Enhertu potential broadens as new data point to frontline breast cancer role

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CHICAGO — Enhertu, the antibody-drug conjugate developed by AstraZeneca and Daiichi Sankyo, year by year proves more indispensable in the treatment of metastatic breast cancer.
Already enmeshed in clinical practice as a go-to choice for tumors that have come back once, Enhertu could soon have a role to play in initial treatment as well. On Monday, researchers shared results from a large trial showing Enhertu together with an older drug called Perjeta offer greater benefit in certain tumors than the current first-line standard, which includes Perjeta, the stalwart breast cancer drug Herceptin and chemotherapy.
The data will be presented Monday morning at the American Society of Clinical Oncology's annual meeting held here.
Known as Destiny-Breast09, the Phase 3 trial focused on people whose breast tumors were either locally advanced or had metastasized, and tested positive for a protein, HER2, that typically signals faster-spreading cancer. About 15% to 20% of breast cancers are HER2-positive and for decades now have been treated by Herceptin, Perjeta and other treatments that home in on the protein.
Enhertu is one of the newest — and most powerful — iterations. It consists of a HER2-targeting antibody linked to a tumor-killing toxin. Since winning its first U.S. approval in 2019, the drug has marched upwards through breast cancer treatment lines and into new uses in lung and stomach cancers. Last year, sales reached $3.7 billion.
Sales could rise further should findings from Destiny-Breast09 support frontline use in HER2-positive metastatic disease. In the trial, treatment with Enhertu and Perjeta delayed cancer growth for longer than the established regimen of Perjeta, Herceptin and chemotherapy, which is known by the acronym THP. Progression-free survival, which measures time from treatment to disease progression or death, reached a median of nearly 41 months among the 383 patients who received Enhertu and Perjeta, versus 27 months among the 387 given THP.
'That's a phenomenal advantage in progression-free survival and it's definitely practice-changing,' said Vishwanath Sathyanarayanan, a medical oncologist and an academic advisor at Apollo Hospitals in Bangalore, India.
Eleonora Teplinsky, head of breast and gynecologic medical oncology at New Jersey's Valley-Mount Sinai Comprehensive Cancer Care, agreed, although she cautioned that Enhertu comes with its own safety risks. 'While keeping an eye on [Enhertu's] toxicity, it's really hard to ignore that data.'
About 15% of patients given Enhertu plus Perjeta had a complete response following treatment — meaning no detectable signs of cancer — versus 8.5% among those on THP.
Researchers could not yet statistically determine whether the Enhertu regimen offered a benefit in survival, but reported that data are trending in that direction. Patients will continue to be monitored for further analysis later.
AstraZeneca and Daiichi Sankyo, which announced Destiny-Breast09 succeeded in late April, have said they plan to share the trial data with regulators. But they haven't clarified when they might seek an approval of Enhertu as part of first-line treatment.
Should it win an OK, doctors will have to grapple with a number of trade-offs and unanswered questions, not least of which are Enhertu's side effects. The drug's current labeling carries a 'black box' warning for interstitial lung disease and pneumonitis, which can be life-threatening. In Destiny-Breast09, this side effect occurred in 46 patients treated with Enhertu and Perjeta, compared to only 4 who received THP. While most cases were mild, two of the Enhertu-treated patients died.
Most participants in the trial were under 65 years old. As a result, Teplinsky said, it is not clear how well older patients might fare with Enhertu and Perjeta in the first-line setting.
Results from another study presented at ASCO suggest that, in mild cases of interstitial lung disease, Enhertu can be reintroduced after the side effect has been brought under control.
Moving Enhertu earlier in treatment also raises questions about how long it should be given and, if patients' disease progresses, what should be administered afterwards.
'Is this for all patients at the beginning of treatment? We don't know,' said Rebecca Dent, the deputy clinical chief executive officer at National Cancer Center Singapore, in a press conference with reporters. 'Is there a way to sequence this induction therapy that includes [Enhertu] followed by a maintenance stage of treatment?'
Destiny-Breast09 is also evaluating a third group of 387 patients who were given only Enhertu and a placebo. Researchers didn't yet have sufficient data to compare that arm to the other two when they conducted their initial, interim analysis.
Evidence supporting Enhertu monotherapy over THP would be significant if it materializes, said Sathyanarayanan, who noted that giving multiple, expensive drugs in combination can be challenging in low- and middle-income countries.
AstraZeneca and Daiichi Sankyo are studying Enhertu in even earlier settings, testing whether it could be given before or after surgery to remove a tumor. Last month, the companies said a study called Destiny-Breast11 succeeded, finding Enhertu followed by THP improved complete response rates versus standard of care when used before surgery.
And in stomach cancer, study data presented at ASCO on Saturday could help cement Enhertu's place as a second-line treatment option for gastric tumors.
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