The drug Enhertu has been shown to enable women with advanced breast cancer to live six months longer than others treated with conventional chemotherapy, new data from AstraZeneca and the Japanese drug-maker, Daiichi Sankyo, show.
The study, presented at the annual meeting of the American Society of Clinical Oncology and and published in the New England Journal of Medicine, would change how medicine was practiced, cancer specialists said, according to The New York Times.
And the evidence suggests the drug could one day be used to treat many other types of tumours, opening broad opportunities for Enhertu and other drugs like it, notes the Sunday Times Daily.
Enhertu is what’s known as an antibody-drug conjugate because it uses an antibody to home in on a tumour cell before releasing a payload of toxic chemotherapy to kill it. This drug’s antibody zeroes in on a protein called HER2, a growth signal that in some breast cancers becomes too amped up. The US Food and Drug Administration (FDA) approved Enhertu in late 2019 for some so-called “HER2-positive” cancers or tumours that on a diagnostic test show a certain threshold of that signal.
The new data are from breast cancers that have low, even negligible levels of HER2. That means a far wider range of patients might benefit from the drug — as many as 55% of breast cancers that were previously considered “HER2-negative” could actually have these low levels of the protein.
Other HER2-targeted drugs have been studied in patients whose tumours express low levels of the protein, but none has helped. Oncologists have a few theories about what makes Enhertu different.
One possibility is that there’s just enough HER2 being expressed on the cancer-cell surface to make it “sticky” enough for Enhertu’s antibody to attach and then deliver the powerful chemo.
The evidence adds to a growing body of research suggesting that antibody-drug conjugates will one day replace conventional chemo for most patients.
The design of the drug itself could also matter. Daiichi Sankyo, which discovered the drug before striking a deal to develop it with AstraZeneca in 2019, seems to have ironed out many of the kinks that limited the success of earlier antibody-drug conjugates. Enhertu uses a different, more powerful chemo payload and a bigger one too. Whereas most antibody-drug conjugates carry two to four chemo molecules, Enhertu delivers eight. The payload’s effect is also more fleeting, to help minimise side effects from the very toxic chemo.
This suggests that, after decades of trial and error with antibody-drug conjugates, cancer researchers are finally starting to understand how best to design and use them.
The drugs are not without downsides. Enhertu’s design allows an otherwise too-toxic chemotherapy to be used, but the side effects of the drug — and antibody-drug conjugates in general — are similar to those of all chemo. And these drugs are much more expensive, potentially putting them out of reach for the uninsured or for breast cancer patients in low-income countries.
Nevertheless, Enhertu is teaching the field how to design drugs in this class to maximise their benefit. That could mean effective treatment for a wide universe of patients.
Study details
Trastusumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer
Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura.
Published in the New England Journal of Medicine on 5 June 2022
Abstract
Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these “HER2-low” cancers.
Methods
We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician’s choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor–positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor–positive cohort and among all patients.
Results
Of 557 patients who underwent randomisation, 494 (88.7%) had hormone receptor–positive disease and 63 (11.3%) had hormone receptor–negative disease. In the hormone receptor–positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P=0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P=0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.
Conclusions
In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials)
ABC article – Researchers: Breast cancer drug could help more patients (Open access)
Bloomberg article – This Drug Could Transform Breast Cancer Treatment (Restricted access)
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Enhertu improved progression-free and overall survival in metastatic breast cancer
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