Rationale for Correct Answer

The correct answer is: HER2-activating mutations

Trastuzumab deruxtecan was FDA approved in December 2022 for patients with unresectable or metastatic NSCLC whose tumors have HER2-activating mutations and who have received a prior systemic therapy.1 This therapy was investigated in the Destiny-Lung01 trial, which found a 55% objective response rate (ORR) for patients with HER2-activating mutations (n = 91) and a 24.5% ORR for patients with HER2-overexpression (n = 49). All patients received a dose of 6.4 mg/kg in this trial.2,3 Another trial, Destiny-Lung02, did not enroll patients with HER2-overexpression, and found an ORR of 58% for patients with HER2-activating mutations who received a lower dose of 5.4 mg/kg (n = 52). The lower dose was tested to improve the benefit/risk ratio of this therapy.4

1. U.S. Food & Drug Administration (FDA). Oncology (Cancer) / Hematologic Malignancies Approval Notifications. Reviewed June 20, 2023. Accessed June 20, 2023. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm.
2. Li BT et al. N Engl J Med. 2022;386:241-251.
3. Nagakawa K et al. Presented at WCLC 2020; January 2021. Abstract OA04.05
4. Goto K et al. Presented at European Society for Medical Oncology (ESMO) 2022; September 2022. Abstract LBA55.