Trastuzumab deruxtecan induces durable responses in HER2-mutated NSCLC
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Trastuzumab deruxtecan demonstrated strong antitumor activity among patients with previously treated HER2-mutated non-small cell lung cancer, according to results of a phase 2 trial presented during the virtual ESMO Congress 2021.
The HER2 antibody-drug conjugate also had a manageable safety profile similar to that observed in previous studies, according to the results, published simultaneously in The New England Journal of Medicine.
Data derived from Li BT, et al. Abstract LBA46. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
“HER2 mutations drive approximately 3% of nonsquamous NSCLCs and are associated with younger age, female sex, never-smoking history, a poor prognosis and an increased incidence of brain metastasis,” Bob T. Li, MD, PhD, MPH, of the thoracic oncology and early drug development service at Memorial Sloan Kettering Cancer Center, said during a presentation. “There are currently no approved HER2-targeted therapies for patients with NSCLC. This patient population is typically treated with standard chemotherapy and/or immunotherapy, with limited efficacy in the second or later-line settings.”
Trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) has been approved for treatment of metastatic HER2-positive breast and gastric cancers.
The DESTINY-Lung01 trial enrolled 91 patients (median age, 60 years; 65.9% women), including 49 in an expansion cohort, with HER2-mutant nonsquamous NSCLC refractory to standard treatment. Most patients (93.4%) had an HER2 kinase domain mutation, and 36.3% had asymptomatic central nervous system metastasis that did not require ongoing treatment. More than half (57.1%) were never smokers. Patients had a median two previous lines of cancer treatment, which included platinum-based (94.5%) and PD-1-PD-L1 (65.9%) therapy. Patients received trastuzumab deruxtecan dosed at 6.4 mg/kg every 3 weeks.
Objective response rate by independent central review served as the primary endpoint. Duration of response, PFS, OS and safety served as secondary endpoints. Researchers also analyzed biomarkers of HER2.
Median follow-up was 13.1 months, with a data cutoff date of May 3.
Results showed a confirmed ORR of 54.9% (95% CI, 44.2-65.4), including one complete response and 49 partial responses. Median duration of response was 9.3 months (95% CI, 5.7-14.7). Thirty-four patients (37.4%) had stable disease, three (3.3%) had progressive disease and four (4.4%) could not be evaluated.
Responses occurred among various HER2 mutation subtypes and among patients with no HER2 expression or HER2 amplification.
Li reported median PFS of 8.2 months (95% CI, 6-11.9) and median OS of 17.8 months (95% CI, 13.8-22.1). Fifteen patients remained on treatment as of the data cutoff date, whereas 76 (83.5%) discontinued primarily because of progressive disease (37.4%) and adverse events (29.7%).
Nearly half of patients (46.2%) experienced grade 3 or higher treatment-related adverse events, the most common of which were neutropenia (18.7%), anemia (9.9%) and nausea (8.8%). Eighteen patients (19.8%) experienced serious treatment-related adverse events.
Drug-related adverse events associated with dose reduction occurred among 34.1% of patients, the most common of which were nausea and fatigue. One-quarter of patients (25.3%) discontinued treatment due to drug-related adverse events, most often due to drug-induced pneumonitis or interstitial lung disease. Two patients died of these events.
“Although most [interstitial lung disease] and pneumonitis cases were of low grade and managed, it remains an important identified risk,” Li said. “Effective early detection and management are critical.”
A 5.4 mg/kg lower dose of trastuzumab deruxtecan is being studied in the DESTINY-Lung02 clinical trial in an effort to further optimize the dosing regimen, he said.
“Overall, DESTINY-Lung01 provides compelling evidence of positive benefit/risk balance with [trastuzumab deruxtecan] in the second-line or beyond settings and supports its establishment as a potential new treatment standard for this patient population of unmet medical need,” Li said.
References:
- Li BT, et al. Abstract LBA46. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
- Li BT, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2112431.
Perspective
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Fred R. Hirsch, MD, PhD, FASCO
The DESTINY-Lung01 study addresses an important gap in the management of patients with lung cancer and HER2 mutations. Although HER2 mutations are relative rare, this population includes a numerically high number of patients for whom no effective therapy has been established so far in lung cancer.
The objective response rate of 54.9% and disease control rate (objective response plus stable disease) of 84% — with median PFS of 8.2 months and median OS of 17.8 months — in this disease setting is very encouraging and could lead to a new standard of care for this subtype of lung cancer. The tolerability also was acceptable.
This new drug also represents a new drug category, antibody-drug conjugate, which is coming more and more into the treatment scenario of cancer. This drug category should be more specific and have potentially fewer side effects than previous antibody therapy. These results with trastuzumab deruxtecan support the encouragement of this new drug development.
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Li BT, et al. Abstract LBA45. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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