Novel Drug Elicits Favorable Outcomes in Advanced, Metastatic TNBC

Data from an early-phase trial demonstrated that the use of datopotamab deruxtecan was associated with promising and long-lasting treatment responses in patients with advanced or metastatic triple-negative breast cancer (TNBC).

The study authors noted that standard treatment options for patients with advanced or metastatic TNBC which has relapsed or is refractory to therapy are lacking.

To address the scarcity of options, researchers initiated the TROPION-PanTumor01 study, where investigators are assessing the safety and efficacy of datopotamab deruxtecan — an antibody drug conjugate that targets the transmembrane glycoprotein trophoblast cell surface antigen 2 (TROP2) — in patients with a variety of solid tumors. Of note, TROP2 can promote tumor growth and its overexpression is common in many solid tumors, including breast cancer.

At the 2021 San Antonio Breast Cancer Symposium, Dr. Ian E. Krop and colleagues presented data from the TNBC patient cohort of the phase 1 trial.

Patients enrolling in the trial were required to have relapsed/refractory advanced or metastatic solid tumors. Additionally, patients needed to be at least 18 years old in the United States or 20 years old in Japan and be unselected for TROP2 expression. Patients with stable and treated brain metastases were permitted to enroll in the trial.

In the TNBC cohort, 42 of 44 patients (median age, 53 years; range, 32 to 82 years) received datopotamab deruxtecan intravenously at 6 mg/kg every three weeks, while the other two patients received the study drug delivered via IV at 8 mg/kg every three weeks. The decision to use the 6-mg/kg dose, which has been selected for expansion across other tumors in this study, as well as in the phase 3 TROPION-Lung01 (NCT04656652) and TROPION-Breast01 (NCT05104866) studies, was based on clinical results and exposure-response analyses for safety and efficacy.

Analyzing safety and tolerability was the main goal of this study. Additional goals included assessing the efficacy of the study drug, as well as how the drug is absorbed into the body and the presence of anti-drug antibodies.

Most of the patients (70%) were residents of the U.S. Moreover, 11% of the TNBC cohort had brain metastases.

The median number of prior therapies among patients with TNBC in the metastatic setting was three (range one to 10), and 68% of patients had received at least two prior lines of treatment.

At a median follow-up of 7.6 months, the overall response rate (the proportion of patients whose disease partially or completely responded to treatment) among the TNBC cohort was 34%. The data indicated that one patient achieved a complete response, 14 patients achieved a partial response and 17 patients had stable disease.

The study results also noted that at a median follow-up of 8.8 months, treatment with the study drug led to an overall response rate of 52% in patients with TNBC who had not received prior treatment with a TOPO1 inhibitor-based antibody drug conjugate (27 patients).

A median duration of treatment response had not yet been reached, as most responses were still ongoing as of July 30, 2021 (the data cutoff for reporting).

“There are clear responses or clear tumor regressions in those patients who had prior Topo-based (antibody drug conjugates) with at least one confirmed partial response,” lead study author Krop, associate chief of the Susan F. Smith Center for Women’s Cancer at Dana-Farber Cancer Institute in Boston, said in a presentation during the conference. “However, because a full 30% of the patients on this study had a prior Topo I inhibitor(-based) (antibody drug conjugate), and that is the same class of payload as (datopotamab deruxtecan), there is a possibility of cross resistance. Therefore, we did want to look at specifically the subset of patients who had not had one of these prior (antibody drug conjugates).”

At the data cutoff date, 31 patients had discontinued treatment, including 30 due to disease progression, and one patient due to a side effect. Of note, 13 patients remained on treatment as of the time of data presentation.

Furthermore, treatment with datopotamab deruxtecan was associated with a manageable safety profile with no new safety signals. The most frequent treatment-emergent side effects included nausea, stomatitis (painful swelling and sores inside the mouth), vomiting and fatigue. Neutropenia and diarrhea, however, were both uncommon.

Overall, 98% of patients experienced at least one treatment-emergent side effect, 45% of which were considered serious or severe. Side effects led to dose reductions in 18% of patients and 14% of patients experienced a treatment interruption because of side effects.

Krop added that the hormone receptor-positive, human epidermal growth factor receptor 2-negative cohort of TROPION-PanTumor01 is now fully enrolled and data are forthcoming. Datopotamab deruxtecan is also being explored in the phase 1b/2 BEGONIA trial (NCT03742102), which is testing the agent in combination with Imfinzi (durvalumab) as a first-line treatment for patients with metastatic TNBC.

Additionally, the phase 3 TROPION-Breast01 trial is investigating datopotamab deruxtecan in HR-positive, HER2-negative breast cancer. A phase 3 trial of datopotamab deruxtecan in patients with TNBC is being planned, Krop said.

“We have come a long way in TNBC when we're talking about comparing different targeted therapies, when up until a few years ago, there were no targeted therapies at all,” Krop concluded. “This is good progress. There is potential room for looking at this drug both in pretreated patients, like what was seen here, as well as earlier lines of therapy.”

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