Astra works to avoid a datopotamab double dip

Can AstraZeneca/Daiichi Sankyo repeat the Enhertu trick with their next ADC, datopotamab deruxtecan? That’s been a question in the minds of many over the past year, and today the markets have more body language to go on, as dato’s Tropion-Breast01 study has been toplined positive for progression-free survival.

Even more importantly, Astra has reported a “trend in improvement for the dual primary endpoint of overall survival”, which represents a key metric given that dato’s anti-TROP2 ADC rival Trodelvy, from Gilead, already boasts this on its label. With disappointment over dato’s first big reveal, in the Tropion-Lung01 trial, casting a long shadow, there could be sighs of relief today.

It was such considerations that perhaps lay behind Astra’s insistence on getting the OS wording into this morning’s press release. Notably such assurance was absent from Daiichi’s statement, which simply said the overall survival data were immature at this interim analysis, and that Tropion-Breast01 would continue as planned to assess OS.

Filings under way

Tropion-Breast01 concerns ER-positive, HER2-negative breast cancer patients in a second or third-line setting. Astra/Daiichi said that plans for regulatory submissions were under way after today’s positive PFS result versus chemotherapy.

It is unclear whether this alone will suffice, as Gilead’s Trodelvy boasts a PFS as well as OS benefit on its label. Trodelvy’s Tropics-02 trial was statistically significant, and though a 1.5-month median PFS benefit versus chemo was seen as underwhelming Gilead salvaged some pride with a more impressive median OS result at last year’s ESMO meeting.

The battle of anti-TROP2 ADCs in ER-positive HER2-negative breast cancer

Source: US prescribing information & company statements.

The cross-trial comparison is complicated, however, by the fact that Tropics-02 recruited sicker patients, mandating failure on at least two prior therapies in the metastatic setting.

The extent of the survival benefit in Tropion-Breast01 won’t be clear until the data are presented in full, though importantly both Astra and Daiichi refer to the PFS benefit as clinically meaningful. That was missing from dato’s big lung cancer reveal, the Tropics-Lung01 study, where absence of the words “clinically meaningful” contributed to sharp drops in the two companies’ share prices.

Another big perceived problem with the lung cancer trial was mention of “some” deaths due to interstitial lung disease (ILD), a known toxicity with Enhertu that hangs over all Daiichi ADCs. Today’s statements say that all-grade ILD rates “were low” in Tropion-Breast01 – wording that doesn’t imply an absence of some grade 5 events, it must be stressed.

Another battle

While Daiichi has argued that dato has a more stable linker than Trodelvy, as well as a lower drug-to-antibody ratio, whether this results in reduced toxicity has yet to be shown. A third TROP2 player, Merck & Co’s Kelun-derived sacituzumab tirumotecan, uses the same MAb as Trodelvy, but has yet to yield data in breast cancer.

And the threat to Trodelvy of Astra/Daiichi’s HER2-directed ADC star, Enhertu, should also not be underestimated. Enhertu is already approved in second-line ER-positive breast cancer that is said to be “HER2-low”, a setting effectively established by that drug’s Destiny-Breast04 study.

Why is this important? Because HER2-low status is defined as breast cancer expressing HER2 at 1+ via immunohistochemistry, or 2+ with a negative in-situ hybridisation test. Until recently that was caught within the definition of HER2-negativity, so the harsh reality for Trodelvy is that Enhertu is already impinging on the Gilead drug’s approved use.

Tellingly, Astra/Daiichi today referred to Tropin-Breast01, technically a HER2-negative trial, as a study in “HER2-low or negative” breast cancer. Astra had paid Daiichi $1bn for rights to dato, after handing across $1.35bn for Enhertu, and with much riding on the data it’s understandable why it wants to hammer the message home.

How Enhertu has narrowed the definition of HER2-negativity

Notes: ICH=immunohistochemistry; ISH=in-situ hybridisation; *approved use; **technically HER2-negative, as stated on clinicaltrials.gov.