FDA expanded Enhertu (trastuzumab deruxtecan) use in early HER2-positive breast cancer based on phase 3 neoadjuvant and adjuvant trial data.
The FDA has expanded Enhertu’s (trastuzumab deruxtecan; AstraZeneca, Daiichi Sankyo) role in HER2-positive Stage II or Stage III breast cancer, approving two new indications last week.
The agency approved an expanded indication in the neoadjuvant setting for Enhertu followed by a taxane, trastuzumab, and pertuzumab (THP) for the treatment of adult patients with HER2-positive Stage II or Stage III breast cancer; whereas in the adjuvant setting, Enhertu has been approved for the treatment of adult patients with HER2-positive breast cancer who have residual invasive disease following trastuzumab (with or without pertuzumab) and taxane-based treatment.1-4
“HER2-positive early disease is considered highly curable, however up to one in four patients still experience disease recurrence, underscoring the need for new options in this setting,” Dave Fredrickson, executive vice president, Oncology Hematology Business Unit, AstraZeneca, said in a press release. “These approvals mark an important step forward, expanding the possibility of cure to more patients for the first time in many years and positioning Enhertu as a foundational treatment in early breast cancer.”1
For pharmaceutical and oncology leaders, the approvals are notable not only because they broaden the clinical use of a high-profile antibody-drug conjugate, but also because they bring a newer HER2-directed agent into direct competition with established perioperative regimens.
“HER2 positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence as early as possible to achieve the best long‑term outcomes. The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery,” said Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center and principal investigator for the DESTINY-Breast11 trial, in the press release.
In the neoadjuvant setting, the agency approved Enhertu followed by taxane, trastuzumab and pertuzumab for adults with HER2-positive stage 2 or stage 3 breast cancer. In the adjuvant setting, it approved Enhertu for adults with HER2-positive breast cancer who have residual invasive disease after neoadjuvant trastuzumab, with or without pertuzumab, and taxane-based treatment.1
The neoadjuvant approval was based on the phase 3 DESTINY-Breast11 trial, an open-label, randomized study enrolling 927 patients globally.1 In the regimen that led to approval, four cycles of Enhertu were followed by four cycles of taxane, trastuzumab and pertuzumab. The comparator arm received dose-dense doxorubicin and cyclophosphamide followed by taxane, trastuzumab and pertuzumab. The primary end point was pathologic complete response (PCR).
According to the company statement, PCR was achieved in 67.3% of patients receiving Enhertu followed by taxane, trastuzumab and pertuzumab, compared with 56.3% in the comparator group, for an absolute difference of 11.2% (95% confidence interval, 3.9-18.3; P = .003). PCR in HER2-positive disease has been associated with improved long-term outcomes, though it remains a surrogate rather than a direct survival measure.4
The adjuvant approval relied on DESTINY-Breast05, another phase 3, open-label, randomized trial that enrolled 1,635 patients with residual invasive disease after neoadjuvant therapy and who were considered at high risk of recurrence. In this study, Enhertu was compared with trastuzumab emtansine, the post-neoadjuvant standard established by the KATHERINE trial.3
The company reported that Enhertu reduced the risk of invasive disease recurrence or death by 53%, with a hazard ratio of 0.47 (95% confidence interval, 0.34-0.66; P < .0001).^1 Three-year invasive disease-free survival was 92.4% with Enhertu and 83.7% with trastuzumab emtansine. Disease-free survival results were similar, with a hazard ratio of 0.47 and three-year rates of 92.3% vs 83.5%, respectively.1 The data were published in The New England Journal of Medicine and subsequently incorporated into National Comprehensive Cancer Network guidance as a category 1 recommendation for selected high-risk patients in the adjuvant setting.1,3
HER2-positive early breast cancer is often curable, but recurrence remains clinically and commercially important. About one in five breast cancers are HER2-positive, and a meaningful subset of early-stage patients remain at risk despite neoadjuvant and adjuvant HER2-directed therapy.1,2 The move of Enhertu into earlier lines expands its addressable population and reinforces a broader industry trend: antibody-drug conjugates are no longer confined to refractory metastatic disease.
The approvals also carry direct financial implications. Under the collaboration terms described in the announcement, $155 million in milestone payments become due following the two US approvals.1 More broadly, the decision may influence capital allocation across competing HER2 programs, manufacturing investment in antibody-drug conjugate supply chains, and partnering strategies around earlier-line oncology assets.
The label continues to carry boxed warnings for interstitial lung disease or pneumonitis and embryo-fetal toxicity. In DESTINY-Breast11, interstitial lung disease or pneumonitis occurred in 4.4% of patients receiving Enhertu followed by taxane, trastuzumab and pertuzumab, with one fatal case reported. In DESTINY-Breast05, adjudicated drug-related interstitial lung disease occurred in 10% of patients, including grade 3 or 4 events in 0.9%, and fatal cases were also reported.1
That safety profile will likely shape adoption in curative-intent care, where clinicians and health systems may have lower tolerance for serious toxicity than in metastatic settings. The open-label design of both trials and the immaturity of overall survival data also leave unanswered questions about long-term benefit-risk balance, sequencing, and patient selection.
“Enhertu has redefined the treatment of HER2-expressing breast cancer with practice-changing data across six breast cancer indications in seven years,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., in the press release. “Enhertu is now approved in the US across both early and metastatic HER2-positive breast cancer, accomplishing what we set out to achieve a little over a decade ago for patients at the start of our comprehensive clinical development program.”1
Sources
