After historic win, AstraZeneca and Daiichi's Enhertu could pressure Gilead's Trodelvy in breast cancer: experts

AstraZeneca and Daiichi Sankyo’s HER2-targeted medicine Enhertu recently turned in stellar results in a group of patients who were traditionally considered as having HER2-negative breast cancer. That could open up a broad market for the antibody-drug conjugate, potentially pressuring Gilead Sciences’ Trodelvy, experts say.

Enhertu could challenge Trodelvy in triple-negative breast cancer (TNBC) and might eventually leap ahead of the Gilead drug in the treatment sequence, two experts said during an SVB Securities event, according to a recent investor note.

Trodelvy’s limited off-label use in HR-positive breast cancer is also under threat, and, in that much larger disease area, Enhertu will become standard of care regardless of HER2 expression status, the experts said.

The rosy note for Enhertu comes after the drug posted what the experts believe will be paradigm-shifting results in HER2-low breast cancer. In previously treated patients, Enhertu cut the risk of disease progression or death by 50% and the risk of death by 36% compared with chemo, according to data from the phase 3 DESTINY-Breast04 study presented at the recent American Society of Clinical Oncology annual meeting.

In a small subgroup of TNBC patients, Enhertu cut the risk of disease progression or death by 54%. Based on cross-trial comparisons, one breast oncologist expects Enhertu to outperform Trodelvy in the TNBC arena.

But some good news for Trodelvy: Because the TNBC group in DESTINY-Breast04 was small, the experts indicated that they expect Enhertu will only show a clear efficacy advantage over time, SVB noted. Therefore, the SVB team said it doesn’t see a near-term threat to Trodelvy's sales in TNBC.

Because of their different mechanisms of action—Enhertu targets HER2, while Trodelvy goes after TROP-2—the experts suggested that the two drugs could be used sequentially, although Enhertu will likely be used first given its seemingly superior efficacy.

Both drugs are eyeing the larger HR-positive population. While Trodelvy’s interim readout cast doubts, the experts said they expect Enhertu will eventually become the standard of care.

“HER2 zero cancers are an endangered species,” SVB quoted from pathologists in one expert’s institution.

“The comment suggests an increasing number of tumors will be classified as falling within [Destiny-Breast04’s] inclusion criteria and many patients could receive Enhertu, leaving a shrinking HER2-[negative] population to potentially receive Trodelvy,” the SVB analysts said.

For DESTINY-Breast04, patients had HER2 expression covering at least 10% of tumor cells. Certain patients above that threshold had previously been considered HER2-negative, but now they may be considered “HER2-low” and potentially be eligible for treatment with Enhertu. 

One area where Trodelvy could put up a fight is tolerability, the SVB analysts said. Enhertu is known to cause interstitial lung disease, and that could be problematic for some patients in earlier lines of treatment.

As Enhertu treats earlier disease, it’s also starting to show milder and more manageable lung complications. But despite oncologists’ increased experience with the side effect and regular scans, the roughly 10% case rate suggests that Enhertu may have a hard time getting into early-stage disease and may continue to be limited to the metastatic setting, the SVB team said.

In HR-positive disease, the experts argued that Enhertu may initially be used after aromatase inhibitors, CDK4/6 inhibitor and SERDs, but could potentially jump into earlier settings. In addition, compared with sequential treatment, the experts weren’t sure whether combining Enhertu and endocrine therapy would be a good strategy given additional toxicity, infusions and clinical burden.