FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2+ NSCLC


Trastuzumab deruxtecan for the treatment of patients with unresectable or metastatic non–small cell lung cancer has been granted priority review by the FDA.

The FDA has granted priority review to a supplemental biologics license application (sBLA) for fam-trastuzumab deruxtecan-nxki (Enhertu) as treatment of adult patients with unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and who have received a prior systemic therapy.1

Approval of the application comes from the findings of the phase 2 DESTINY-Lung01 (NCT03505710) trial and the phase 1 DS8201-A-J101 (NCT02564900) trial.

“The DESTINY-Lung01 trial confirmed the HER2 mutation as an actionable biomarker in NSCLC. If approved, Enhertu has the potential to become a new standard treatment in this patient population, offering a much-needed option for patients with HER2-mutant metastatic NSCLC who currently have no targeted treatment options,” stated Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, in the press release.

Breakthrough therapy designation to trastuzumab deruxtecan was granted by the FDA in May 2020, for the treatment of patients with HER2-mutant NSCLC with disease progression on or after platinum-based therapy based on data from both the DS8201-A-J101 and DESTINY-Lung01 trial.

Findings from the phase 1, dose-expansion trial, DS8201-A-J101, showed trastuzumab deruxtecan in patients with advanced solid tumors showed significant activity in patients with HER2-mutant NSCLC. An overall response rate (ORR) of 72.7% (n = 8) was demonstrated and median progression-free survival (PFS) in these patients was 11.3 months (95% CI, 8.1-14.3).

In the phase 2 study, an ORR of 54.9% (n = 50; 95% CI, 44.2%-65.4%) among 91 patients with HER2-mutant NSCLC was reported with the antibody-drug conjugate (ADC). The median PFS in these patients was 8.2 months (95% CI, 6.0-11.9).

DESTINY-Lung01 is a global, open-label, multicenter trial that is evaluating both the safety and efficacy of trastuzumab deruxtecan in patients with HER2-mutant or HER2-overexpressing unresectable and metastatic nonsquamous NSCLC.

Patients are eligible for enrollment in the study, if they have progressed after ≥1 systemic regimen which can include chemotherapy, targeted therapy, or immunotherapy, and have HER2 expression defined as IHC 2+ or 3+.

The study is divided into 2 cohorts. Cohort 1 is for patients with HER2 mutations (n = 90), and cohort 2 is for patients with HER2 overexpression. Patients in cohort 1 received trastuzumab deruxtecan at a dose of 6.4mg/kg or 5.4mg/kg, while patients in cohort 2 received the drug at a dose of 6.4mg/kg.

The study’s primary end point is objective response rate with key secondary end points of duration of response, disease control rate, PFS, and overall survival.

Findings from the second cohort (n = 42) who were treated with 6.4 mg/kg of trastuzumab deruxtecan every 3 weeks, a total of 19 patients remained on treatment at the time of the data cutoff and 23 patients had discontinued. Discontinuation was due to progressive disease or adverse events. The median treatment duration was 7.8 months (range, 0.7-14.3).

The confirmed ORR for this cohort was 61.9% (95% CI, 45.6%-76.4%), with complete responses seen in 2.4% and partial responses in 59.5%. Additionally, 28.6% had stable disease, and a disease control rate of 90.5% (95% CI, 77.4%-97.3%). A total of 2 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), and neither the median DOR nor the median OS were evaluable.

Treatment-emergent adverse events (TEAEs) were observed in all patients with grade ≥3 consisting in 64.3% Those which were considered drug related took place in 52.4%. The most common (≥20%) TEAEs of any grade 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%.

The regulatory agency is expected to decide on the sBLA during the third quarter of 2022 under the Prescription Drug User Fee Act.

“The results of DESTINY-Lung01 showed that Enhertu is the first HER2-directed therapy to demonstrate a strong and robust tumor response in more than half of patients with previously treated HER2-mutant metastatic NSCLC,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, added in the release. “Seeking approval in the United States for a third tumor type in three years further demonstrates the significant potential of Enhertu in treating multiple HER2-targetable cancers.”

  1. Enhertu granted priority review in the US for patients with previously treated HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca. April 19, 2022. Accessed April 19, 2022. https://bit.ly/3EqCxB3

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