Trastuzumab Deruxtecan Approved in Japan for HER2-Mutated Metastatic NSCLC

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