FDA Grants Accelerated Approval to Trastuzumab Deruxtecan for Unresectable or Metastatic HER2+ Solid Tumors


The FDA granted accelerated approval to trastuzumab deruxtecan for pretreated, unresectable or metastatic HER2-positive solid tumors.



The FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.

The regulatory decision was supported by data from 192 adult patients with previously treated, unresectable or metastatic HER2-positive solid tumors enrolled in the phase 2 DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials.

Findings from DESTINY-PanTumor02 showed that patients experienced an overall response rate (ORR) of 51.4% (95% CI, 41.7%-61.0%) and a median duration of response (DOR) of 19.4 months (range, 1.3 to 27.9+).

Those treated In DESTINY-Lung01 achieved an ORR of 52.9% (95% CI, 27.8%-77.0%) and a median DOR of 6.9 months (range, 4.0 to 11.7+).

Findings from DESTINY-CRC02 showed that the ORR was 46.9% (95% CI, 34.3%-59.8%), and the median DOR was 5.5 months (range, 1.3+ to 9.7+).


In the primary analysis of the open-label study, patients treated across 7 tumor cohorts (n = 267) experienced an ORR of 37.1% (95% CI, 31.3%-43.2%). The cohorts included patients with endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other cancer types who had HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic tumors after at least 1 systemic treatment or without alternative treatments. Notably, responses were observed across all cohorts.2

All patients received trastuzumab deruxtecan at 5.4 mg/kg once every 3 weeks. ORR served as the trial's primary end point, and secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and safety.

Additional data showed that the antibody-drug conjugate elicited a median DOR of 11.3 months (95% CI, 9.6-17.8), a median PFS of 6.9 months (95% CI, 5.6-8.0), and a median OS of 13.4 months (95% CI, 11.9-15.5).

Notably, patients with a HER2 expression of IHC 3+ (n = 75) achieved an ORR of 61.3% (95% CI, 49.4%-72.4%), a median DOR of 22.1 months (95% CI, 9.6–not reached [NR]), a median PFS of 11.9 months (95% CI, 8.2-13.0), and a median OS of 21.1 months (95% CI, 15.3-29.6).


In this open-label, single-arm study, cohorts 1 and 1a included patients with unresectable or metastatic non-squamous non–small cell lung cancer (NSCLC) with a HER2 expression of IHC 3+ or 2+ without known HER2 mutations. Patients needed to be relapsed following or be refractory to standard treatment, or have standard treatment available.3

Patients in cohort 1 received trastuzumab deruxtecan at 6.4 mg/kg once every 3 weeks, and those in cohort 1a were administered the agent at 5.4 mg/kg once every 3 weeks. ORR was the primary end point.

Findings showed that in cohort 1 (n = 49), the confirmed ORR was 26.5% (95% CI, 15.0%-41.1%), and in cohort 1a (n = 41), the confirmed ORR was 34.1% (95% CI, 20.1%-50.6%).


Patients treated with 5.4 mg/kg of trastuzumab deruxtecan (n = 82) achieved a confirmed ORR of 37.8% (95% CI, 27.3%-49.2%), and those given 6.4 mg/kg of the ADC (n = 40) had a confirmed ORR of 27.5% (95% CI, 14.6%-43.9%). The median DORs were 5.5 months (95% CI, 4.2-8.1) and 5.5 months (95% CI, 3.7–not estimable [NE]), respectively.4

The study included patients with metastatic colorectal cancer (mCRC) with a HER2 expression of IHC 3+ or IHC 2+/in situ hybridization positive. Patients with RAS wild-type or mutant mCRC were not allowed to enroll, and prior treatment with anti-HER2 therapy was permitted.

In the first part of the study, patients were randomly assigned 1:1 between the 5.4 and 6.4 mg/kg doses, and in stage 2, additional patients were enrolled to receive the 5.4 mg/kg dose.

Confirmed ORR was the trial's primary end point, and secondary end points included PFS, DOR, OS, and safety.

Overall Safety

Data from all patients across the 3 studies showed that the most common adverse effects reported in at least 20% of patients included decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection.1

Trastuzumab deruxtecan includes a boxed warning for interstitial lung disease and embryo-fetal toxicity.

The recommended dosage for this indication is 5.4 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.


  1. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed April 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
  2. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
  3. Smit EF, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024;25(4):439-454. doi:10.1016/S1470-2045(24)00064-0
  4. Raghav K, Siena S, Takashima A, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol. 2023;41(suppl 16):3501. doi:10.1200/JCO.2023.41.16_suppl.3501

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