Confirmatory study setback could jeopardise Trodelvy’s full approval for bladder cancer

31 May 2024
Phase 3ADCClinical ResultDrug ApprovalAccelerated Approval
Gilead Sciences announced that its Trop-2-directed antibody-drug conjugate (ADC) Trodelvy (sacituzumab govitecan-hziy) missed the primary endpoint of overall survival (OS) in a confirmatory Phase III study of patients with locally advanced or metastatic urothelial cancer (mUC) previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy.
Despite having received accelerated FDA clearance in this indication in 2021 based on the Phase II TROPHY study, Trodelvy’s continued approval could depend on confirmatory trials, including TROPiCS-04, the company indicated.
The TROPiCS-04 trial enrolled 711 patients with mUC who were randomised to receive either Trodelvy or one of three standard-of-care chemotherapies - paclitaxel, docetaxel, or vinflunine. The primary endpoint was OS, with progression-free survival (PFS) being a key secondary goal, alongside overall response rate (ORR).
Poorer survival, higher AE-related deaths
Top-line results showed that Trodelvy failed to hit the main goal of OS improvement compared with chemotherapy in the intention-to-treat population. However, a numerical improvement in OS favouring Trodelvy was noted, along with trends toward improvement in certain pre-specified subgroups and secondary endpoints, including PFS and ORR.
Notably, the Trodelvy group had more deaths from adverse events (AEs) seen early in treatment than the chemotherapy group, primarily attributed to neutropenic complications, including infection. The company noted that the ADC’s safety profile in the study was consistent with that seen in previously approved indications and studies. Trodelvy’s label carries a boxed warning highlighting the risk of severe or life-threatening neutropenia.
Next steps
Regarding the disparity in AE-related deaths, the drugmaker plans to further analyse these data and emphasise to physicians the value of using granulocyte-colony stimulating factor (G-CSF) to prevent neutropenic complications. Gilead also said it intends to engage with the FDA upon completion of the full data analysis to chart the drug’s path ahead in bladder cancer.
The readout marks a second failure for Trodelvy this year after it missed the survival goal in the Phase III EVOKE-01 study for non-small-cell lung cancer. The ADC, which generated global sales of $1.1 billion last year, has also been approved by the FDA for advanced triple-negative breast cancer and HR+/HER2- breast cancer.
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