Trastuzumab Deruxtecan Wins EU Approval for HER2-Mutated Advanced NSCLC

The European Commission (EC) has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy.¹

The regulatory decision was supported by data from the phase 2 DESTINY-Lung02 trial (NCT04644237), which showed that patients with previously treated, HER2-mutated, advanced or metastatic NSCLC treated with 5.4 mg/kg of the antibody-drug conjugate (n = 102) experienced a confirmed overall response rate (ORR) of 49.0% (95% CI, 39.0%-59.1%) per blinded independent central review (BICR) assessment.²

Among responders, 1.0% achieved a complete response (CR) and 48.0% experienced a partial response (PR); 44.1% of patients had stable disease (SD), 3.9% had progressive disease (PD), and 2.9% were not evaluable for response. The disease control rate (DCR) was 93.1% (95% CI, 86.4%-97.2%). The median duration of response (DOR) was 16.8 months (95% CI, 6.4-not evaluable), and the median time to initial response (TTIR) was 1.8 months (range, 1.2-7.0).

“HER2-mutant NSCLC is more commonly diagnosed in patients who are younger and female, and there are limited treatment options, which often results in a poor prognosis,” Martin Reck, MD, head of the Department of Thoracic Oncology at the Lung Clinic Grosshansdorf in Germany, stated in a news release.¹ “[Trastuzumab deruxtecan] is the first HER2-directed therapy to demonstrate strong and durable results for these patients, and this approval in the European Union marks an important step forward in how the disease can be treated.”

In August 2022, the FDA granted accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy.³ That decision was also based on findings from DESTINY-Lung02.

The blinded, multicenter, phase 2 study enrolled patients at least 18 years of age with metastatic NSCLC harboring a known activating HER2 mutation who received at least 1 prior treatment in the metastatic/locally advanced setting and were not amenable to curative surgery or radiation.² Patients were also required to have at least 1 measurable lesion by BICR per RECIST v1.1 criteria.

The trial excluded patients with known driver mutations in EGFR, BRAF, or MET exon 14, or known ALK, ROS1, RET, or NTRK fusions. Those with spinal cord compression or clinically active, untreated and symptomatic brain metastases, or those requiring therapy with corticosteroids or anticonvulsants, were excluded. However, those with stable baseline brain metastases not requiring corticosteroids or anticonvulsants were permitted.

The study included 152 patients who were randomly assigned 2:1 to received 5.4 mg/kg of trastuzumab deruxtecan once every 3 weeks (n = 102) or 6.4 mg/kg of trastuzumab deruxtecan once every 3 weeks (n = 50).

BICR-assessed confirmed ORR per RECIST v1.1 criteria served as the trial’s primary end point. Key secondary end points consisted of investigator-assessed ORR, DCR, DOR, progression-free survival, and overall survival. TTIR, best percentage change in the sum of diameters of target lesions, and biomarkers were exploratory end points.

Findings from the 6.4-mg/kg arm showed that patients achieved a confirmed ORR of 56.0% (95% CI, 41.3%-70.0%), which included a CR rate of 4%, a PR rate of 52%, and a SD rate of 36%. Four percent of patients had PD, and 4% were not response evaluable. The DCR in this group was 92% (95% CI, 80.8%-97.8%), the median DOR was NE (95% CI, 8.3-NE), and the median TTIR was 1.6 months (95% CI, 1.2-11.2).

Regarding safety, any-grade drug-related treatment-emergent adverse effects (TEAEs) were reported 96.0% of evaluable patients in the 5.4-mg/kg arm (n = 101) and all evaluable patients in the 6.4-mg/kg arm (n = 50). The rates of drug-related TEAEs that were grade 3 or higher were 38.6% (95% CI, 29.1%-48.8%) and 58.0% (95% CI, 43.2%-71.8%), respectively.

Adjudicated drug-related interstitial lung disease (ILD) occurred in 12.9% of patients in the 5.4-mg/kg arm, and included four grade 1 events, seven grade 2 events, one grade 3 event, and one grade 5 event. Twenty-eight percent of patients in the 6.4-mg/kg arm experienced drug-related ILD, including four grade 1 events, nine grade 2 events, and one grade 5 event.

In the 5.4-mg/kg arm, drug-related TEAEs led to drug discontinuation in 13.9% of patients, dose reduction in 16.8% of patients, and drug interruption in 26.7% of patients. In the 6.4-mg/kg arm, those rates were 20.0%, 32.0%, and 48.0%, respectively.

References

1. Enhertu approved in the EU as the first HER2 directed therapy for patients with HER2 mutant advanced non-small cell lung cancer. News release. Daiichi Sankyo. October 23, 2023. Accessed October 23, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202310/20231023_E.pdf
2. Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial. J Clin Oncol. Published online September 11, 2023. doi:10.1200/JCO.23.01361
3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed October 23, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung