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T-DXd for <em>HER2</em>mut NSCLC
Trastuzumab Deruxtecan: An Emerging Option for HER2-Mutated NSCLC

Released: October 22, 2020

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Lung cancer is an ever‑changing field, and this seems particularly true in 2020 with a historic 7 new drug approvals for advanced non-small-cell lung cancer (NSCLC) in May 2020 alone. The approval of the targeted therapies selpercatinib and pralsetinib for RET fusion–positive NSCLC and capmatinib for METex14-positive NSCLC recently expanded the list of biomarkers we should be testing for in the tumor of every patient with newly diagnosed nonsquamous NSCLC before starting therapy to include ALK, EGFR, ROS1, BRAF V600E, NTRK fusions, METex14, or RET fusions. However, it doesn’t stop there—we expect to see additional drugs approved that target HER2 and EGFR exon 20 insertions in the not-too-distant future, with KRAS G12C–targeted agents a little further down the road. 

In this commentary, I focus on promising new data from ASCO 2020 for the HER2-targeted antibody–drug conjugate trastuzumab deruxtecan in the treatment of advanced NSCLC with HER2 mutations, which are found in 2% to 4% of patients with advanced NSCLC and for which no HER2-directed therapies have yet been approved.

Trastuzumab Deruxtecan: HER2-Targeted Antibody–Drug Conjugate
Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate comprising a HER2-directed monoclonal antibody, trastuzumab, conjugated to a cytotoxic chemotherapy “payload,” deruxtecan, by a cleavable linker. The aim of this approach is the delivery of the chemotherapy payload directly into the tumor cell via binding of the monoclonal antibody portion to the HER2 receptor expressed on cancer cells. T-DXd is currently approved by the FDA for the treatment of unresectable or metastatic HER2-positive breast cancer after ≥ 2 previous lines of anti-HER2–based regimens. In a phase I multicohort trial, T-DXd showed preliminary efficacy (ORR: 62.5%) in 12 patients with HER2-mutated or HER2-expressing NSCLC, leading to its further evaluation for the treatment of advanced NSCLC in the phase II DESTINY‑Lung01 study.

DESTINY‑LUNG01: T-DXd in Advanced HER2-Mutated NSCLC
In DESTINY-Lung01, patients with HER2-mutated or HER2-expressing (IHC 2+ or IHC 3+), unresectable or metastatic nonsquamous NSCLC that was relapsed or refractory to standard therapy received T-DXd 6.4 mg/kg every 3 weeks. The primary endpoint was confirmed ORR by independent central review. 

At ASCO 2020, results from an interim analysis of 42 individuals in the HER2-mutated cohort were presented. At entry, median age was 63 years, 90.5% of patients had a HER2 mutation in the kinase domain, and 45.2% had central nervous system metastases. Most (90.5%) patients had received a previous platinum‑based therapy, and more than one half (54.8%) had received an anti–PD-(L)1 immune checkpoint inhibitor.

The ORR at this interim analysis was 61.9%, with 1 person (2.4%) achieving a CR and 25 patients (59.5%) achieving PRs. What was really striking was that only 2 patients (4.8%) had progressive disease, and looking at the waterfall plot depicting best change in tumor size for 39 of the responding patients, not a single tumor grew. This is rare to see in the setting of lung cancer and really caught everyone’s attention. 

However, were these notable responses durable and did they translate into a survival benefit? So far, we know that the overall disease control rate was high at 90.5% but the median duration of response has not been reported due to a high proportion of patients still receiving therapy at the time of data cutoff. Regarding survival, the median PFS was 14.0 months (95% CI: 6.4-14.0 months), with a nice flattening of the curve at approximately 7 months; median OS was not reached at the time of this analysis. Overall, these are impressive data and the types of numbers we expect to see when a treatment—here, T-DXd—is truly a good match for a driver mutation—here, a HER2 mutation.

Regarding the safety of T-DXd, most treatment-emergent adverse events were grade 1/2. However, grade ≥ 3 treatment-emergent adverse events, including myelosuppression, occurred in 64.3% of patients, of which 52.4% were considered related to T-DXd. There was need for dose reduction in some patients (38.1%), mainly for fatigue (11.9%) or nausea (9.5%), and 59.5% of patients interrupted dosing, most often for neutropenia (19.0%) or lung infection (7.1%). There were 5 deaths, none of which was considered related to treatment.

Of note, there is a concern for the development of interstitial lung disease (ILD) with the use of T-DXd. In DESTINY-Lung01, 5 patients (11.9%) had ILD, all grade 2. The drug was withdrawn in 4 patients and interrupted in the other, and all 5 received steroid treatment. However, no deaths from ILD were reported. Although ILD is certainly something to watch out for when giving T-DXd, it appeared manageable in this study.

Clinical Implications
Early results from this interim analysis of DESTINY-Lung01 show an encouraging response rate and median PFS with T-DXd in patients with HER2‑mutated metastatic nonsquamous NSCLC who were previously treated with platinum chemotherapy and also immune checkpoint inhibitor therapy for some. Together with a lack of any new safety signals of concern, I feel encouraged that HER2 may be the next biomarker added to our list of oncogenic drivers with an approved targeted therapy. However, we await final data, including reports of duration of response and OS and results from an additional expansion cohort in DESTINY-Lung01 to further characterize the risk-to-benefit ratio of T-DXd in this pretreated patient population.

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Are you using next-generation sequencing to identify rare actionable driver mutations such as HER2 mutations in your patients with advanced NSCLC? I encourage you to answer the polling question and post your thoughts and questions in the discussion box below.

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