Trastuzumab Deruxtecan (Enhertu) Receives FDA Approval for HER2-Low Breast Cancer
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On 5 August 2022, the FDA (US Food and Drug Administration) approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo Inc.) for adults with unresectable or metastatic HER2-low breast cancer. To receive Enhertu, these patients must have previously received chemotherapy for metastatic breast cancer or developed recurrence during adjuvant chemotherapy (protective treatment after surgery), or within six months of completing it.
When pathologists examine breast cancer tissue under a microscope, they determine tumour HER2 status using special immunohistochemical (IHC) stains. In the traditional approach, the staining results are interpreted as follows:
- 0: HER2 “negative”;
- 1+: HER2 “low positive”;
- 2+: HER2 “equivocal positive”. In this case, HER2 must be examined with a FISH test for confirmation. Whether FISH is positive or negative determines the tumour’s final HER2 status.
- 3+: HER2 “positive”.
Before this approval, anti-HER2 targeted medicines were approved only for definitely positive cases (HER2 IHC 3+ or FISH-positive).
The DESTINY-Breast04 study enrolled patients with “low-positive” HER2 results (IHC 1+, or IHC 2+ / FISH-negative) in breast cancer.
As patients with HER2-low tumours account for 50% of all patients with breast cancer, this is an important approval.
FDA Approval Based on the DESTINY-Breast04 Study
We reported the detailed results of DESTINY-Breast04, which demonstrated Enhertu’s effectiveness in HER2-low breast cancer, in our article “The Most Important Development in Oncology in 2022”.
The phase-III DESTINY-Breast04 study, conducted in Asia, Europe and North America, enrolled patients with hormone receptor (HR)-negative or positive, HER2-low, unresectable and/or metastatic breast cancer previously treated with one or two lines of therapy: 557 patients in total.
Patients were randomised 2:1 to trastuzumab deruxtecan or one of several standard chemotherapy medicines chosen by their doctor.
The planned primary endpoint in the hormone receptor-positive group was progression-free survival. Secondary endpoints were progression-free survival in all patients, and overall survival in both the hormone receptor-positive group and all patients.
Results
Of 557 patients, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease.
After median follow-up of 18.4 months,
- Trastuzumab deruxtecan reduced the risk of progression by 49% and the risk of death by 36% compared with chemotherapy.
- The group also had longer progression-free survival (10.1 versus 5.4 months) and overall survival (23.9 versus 17.5 months).
Adverse effects were similar between groups (52.6% with trastuzumab deruxtecan and 67.4% with chemotherapy), but 12% of the trastuzumab deruxtecan group developed pulmonary toxicity, resulting in 3 deaths (0.8%). Previous trastuzumab exposure has been associated with interstitial lung disease/pneumonia; an earlier meta-analysis found a 2.4% incidence and 0.2% mortality rate.
The recommended Enhertu dose for breast cancer is 5.4 mg/kg as an intravenous infusion every 3 weeks (a 21-day cycle) until disease progression or unacceptable toxicity.
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Enhertu, whose active ingredient is trastuzumab deruxtecan, had previously received FDA approval:
- in 2019, for advanced HER2-positive breast cancer after at least 2 anti-HER2 treatment regimens;
- in 2021, for previously treated advanced HER2-positive gastric cancer; and
- in May 2022, for advanced HER2-positive breast cancer after one prior anti-HER2 treatment line.
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