EMA Validates Type II Application for Trastuzumab Deruxtecan in Advanced HER2-Mutated NSCLC

The European Medicines Agency (EMA) has validated an application for the use of fam-trastuzumab deruxtecan-nxki (Enhertu) for adults with previously treated unresectable or metastatic non–small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations.¹

Validation confirms that the application is complete, and the EMA’s Committee for Medicinal Products for Human Use will now begin the scientific review process.

“[Trastuzumab deruxtecan] is the first HER2-directed medicine shown to have a clinically meaningful tumor response in patients with previously treated HER2-mutant metastatic NSCLC,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, said in a news release. “As there are no approved therapies targeting HER2-mutant NSCLC in Europe, we look forward to working closely with the EMA to potentially bring a new treatment option to these patients.”

This application is based on data from the phase 2 DESTINY-Lung02 trial (NCT04644237) presented in September at the ESMO 2022 Congress and the phase 2 DESTINY-Lung01 trial (NCT03505710). Data from DESTINY-Lung01 were published in The New England Journal of Medicine in January 2022 with updated data presented at ESMO 2022.

Investigators in DESTINY-Lung02 randomly assigned patients to 5.4 mg/kg of trastuzumab deruxtecan (cohort 1; n = 102) or 6.4 mg/kg of trastuzumab deruxtecan (cohort 2; n = 50). The primary end point of the trial was confirmed objective response rate (ORR) as assessed by blinded independent central review.²

The confirmed ORR in the prespecified early cohort (PEC) of the study was 53.8% (95% CI, 39.5%-67.8%) at the lower dose level and 42.9% (95% CI, 24.5%-62.8%) at the higher dose. The lower dose also showed superior safety and tolerability, including a lower rate of interstitial lung disease.

In the 5.4 mg/kg arm of the PEC, there were 27 (51.9%) partial responses (PRs), 1 (1.9%) complete response (CR), 19 (36.5%) patients with stable disease (SD), 2 (3.8%) with progressive disease (PD), and 3 (5.8%) who were not estimable (NE). In the 6.4 mg/kg arm, there were 11 (39.3%) PRs, 1 (3.6%) CR, 14 (50.0%) SD, 1 (3.6%) PD, and 1 (3.6%) NE.

The confirmed disease control rate was 90.4% (95% CI, 79.0%-96.8%) the lower-dose arm and 92.9% (95% CI, 76.5%-99.1%) in the higher-dose arm. The median duration of response (DOR) was NE (range, 4.2 months–NE) and 5.9 months (range, 2.8–NE) for the lower- and higher-dose arms, respectively.

An additional analysis of the response at a data cutoff of June 22, 2022, showed the median DOR was 8.7 months (95% CI, 7.1–NE) and the confirmed ORR was 57.7% (95% CI, 43.2%-71.3%) for the 5.4 mg/kg arm.

The earlier DESTINY-Lung01 trial evaluated the efficacy and safety of 5.4 mg/kg or 6.4 mg/kg of trastuzumab deruxtecan in patients with HER2-mutant (cohort 2, n = 91) or HER2-overexpressing (cohorts 1 and 1a, n = 90), as defined as immunohistochemistry (IHC) 3+ or IHC 2+, unresectable or metastatic nonsquamous NSCLC relapsed from or refractory to standard treatment or for which no standard treatment is available.^3,4

In December 2022, Daiichi Sankyo filed a supplemental new drug applicationwith Japan’s Ministry of Health, Labor, and Welfare for the use of trastuzumab deruxtecan in adults with previously treated HER2-mutant unresectable advanced or recurrent NSCLC based on these findings.⁵

In August 2022, the FDA granted an accelerated approval to trastuzumab deruxtecanfor use in adults with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received prior systemic therapy, based on data from DESTINY-Lung02.⁶

References

1. Enhertu Type II variation application validated by EMA for the treatment of HER2-mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo and AstraZeneca. January 4, 2023. Accessed January 4, 2023. https://bit.ly/3ik1NC6
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):S808-S869. doi:10.1016/annonc/annonc1089
3. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431
4. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients (pts) with HER2-overexpressing (HER2-OE) metastatic non-small cell lung cancer (NSCLC): Results from the DESTINY-Lung01 trial. Ann Oncol. 2022;33(suppl_7):S448-S554. doi:10.1016/annonc/annonc1064
5. ENHERTU® supplemental new drug application submitted in Japan for patients with HER2 mutant metastatic non-small cell lung cancer. News release. Daiichi Sankyo. December 13, 2022. Accessed January 4, 2023. https://bit.ly/3uTVR5G
6. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 11, 2022. Accessed January 4, 2023. https://bit.ly/3bVts9g