Gilead's Trodelvy snags vital breast cancer nod. But AZ, Daiichi's Enhertu casts long shadow

Thanks to a new FDA approval, Gilead Sciences’ Trodelvy has entered a breast cancer arena that’s crucial to the drug’s commercial success—as well as the company’s larger oncology ambitions. 

The FDA has approved Trodelvy for previously treated HR-positive, HER2-negative breast cancer, Gilead said Friday. To be eligible for the therapy, patients must have tried endocrine therapy and at least two additional therapies in the metastatic setting.

Before Friday’s approval, Trodelvy was approved to treat triple-negative breast cancer. But HR-positive, HER2-negative disease represents a much larger group of patients, accounting for about two-thirds of all breast cancer cases.

Meaningful penetration in HR-positive, HER-2 negative breast cancer could give Trodelvy a major sales boost. But a recent market shift, pioneered by AstraZeneca and Daiichi Sankyo’s Enhertu, casts a layer of uncertainty over the opportunity.

When Gilead splashed a whopping $21 billion to purchase Trodelvy maker Immunomedics in 2020, analysts said Trodelvy must reach at least $4 billion in peak sales to justify Gilead’s investment. A pretreated HR+/HER2- indication could contribute $1.1 billion for the drug, RBC Capital Markets analysts said in an investor note last fall.

The RBC team reached that number after Gilead unveiled patient survival data from the phase 3 TROPiCS-02 trial, which supported the current approval.

To reach that, Gilead took investors on a roller-coaster ride—before reigniting their blockbuster hopes.

Trodelvy, a TROP2-targeted antibody-drug conjugate (ADC), first failed to impress in its ability to stall tumor progression or death. Shortly after, Enhertu, a HER2-directed ADC, came up with practice-changing data, slashing the risk of progression or death by 50% and the risk of death by 36% against chemotherapy in previously treated patients who fall into a new breast cancer category called HER2-low. Based on the impressive showing, the FDA in August approved Enhertu to treat HER2-low breast cancer.

Luckily for Gilead, Trodelvy later came back with a better-than-expected overall survival win. After a longer follow-up of TROPiCS-02, Trodelvy treatment led to a 21% decrease in the risk of death compared with chemo. Trodelvy also improved patients’ median overall survival by 3.2 months, clearing a clinical relevance bar, according to physicians surveyed by RBC. As for progression-free survival, Trodelvy pared down the risk by 34% with a mere 1.5-month improvement at the median.

But because HER2-low patients were previously part of the HER2-negative grouping, there’s an overlap between Enhertu’s and Trodelvy’s target populations. And although Enhertu’s trial enrolled patients in an earlier line of treatment, the drug’s efficacy showing was so impressive that it effectively stole Trodelvy’s thunder.

Still, more therapeutic options are necessary in breast cancer treatment, Hope Rugo, M.D., of the UCSF Helen Diller Family Comprehensive Cancer Center, and lead investigator of TROPiCS-02, said in an interview. She noted that many breast cancer patients die because they run out of treatment options.

Rugo argued that patients who had multiclass-resistant tumors were driving the median progression-free survival curve for Trodelvy’s TROPiCS-02. She pointed to the one-year landmark data, where Trodelvy’s 21% progression-free survival rate was three times that of chemo, suggesting that there is a meaningful group of patients who can benefit more from Trodelvy.

What's more, Trodelvy's efficacy doesn’t seem to be limited by HER2 expression or TROP2 expression, which presents the Gilead drug with an opportunity against its rival. Enhertu is not approved for HER2-zero patients.  

Even outside the HER2-zero population, Rugo believes Trodelvy has a role to play at least for some patients. Enhertu’s increased risk of a potentially fatal immune-related side effect called interstitial lung disease remains a concern, she noted.

For now, Trodelvy is approved one treatment line behind Enhertu. The true battle will come when both drugs move into earlier disease settings. Gilead plans to start the phase 3 ASCENT-07 trial in endocrine-resistant HR+/HER2- breast cancer this year. And AstraZeneca and Daiichi have the phase 3 Destiny-Breast06 trial in a similar post-endocrine setting.

Gilead has designated Trodelvy as a cornerstone of its oncology program as a key component of a broader goal to have a third of its group revenue from oncology drugs by 2030. Rugo also noted that over the long term, AZ and Daiichi’s second ADC, also TROP2-directed datopotamab called deruxtecan, might be a bigger threat to Trodelvy.