FDA Approves Gilead's Trodelvy for First-Line Metastatic Triple-Negative Breast Cancer

The US Food and Drug Administration on June 24 approved Gilead Sciences' Trodelvy (sacituzumab govitecan-hziy) for two first-line uses in adults with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC), according to the agency's notice. Trodelvy, a Trop-2-directed antibody-drug conjugate, was previously approved in the US only for TNBC after earlier therapies and for pre-treated HR-positive, HER2-negative metastatic breast cancer.

The first indication covers Trodelvy as a single agent for patients who are not candidates for PD-1 or PD-L1 inhibitor-based therapy. The second covers Trodelvy with Merck's pembrolizumab (Keytruda or Keytruda Qlex) for patients whose tumors express PD-L1 with a combined positive score (CPS) of 10 or more, as determined by an FDA-authorized test. The FDA said it approved the applications one month ahead of its goal date. The combination indication was approved as a supplement to BLA 761115, according to the FDA's approval letter.

The two Phase 3 trials

ASCENT-03 (NCT05382299) randomized 558 previously untreated patients who were not candidates for PD-1 or PD-L1 inhibitors to Trodelvy or the investigator's choice of chemotherapy. Median progression-free survival, assessed by blinded independent central review, was 9.7 months with Trodelvy and 6.9 months with chemotherapy (hazard ratio 0.62; p<0.0001). Confirmed response rates were 50% and 47%.

ASCENT-04/KEYNOTE-D19 (NCT05382286) randomized 443 previously untreated patients with PD-L1-positive (CPS 10 or more) disease to Trodelvy plus pembrolizumab or chemotherapy plus pembrolizumab. Median progression-free survival was 11.2 months versus 7.8 months (hazard ratio 0.65; p=0.0009), and confirmed response rates were 61% and 55%. Overall survival data were immature in both trials, the FDA said.

Gilead said in its announcement that median duration of response was 12.2 versus 7.2 months in ASCENT-03 and 16.5 versus 9.2 months in ASCENT-04.

"This approval is heartening news for patients and the clinical community, and I believe offers a practice-changing first-line treatment option for all patients across PD-L1 status," said Sara Tolaney of Dana-Farber Cancer Institute, a principal investigator of both trials, in the company's release.

Safety and dosing

Trodelvy's prescribing information carries a boxed warning for neutropenia and diarrhea, along with warnings for hypersensitivity and infusion-related reactions, nausea and vomiting, reduced UGT1A1 activity and embryo-fetal toxicity. The recommended dose, alone or with pembrolizumab, is 10 mg/kg by intravenous infusion on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity.

The FDA's approval letter lists a postmarketing commitment for Gilead to complete ASCENT-04 and provide its prespecified final overall survival analysis. The review was conducted under Project Orbis with regulators in Australia, Israel, Brazil, Canada and Switzerland, whose reviews are ongoing. Gilead said global submissions based on the two trials are underway.