Trastuzumab Deruxtecan Leads to Durable Responses in HER2-Mutant NSCLC

Trastuzumab deruxtecan (Enhertu) induced a high objective response rate (ORR) and durable responses among patients with HER2-mutant non–small cell lung cancer (NSCLC) in a cohort of the phase 2 DESTINY Lung-01 trial (NCT03505710), according to interim findings presented during the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC) Singapore.

“Trastuzumab deruxtecan demonstrated clinical meaningful and promising efficacy in patients with HER2-mutant non–small cell lung cancer,” Egbert F. Smit, MD, PhD, professor of pulmonary medicine of the Netherlands Cancer Institute in Amsterdam, Netherlands. “These data demonstrate the potential of trastuzumab deruxtecan as a new treatment option in patients with HER2-mutated non–small cell lung cancer, a patient population with a high unmet need.”

The open-label, multicenter, multicohort DESTINY-Lung01 study is investigating the use of the HER2-directed antibody-drug conjugate (ADC) across 2 cohorts of patients: cohort 1 includes patients with HER2-overexpressing NSCLC (immunohistochemistry [IHC] 3+ or 2+) and cohort 2 includes patients with HER2-mutated disease.

The study enrolled patients with unresectable or metastatic nonsquamous NSCLC who had relapsed from or are refractory to standard treatment and have an ECOG performance status of 0 or 1. Primary end point for the study is ORR and secondary end points are progression-free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), and safety and tolerability. Although no longer recruiting, the trial is ongoing. With the interim analysis conducted with a data cutoff of November 25, 2019.

During his WCLC presentation, Smit focused on patients in the second cohort (n = 42) who were treated with 6.4 mg/kg of trastuzumab deruxtecan every 3 weeks.

In this cohort, 19 patients remained on treatment as of data cutoff and 23 patients had discontinued, primary due to progressive disease or adverse events. The median treatment duration was 7.8 months (range, 0.7-14.3).

Patients in the second cohort had a median age of 63.0 years (range, 34-83) at baseline, 64.3% were female, and 76.2% had an ECOG performance status of 1. The HER2 mutation was identified in the kinase domain for 90.5% of patients, in the extracellular domain for 4.8%, and missing for 4.8%. Nineteen patients (45.2%) had central nervous system metastasis at baseline.

All but 1 patient (97.6%) had received prior systemic therapy, which included platinum-based therapy for 90.5%, anti–PD-1/PD-L1 therapy for 54.8%, doctaxel for 19.0%, poziotinib (7.1%), afatinib (Gilotrif; 4.8%), and mobocertinib (2.4%). The median number of prior lines of therapy was 2 (range, 1-6).

The confirmed ORR was 61.9% (95% CI, 45.6%-76.4%), which consisted of complete responses in 2.4% and partial responses in 59.5%. An additional 28.6% had stable disease, for a DCR of 90.5% (95% CI, 77.4%-97.3%). Two patients had progressive disease and another 2 were not evaluable.

At a median follow-up of 8 months (range, 1.4-14.2), the median PFS was 14 months (95% CI, 6.4-14.0). Neither the median DOR nor the median OS were evaluable.

Smit noted that the safety profile in the HER2-mutated cohort was generally consistent with previous reports for the ADC. Treatment-emergent adverse events (TEAEs) were observed in all patients and events were grade ≥3 in 64.3%, of which 52.4% were considered drug related.

The most common (≥20%) TEAEs of any grade with trastuzumab deruxtecan in cohort 2 were nausea, alopecia, anemia, decreased appetite, neutrophil count decrease, vomiting, diarrhea, weight decrease, constipation, fatigue, white blood cell count decrease, and aspartate aminotransferase increase.

Five patients had grade 5 TEAEs, which included disease progression in 2 patients, and 1 patient each had seizure, delirium, and pneumonia; these were not considered to be related to treatment. Five patients had adjudicated drug-related interstitial lung disease (ILD), all of grade 2 in severity.

TEAEs led to dose interruption in 59.5%, dose reduction in 38.1%, and treatment discontinuation in 23.8%.

“Drug-related ILD events observed in this patient population were low grade and there were no deaths,” Smit said. “However, ILD remains an important identified risk for patients treated with trastuzumab deruxtecan and requires careful monitoring and management.”

The cohort was expanded to enroll an additional 50 patients to help further characterize the efficacy of trastuzumab deruxtecan in patients with HER2-mutant NSCLC. Follow-up in this study is ongoing.

_Reference:

_{Smit EF, Nakagawa K, Nagasaka M, et al; DESTINY-Lung01 Investigators. Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non–Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract MA11.03.}