News

Article

Trastuzumab Deruxtecan Approved in Japan for HER2-Mutated Metastatic NSCLC

Author(s):

Japan’s Ministry of Health, Labour, and Welfare has approved fam-trastuzumab deruxtecan-nxki for use in adult patients with unresectable advanced or recurrent, HER2-mutant non–small cell lung cancer that has progressed following chemotherapy.

Wataru Takasaki, PhD

Wataru Takasaki, PhD

Japan’s Ministry of Health, Labour, and Welfare has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for use in adult patients with unresectable advanced or recurrent, HER2-mutant non–small cell lung cancer (NSCLC) that has progressed following chemotherapy.1

The decision was based on data from the phase 2 DESTINY-Lung02 trial (NCT04644237), in which the antibody-drug conjugate, when given at a dose of 5.4 mg/kg (n = 52), elicited a confirmed objective response rate (ORR) of 53.8% (95% CI, 39.5%-67.8%) by blinded independent central review (BICR) at a data cutoff date of March 24, 2022.2 Among responders, 1.9% had a complete response (CR), 51.9% experienced a partial response (PR), and 36.5% achieved stable disease (SD); 3.8% of patients had disease progression (PD) and 5.8% were not evaluable.

In this group, the disease control rate (DCR) was 90.4% (95% CI, 79.0%-96.8%), the median duration of response (DOR) was not evaluable (NE; 95% CI, 4.2-NE), and the median time to initial response (TTIR) was 1.4 months (range, 1.2-5.8).

HER2-mutant NSCLC is a rare but serious disease, and now, patients and physicians in Japan have the potential to benefit from the first HER2-directed treatment option approved specifically for this type of lung cancer,” Wataru Takasaki, PhD, executive officer, and head of the R&D Division in Japan at Daiichi Sankyo, stated in a press release.1 “This is the fourth indication secured for [trastuzumab deruxtecan] in Japan in just over 3 years, and the second approval this year alone, underscoring the benefit of this medicine across a range of HER2-targetable cancers.”

The international, multicenter, non-comparative, 2-arm, phase 2 DESTINY-Lung02 trial enrolled patients with metastatic NSCLC with an activating HER2 mutation who had previously received 1 or more anticancer therapies, including platinum-based chemotherapy.2 Patients were required to have measurable disease by BICR and RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.

Study participants (n = 152) were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 102) or at 6.4 mg/kg every 3 weeks (n = 50). A key stratification factor was prior use of an anti–PD-1/PD-L1 agent.

The prespecified early cohort comprised patients who underwent randomization at least 4 months prior to the interim analysis data cutoff to have a more robust efficacy assessment; this included 52 patients who received trastuzumab deruxtecan at 5.4 mg/kg and 28 patients who received it at 6.4 mg/kg. To qualify for this cohort, patients needed to have undergone at least 3 post-baseline assessments at the time of cutoff.

Because the median DOR for trastuzumab deruxtecan given at a dose of 5.4 mg/kg had not yet been reached at the data cutoff date of March 24, 2022, investigators conducted an additional 90-day follow-up analysis for response. At this time point, the confirmed ORR with the ADC was 57.7% (95% CI, 43.2%-71.3%), which included a CR rate of 1.9% and a PR rate of 55.8%. The median DOR was 8.7 months (95% CI, 7.1-NE).

In this group, the mean best minimum change in tumor size by BICR was -38.6% (range, -100 to 6.0).

In the group of patients who received trastuzumab deruxtecan at 6.4 mg/kg, the confirmed ORR was 42.9% (95% CI, 24.5%-62.8%), which included a CR rate of 3.6%, a PR rate of 39.3%, and a SD rate of 50%. Here, 3.6% of patients experienced PD and 3.6% were not evaluable for response. At a median follow-up was 5.4 months (range, 0.6-12.1), the DCR was 92.9% (95% CI, 76.5%-99.1%), the median DOR was 5.9 months (95% CI, 2.8-NE), and the median TTIR was 1.4 months (95% CI, 1.2-3.0). The best percent change in tumor size by BICR in this group was -34.6% (range, -100 to 7.0).

Patients who received trastuzumab deruxtecan at 5.4 mg/kg (n = 101) had a median treatment duration of 3.7 months (range, 0.7-11.8). At a median follow-up of 3.8 months (range, 0-11.7), 92.1% of these patients experienced any-grade treatment-emergent adverse effects (TEAEs) with 31.7% experiencing grade 3 or higher effects. TEAEs that required dose interruptions or reductions were observed in 13.9% and 9.9% of patients, respectively; 7.9% experienced TEAEs that led to discontinuation. TEAEs resulted in death in 1.0% of patients.

Any-grade adjudicated drug-related interstitial lung disease (ILD) was observed in 5.9% of patients; of these patients, 3% had grade 1 events, 2% had grade 2 events, and 1% had grade 3 events. No grade 4 or 5 cases of ILD was observed. Half of cases resolved. The median time to onset of first adjudicated ILD was 67.5 days (range, 40-207). Notably, the rate of this effect proved to be lower at the 5.4-mg/kg dose vs the 6.4-mg/kg dose of the ADC (any grade, 14%).

Treatment-related AEs (TRAEs) were observed in 92.1% of those who received trastuzumab deruxtecan at 5.4 mg/kg.1 The most common TRAEs included nausea (59.4%), decreased neutrophil count (33.7%), anemia (28.7%), reduced appetite (28.7%), fatigue (25.7%), constipation (24.8%), decreased leukocyte count (23.8%), and vomiting (22.8%).

References

  1. ENHERTU approved in Japan as first HER2 directed therapy for patients with HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. August 23, 2023. Accessed August 23, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202308/20230823_E.pdf
  2. Goto K, Sang-We K, Kubo T, et al. LBA55 trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol. 2022;33(suppl 7):S1422. doi:10.1016/j.annonc.2022.08.057
Related Videos
Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, on progression patterns and subsequent therapies after lorlatinib in ALK-positive NSCLC.
Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, discuss preclinical CNS data for the ROS1 inhibitor zidesamtinib.
Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, discuss data for zidesamtinib in ROS1-positive non–small cell lung cancer.
Massimo Cristofanilli, MD, attending physician, NewYork-Presbyterian Hospital; professor, medicine, Weill Cornell Medical College, Cornell University
Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, discuss data for NVL-655 in ALK-positive NSCLC and other ALK-positive solid tumors.
Gregory J. Riely, MD, PhD, and Benjamin Besse, MD, discuss testing for ALK-positive and ROS1-positive non–small cell lung cancer.
Nicolas Girard, MD
Sally Lau, MD
Andrea Wolf, MD, MPH
Jacob Sands, MD