In the span of half a year, Gilead Sciences' Trodelvy has flopped a second phase 3 trial.
Following a high-profile setback in non-small cell lung cancer (NSCLC) in January, Gilead said Thursday that Trodelvy also failed to move the needle in a bladder cancer study.
The TROP2-directed antibody-drug conjugate couldn’t outperform single-agent chemotherapy at extending the lives of urothelial cancer patients who had tried prior treatment with a chemotherapy and a PD-1/L1 therapy.
The negative readout, from the TROPiCS-04 study, could force Gilead to withdraw a Trodelvy accelerated approval from 2021 in previously treated bladder cancer. And it could damage Gilead’s position in a potential TROP2 ADC showdown against rivals Merck & Co. and the partnership between AstraZeneca and Daiichi Sankyo.
The company said it’s continuing to analyze the data and will discuss the results and next steps with the FDA.
Trodelvy’s accelerated approval in bladder cancer was based on a single-arm study showing it could trigger a response in 27.7% of patients following chemo and PD-1/L1 therapies. Now, the drug only demonstrated a numerical improvement in patient survival compared with single-agent chemo rather than a statistically significant benefit.
What’s more, the study linked Trodelvy to a higher number of deaths due to adverse events compared with chemo. The deaths were mostly seen early in treatment and related to complications from neutropenia, including infection, the company said.
Neutropenia is currently included in a boxed warning on Trodelvy’s label, and Gilead said it’s working to communicate with doctors the importance of using G-CSF to prevent neutropenic complications.
The bladder cancer failure marks the latest in a string of disappointments for Trodelvy. The first one came in 2022, when investors questioned the drug’s magnitude of benefit in HR-positive, HER2-negative breast cancer. Although that trial, coded TROPiCS-02, was positive, it was outshone by AstraZeneca and Daiichi Sankyo’s landmark HER2-low win for Enhertu. At that time, Gilead took $2.7 billion in impairment charges related to Trodelvy.
Then, more bad news dropped in January when Trodelvy sputtered in the phase 3 EVOKE-01 trial testing the medicine against chemotherapy in previously treated NSCLC. As Gilead searches for a regulatory path forward, the California biotech recorded $2.4 billion in impairment charges as a result of the negative readout.
The repeated clinical woes come as Gilead prepares to face off against fellow TROP2 ADCs from Merck and AZ/Daiichi. Merck’s sacituzumab tirumotecan, which is in-licensed from China’s Kelun-Biotech, has yet to report phase 3 data from a global study.
As for AZ and Daiichi’s datopotamab deruxtecan, the drug is under FDA review in HR-positive, HER2-negative breast cancer and in nonsquamous NSCLC.
Neither candidate has any ongoing phase 3 studies in bladder cancer, according to a search of ClinicalTrials.gov.
Trodelvy’s setback in bladder cancer comes in stark contrast to the resounding overall survival win for Pfizer and Astellas’ Nectin-4 ADC Padcev, used in combination with Merck’s Keytruda, in first-line bladder cancer. Padcev won its accelerated approval in the post-PD-1/chemo setting in 2019. The FDA converted the conditional nod into a full approval in 2021.
With Trodelvy losing its luster and sales slowing in Gilead’s cell therapy department, the company’s stated goal to have a third of its revenue from oncology by 2030 could be in jeopardy.