Pharma, BioPharma

Gilead Sciences ADC Flunks Its Confirmatory Test in Advanced Bladder Cancer

Gilead Sciences reported Trodelvy’s Phase 3 test in metastatic urothelial cancer fell short of showing a statistically significant benefit on the overall survival main goal. The antibody drug conjugate had received accelerated FDA approval for this type of cancer in 2021.

Gilead Sciences cancer therapy Trodelvy did not help patients with advanced bladder cancer live longer compared to treatment with chemotherapy, Phase 3 results that now threaten the drug’s accelerated approval in the indication. It’s the drug’s second disappointing data readout this year, following the failure of a separate pivotal study in lung cancer.

Gilead announced the latest trial failure after Thursday’s market close, adding that more detailed results will be presented at a future medical meeting. That presentation won’t happen at this year’s annual meeting of the American Society of Clinical Oncology, kicking off in Chicago Friday. But the ASCO meeting will have data from other tests of Trodelvy.

Trodelvy belongs to the class of targeted therapies known as antibody drug conjugates, or ADCs. The antibody component of the drug targets TROP-2, a protein abundant on the surface of many types of cancer cells. This Gilead drug was first approved in 2020 for treating advanced cases of triple-negative breast cancer. In 2021, the FDA granted Trodelvy accelerated approval for locally advanced or metastatic urothelial cancer, an aggressive form of bladder cancer with poor survival rates.

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The confirmatory Phase 3 test enrolled 711 patients whose bladder cancer had advanced after treatment with platinum chemotherapy and a type of immunotherapy called a checkpoint inhibitor. The open-label study compared Trodelvy to the physician’s choice of one of three chemotherapies that are standard of care options for this cancer. The main goal was to show improvement in overall survival.

Gilead said that in the overall study population, the Trodelvy arm had a higher number of deaths due to adverse events compared with the chemotherapy arms. The complications, observed mainly in the early stages of treatment, were related to neutropenia, in which a patient has low levels of a type of immune cell called a neutrophil. Low neutrophil levels make patients susceptible to infection. Neutropenia is a known complication risk of Trodelvy, flagged on the drug’s label. Gilead said it will analyze the trial data, adding that it is reiterating to physicians the importance of granulocyte-colony stimulating factor (G-CSF), therapies consisting of proteins that stimulate the bone marrow to produce neutrophils.

Though Trodelvy did not show a statistically significant overall survival benefit, Gilead said the results show a numerical improvement on this goal in favor of Trodelvy. In addition, there were trends in improvement in pre-specified subgroups, including those who previously received treatment with chemotherapy and a checkpoint inhibitor. In a note sent to investors Friday, Leerink Partners analyst Daina Graybosch wrote that these results imply that Trodelvy underperformed in the subgroup of patients who progressed on the chemotherapy cisplatin for early-stage disease and subsequent treatment with a checkpoint inhibitor for metastatic disease. She added that it’s possible Trodelvy had overperformed in the clinical study that was the basis of the drug’s accelerated approval.

“Regardless, we believe it is unlikely that the FDA would be supportive of Trodelvy remaining on label for UC (urothelial cancer) given their stringent stance on removing approvals for drugs that fail their confirmatory trials, particularly as Gilead has no other Phase 3 trials ongoing in UC,” Graybosch said.

Trodelvy has become a blockbuster seller, crossing the $1 billion revenue threshold in 2023. Gilead is counting on the product to be a big piece of its oncology growth strategy. Graybosch said that although metastatic urothelial cancer makes up less than 10% of Trodelvy’s current sales, a potential exit from this market would be a meaningful setback for the drug’s growth prospects.

Trodelvy’s growth prospects dimmed in January, when the company reported preliminary Phase 3 results showing the drug failed to improve overall survival in patients with advanced non-small cell lung cancer. Though the drug fell short of this study’s main goal, the results show numerical improvement in favor of the Gilead drug. No new safety signals were observed. The full results from the failed lung cancer study are scheduled for presentation Friday during the ASCO meeting. Data will also be presented throughout the conference from ongoing clinical trials evaluating Trodelvy in head and neck cancer, metastatic breast cancer, and kidney and bladder cancers.

The Gilead drug’s recent trial failures also hurt its ability to compete against datopotamab deruxtecan, a TROP-2-targeting ADC from AstraZeneca and Daiichi Sankyo. Earlier this week, AstraZeneca reported a Phase 3 study in advanced non-small cell lung cancer has results showing numerical improvement but not statistical significance compared to chemotherapy. But the drug had previously met the dual primary endpoint of progression-free survival. The company says these results support regulatory applications currently under review in the U.S. and Europe.

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