Safety and a focus on diarrhea
Investigator Bardia explained that SG is an antibody-drug conjugate directed at Trop-2, which is highly expressed in breast cancer.
The antibody is linked to SN-38, the active metabolite of irinotecan, via a hydrolyzable linker that makes internalization and enzymatic cleavage by tumor cells unnecessary.
Hydrolysis of the linker releases SN-38 both within the tumor cell and extracellularly to induce a so-called bystander effect, in which neighboring tumors cells may be killed even if they do not express Trop-2.
On the basis of positive results from phase 1/2 trial data, SG was granted accelerated approval by the US Food and Drug Administration for patients with metastatic TNBC who experience disease progression after at least two prior therapies.
ASCENT was therefore a phase 3 confirmatory study. Patients with metastatic TNBC who had received at least two prior chemotherapy regimens were randomly assigned in a 1:1 ratio to receive intravenous SG on days 1 and 8 of a 21-day cycle or to receive physician’s choice of treatment.
Physicians could choose eribulin, vinorelbine, gemcitabine, or capecitabine.
The patients continued receiving treatment until disease progression or unacceptable toxicity occurred. On the unanimous recommendation of the data safety monitoring committee, the trial was ended early because of “compelling evidence of efficacy.”
In all, 267 patients were randomly assigned to receive SG. Of those patients, 15 remain on treatment. Treatment was discontinued for 199 patients who experienced disease progression. In the control arm, 262 patients were included, none of whom are still on treatment; 166 discontinued because of disease progression.
The current analysis is limited to 235 patients in the SG group and, in the control arm, 233 patients who did not have brain metastases. Patients with brain metastases will be the subject of a later analysis.
All but one patient in both treatment groups were women. The median age was approximately 54 years. The median number of prior treatment regimens was four. All patients had previously received chemotherapy, and between 26% and 29% have taken checkpoint inhibitors.
By the data cutoff of March 11, 2020, patients had received a median of seven treatment cycles with SG. Progression-free survival was adjudicated by blind, independent central review. The median duration of response was of borderline significance, at 6.3 months vs 3.6 months (P = .057).
Bardia showed that the results were consistent among all subgroups, including subgroups determined on the basis of age, number of prior therapies, whether patients had received prior immune checkpoint therapy, and the presence of liver metastases.
With respect to safety, the important grade 3 or higher treatment-related adverse events were neutropenia (seen in 51% of SG patients vs 33% of patients in the control arm), diarrhea (10% vs <1%), leukopenia (10% vs 5%), anemia (8% vs 5%), and febrile neutropenia (6% vs 2%).
Despite the fact that the adverse event rate was higher with SG than with physician’s choice of chemotherapy, the percentage of such events that led to treatment discontinuation was numerically lower, at 4.7% vs 5.4%.
Cardoso highlighted the “substantial percentage” of patients with diarrhea and nausea in the trial and noted that “all grades” of these adverse events “affect quality of life.”
The focus therefore should be on patient education, prophylaxis, and “the early management of side effects,” she said.
This point was taken up in the postpresentation debate. Bardia said the high rate of diarrhea “likely relates to the toxic payload, which is SN-38, which is known to cause diarrhea.
“Loperamide or immodium prophylaxis can be used in patients who receive this drug, and in general, our experience with the use of sacituzumab govitecan is you can control the diarrhea,” Bardia said.
He added: “There is also a different side effect that occurs during the infusion of SG, which is abdominal cramping and diarrhea, and that’s more of a cholinergic reaction. For that, atropine is the best medication to use.”
The study was funded by Immunomedics Inc. Bardia has disclosed financial ties with Immunomedics and multiple other pharmaceutical companies. Cardoso has disclosed financial ties to multiple drug companies.
This article first appeared on Medscape.com.