The FDA has approved two first-line indications for sacituzumab govitecan (Trodelvy, Gilead Sciences) for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC).

One of the indications is for use as a single agent for patients who are not candidates for PD-1 or PD-L1 inhibitor-based therapy. The second is for use in combination with pembrolizumab or subcutaneous pembrolizumab for patients whose tumors express PD-L1 as determined by an FDA-authorized test.

The approvals make the TROP2-directed antibody-drug conjugate (ADC) the only ADC to carry a first-line metastatic TNBC indication regardless of anti-PD-L1 eligibility. Sacituzumab govitecan (SG) was previously approved in the second or later lines for unresectable locally advanced or metastatic TNBC, according to a Gilead press release. 

A rival TROP2-directed ADC — datopotamab deruxtecan— is also indicated in the first-line setting for unresectable or metastatic TNBC but only in patients who are not candidates for anti-PD-L1 therapy.

Approval for the monotherapy indication was based on the ASCENT-03 trial in 558 anti-PD-L1 ineligible patients. They were randomized evenly to SG or investigators’ choice of chemotherapy: paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin. 

Median progression-free survival (PFS) was 9.7 months with SG vs 6.9 months with chemotherapy, a 38% reduction in the risk for progression or death with the ADC. 

SG’s approval with pembrolizumab was based on ASCENT-04 in 443 patients with a combined positive score of at least 10 on the FDA-authorized PD-L1 IHC 22C3 pharmDx assay (Agilent). 

ASCENT-04 randomized patients evenly to SG or investigators’ choice of chemotherapy on a background of pembrolizumab every 21 days. 

Median PFS was 11.2 months with SG add-on vs 7.8 months, a 35% reduction in the risk for progression or death. Overall survival data are pending in both trials. 

A quarter or more of SG patients in the studies experienced nausea, diarrhea, alopecia, fatigue, constipation, and vomiting. There was also rash, abdominal pain, and headache in 25% or more of SG patients in ASCENT-04. Two-thirds or more of SG patients across both studies had grade 3 or worse adverse events. 

Serious adverse reactions in 2% or more of SG patients in the trials included diarrhea, neutropenia, febrile neutropenia, and pneumonia, plus fatigue in ASCENT-04. 

SG carries a boxed warning of severe diarrhea and potentially-fatal neutropenia. Labeling also warns of infusion-related reactions, nausea/vomiting, embryo-fetal toxicity, and inhibition of the liver enzyme UGT1A1. 

The recommended SG dosage is the same as in the trials, 10 mg/kg on days 1 and 8 of 21-day cycles. 

M. Alexander Otto is a physician assistant and award-wining journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net