T-DXd Makes Inroads in the Treatment of HER2-Mutant NSCLC

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Previously treated patients with HER2-positive non–small cell lung cancer (NSCLC) achieved encouraging response rates and duration of response to the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) in the phase II DESTINY-Lung01 trial. These results were reported at the European Society for Medical Oncology (ESMO) Congress 2021 and published online in The New England Journal of Medicine to coincide with the presentation.1,2

Among 91 patients enrolled in the trial, the objective response rate was 55%, median duration of response was 9.3 months, median progression-free survival was 8.2 months, and median overall survival was 17.8 months. Toxicity was reported to be manageable, but almost half of the patients enrolled in the trial developed grade < 3 interstitial lung disease.

“T-DXd demonstrated robust and durable anticancer activity in patients with previously treated HER2-mutated NSCLC. Efficacy was consistently observed across subgroups, including those patients with stable central nervous system metastases. Exploratory analyses demonstrated anticancer activity across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 gene amplification. Overall, the safety profile was consistent with previously reported studies,” said lead study author Bob T. Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center, New York.

Bob T. Li, MD, PhD, MPH

Bob T. Li, MD, PhD, MPH

“DESTINY-Lung01 provides compelling evidence of a positive risk/benefit balance with T-DXd in the second-line setting and beyond. These results support the clinical benefit of T-DXd in patients with HER2-mutant NSCLC, a clinical context in which no targeted agents are currently approved,” Dr. Li added.


Up to 3% of all patients with NSCLC have HER2 mutations. These patients tend to be younger, female, and never-smokers compared with other patients who have NSCLC. HER2-mutant NSCLC is associated with a poor prognosis and an increased risk of central nervous system (CNS) metastasis.

Other targeted therapies have had good results in treating subsets of patients with specific mutational aberrations—such as EGFR, ALK, ROS1, and others. Currently, no HER2-directed therapies are approved for lung cancer, and HER2 status is not routinely assessed. Patients with HER2-mutant NSCLC are typically treated with chemotherapy and/or immunotherapy, which has limited activity beyond the first-line setting.

HER2-targeted therapy is approved in the United States and other countries for the treatment of HER2-positive breast and gastric cancers. However, despite over 2 decades of effort, there is no HER2-targeted therapy approved in lung cancer, in part due to its molecular complexity. In contrast to breast and gastric cancers, high-level HER2 protein overexpression or HER2 amplification is uncommon in lung cancers, and HER2 mutations represent a distinct oncogene driver and molecular target.3 A bench-to-bedside-and-back translational study described the mechanism of antibody-drug conjugates in targeting HER2 mutations without protein overexpression, through ubiquitination and internalization, and thus formed the scientific basis for the DESTINY-Lung01 trial.4 T-DXd has two components—an antibody linked to a toxic payload of potent chemotherapy that produces DNA damage and apoptosis to tumor cells.

DESTINY-Lung01 was a multicenter, open-label, two cohort, phase II study conducted at 21 sites in North America, Japan, and Europe designed to evaluate the efficacy and safety of T-DXd in patients with HER2-overexpressing or HER2-mutant NSCLC. Entry criteria included adults with unresectable or metastatic nonsquamous NSCLC, relapsed or refractory disease on standard treatment, one measurable lesion, and an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary endpoint was confirmed objective response rate.


  • The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) demonstrated promising activity in pretreated, refractory HER2-positive non–small cell lung cancer (NSCLC) in a phase II study.
  • More research is needed to determine the ultimate role in NSCLC of this HER2-targeted agent.

A total of 91 patients with HER2-mutant NSCLC were enrolled, with a median age of 60. Two-thirds were female, one-third were Asian, and 57% were never-smokers. HER2 kinase domain mutations were present in 93.4% of patients, and 36% had CNS metastases. At baseline, patients had received a median of two prior lines of therapy (range, 0–7 lines), including platinum-based chemotherapy (95%) anti–PD-1/L1 agents (66%), or both (62.6%). T-DXd was delivered intravenously every 3 weeks at a dose of 6.4 mg/kg of body weight.

Key Findings

At a median follow-up of 13.1 months, the objective response rate was 54.9%; the disease control rate was 92.3% during treatment with T-DXd. The majority of patients (92%) had some evidence of tumor regression. Median progression-free survival was 8.2 months, and median overall survival was 17.8 months. At data cutoff, a total of 47 patients (52%) had died; the other patients continue to be followed for survival.

Responses were also observed in patients treated with a variety of previous anticancer treatments, including immunotherapy and other HER2-targeted agents, and in patients with CNS metastasis at baseline. Among 33 patients with CNS metastasis at baseline, median progression-free survival was 7.1 months, and median overall survival was 13.8 months. Responses were observed in patients with different HER2 mutation subtypes across three exon locations, as well as in patients with no detectable HER2 expression or who tested negative for HER2 amplification.

Reasons for treatment discontinuation were disease progression in 63 patients (70%), completion of therapy in 6 patients (7%), and adverse events in 8 patients (9%).

Among 91 patients, all experienced at least one adverse event; 88 patients (97%) had at least one adverse event reported as related to treatment. Most of the adverse events that occurred in 20% or more of patients were grade 1 or 2. The most common adverse events were gastrointestinal and hematologic events, decreased appetite, and alopecia.

Serious drug-related adverse events were reported in 18 patients (25%). A total of 23 patients (25%) discontinued T-DXd due to drug-related adverse events, including pneumonitis in 12 patients (13%) and interstitial lung disease in 5 patients (5%). A total of 31 patients (34%) had drug-related adverse events leading to dose reduction (eg, nausea and fatigue). Dose interruption due to drug-related adverse events was reported in 29 patients (32%).

Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in two deaths. T-DXd was withdrawn in 16 patients and interrupted in 18 patients due to interstitial lung disease. Of these patients, 13 (> 50%) recovered by the time of data cutoff.

“The development of interstitial lung disease [with T-DXd] was not predictable. Consequently, patients should be carefully monitored,” Dr. Li said. “Research is needed to determine which patients are at greatest risk as well as the optimal management of this potentially fatal adverse event.” 

DISCLOSURE: The study was sponsored by Daiichi Sankyo and AstraZeneca. Dr. Li has received institutional research funding from the National Institutes of Health; is an inventor on institutional patents at MSK; served as uncompensated advisor to and received institutional research funding from Daiichi Sankyo, AstraZeneca, Amgen, Lilly, Genentech/Roche, Hengrui Therapeutics, Bolt Biotherapeutics, and MORE Heath; has been reimbursed for travel expenses by Jiangsu Hengrui Medicine and MORE Health; and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press.


1. Li BT, Smit EFF, Goto Y, et al: Primary data from DESTINY-Lung01. ESMO Congress 2021. Abstract LBA45. Presented September 18. 2021.

2. Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. September 18, 2021 (early release online).

3. Li BT, Ross DS, Aisner DL, et al: HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol 11:414-419, 2016.

4. Li BT, Michelini F, Misale S, et al: HER2-mediated internalization of cytotoxic agents in ERBB2-amplified or mutant lung cancers. Cancer Discov 10:674-687, 2020.

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