Gilead’s Tropics readout makes investors sweat

Tropics-02 reads out positively, but on the question of clinical relevance Gilead’s silence is deafening.

When a trial is upsized, has its primary endpoint changed, and sees its readout delayed the chances are that things are not going well. Gilead investors were reminded of this today when the company’s long-awaited Tropics-02 study of Trodelvy was essentially confirmed as a damp squib.

Technically, of course, the topline result is positive, with a short statement from Gilead saying Tropics-02 had met its primary endpoint with a statistically significant improvement in progression-free survival. Much more important is whether this effect was clinically meaningful, and to this question Gilead did not give an affirmative answer.

The company took the unusual move of filing a separate Q&A document with the SEC, whose first question was: did PFS meet your bar for clinically meaningful? “There is a broad range of views on what is ‘clinically meaningful’ in this population. We are evaluating the data and will explore potential pathways with regulatory authorities,” the company stated.

Analysts did not take kindly to this, with Wells Fargo saying the SEC filing comment sounded negative, and suggested that the bar for clinical relevance might not have been achieved.

Tropics-02 tested Trodelvy versus chemo in third-line Her2-negative ER-positive breast cancer. It represents a major expansion play for the drug, an anti-Trop-2 antibody-drug conjugate that is already approved in third-line or later triple-negative breast cancer, and in post-chemo/PD-(L)1 urothelial bladder cancer.

The readout was especially important because Gilead had paid $21bn for Immunomedics, Trodelvy’s maker, and because several other of the group’s business development moves, including Galapagos and Kite Pharma, have failed to live up to their billing.

Absolute benefit?

Though Gilead this morning pointed out that Tropics-02 had been designed to show a 30% reduction in risk of disease progression or death, the all-important absolute benefit has not been disclosed. Analysts had expected something in the region of two or three months of added PFS benefit, so presumably many must be assuming that this has been missed.

One problem is that the landscape of available treatments for ER-positive Her2-negative breast cancer has been changing. And the signs were that Tropics-02 was heading towards a negative readout when it was enlarged from 400 to 543 patients and had its primary measures amended from PFS and objective response rate to a sole PFS primary endpoint.

Readout slipped from the fourth quarter of 2021 to January/February, and in the event even the new deadline was missed. A further black mark is that the secondary overall survival endpoint is said to have been statistically non-significant, though in fairness today’s was an interim analysis that was likely immature.

But another problem awaits Gilead in the shape of Astrazeneca/Daiichi Sankyo’s Enhertu, which recently scored a major win in Her2-low patients, a population that might overlap significantly with Trodelvy's. And Astra/Daiichi's own anti-Trop-2 ADC datopotamab deruxtecan recently began Tropion Breast-01, a phase 3 study in second/third-line Her2-negative ER-positive breast cancer.

Though virtually nothing is known about the actual result Tropics-02 has generated, the worry must be that in enlarging the trial all Gilead managed to do was ensure its success on a technicality. Those investors who still hope for a happy ending must now sweat it out until the full dataset is presented at a medical meeting.

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