FDA Grants Priority Review to Trastuzumab Deruxtecan for Previously Treated HER2-Mutant NSCLC

The FDA has accepted for priority review a supplemental biologics license application (sBLA) for fam-trastuzumab deruxtecan-nxki (Enhertu) for the 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.^1,2

The application is supported by findings from the phase 2 DESTINY-Lung01 (NCT03505710) and phase 1 DS8201-A-J101 (NCT02564900) trials.

In the phase 1 study, trastuzumab deruxtecan led to an overall response rate (ORR) of 72.7% (n = 8) among 11 patients with HER2-mutant NSCLC. The median progression-free survival (PFS) in these patients was 11.3 months (95% CI, 8.1-14.3).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).^1,2

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

“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,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a news release.^1,2

In May 2020, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for the treatment of patients with HER2-mutant NSCLC with disease progression on or after platinum-based therapy based on findings from DS8201-A-J101 and DESTINY-Lung01.⁴

DESTINY-Lung01 is a global, open-label, two-cohort trial evaluating the safety and efficacy of trastuzumab deruxtecan in patients with HER2-overexpressing (cohort 1) or HER2-mutant (cohort 2) unresectable and/or metastatic nonsquamous NSCLC with disease progression after at least 1 prior systemic therapy.

Patients in cohort 1 received trastuzumab deruxtecan at a dose of 6.4mg/kg or 5.4mg/kg, and patients in cohort 2 received the drug at a dose of 6.4mg/kg.

In the study, HER2 overexpression was defined as immunohistochemistry (IHC)3+ or IHC2+.

The primary end point of the trial was confirmed ORR by independent central review. Key secondary endpoints included duration of response (DOR), disease control rate (DCR), PFS, overall survival (OS), and safety.

Additional results from cohort 2 of DESTINY-Lung01 demonstrated that responses consisted of 1 (1.1%) complete response and 49 (53.8%) partial responses.

A confirmed disease control rate (DCR) of 92.3% (95% CI, 84.8%-96.9%) was reported, with a tumor size reduction observed in most patients. After a median follow-up of 13.1 months, the median DOR with the ADC was 9.3 months (95% CI, 5.7-14.7). The median OS was 17.8 months (95% CI, 13.8-22.1).

Regarding the agent’s safety profile, the adverse effects (AEs) observed with trastuzumab deruxtecan in DESTINY-Lung01 were comparable with those reported in prior clinical trials.

The most common grade 3 or higher drug-related, treatment-emergent AEs included neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%), and vomiting (3.3%).

Twenty-three patients (25%) discontinued treatment because of drug-related, treatment-emergent AEs.

Twenty-six percent of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as adjudicated by an independent committee. The majority of ILD events (75%) were low grade (grade 1, 12.5%; grade 2, 62.5%). Additionally, 4 grade 3 (4.4%) and 2 grade 5 (2.2%) ILD or pneumonitis events were reported.

“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.^1,2 “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.”

References

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/36qBog3
2. ENHERTU granted priority review in the U.S. for patients with previously treated HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. April 19, 2022. Accessed April 19, 2022. https://bit.ly/3rAE1mS
3. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10(5):688-701. doi:10.1158/2159-8290.CD-19-1014
4. Enhertu granted breakthrough therapy designation in the US for HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. May 18, 2020. Accessed April 19, 2022. https://bit.ly/3MgQiES