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

The European Medicines Agency has validated an application for the use of trastuzumab deruxtecan for adults with previously treated unresectable or metastatic non–small cell lung cancer whose tumors have activating HER2 mutations.

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