056/NEJMoa2112431

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