Datopotamab Deruxtecan Demonstrates Highly Promising Efficacy in Advanced or Metastatic TNBC

Ian E. Krop, MD, PhD

Treatment with datopotamab deruxtecan phase 1 TROPION-PanTumor01 trial (NCT03401385) showed promising activity through overall response rates (ORRs) in patients with advanced or metastatic triple-negative breast cancer (TNBC), according to cohort data presented during the 2021 San Antonio Breast Cancer Symposium (SABCS).¹

Among all patients in the TNBC cohort of the trial (n = 44), the ORR by blinded independent central review (BICR) was 34% at a median follow-up of 7.6 months (range, 4-13). This included a confirmed complete response (CR) or partial response (PR) in 14 patients (32%), plus 1 patient (2%) with a CR/PR that was pending confirmation. Seventeen patients (39%) had stable disease (SD), 2 patients (5%) were not evaluable (NE), and 8 patients (18%) had progressive disease (PD). Overall, the disease control rate (DCR) was 77%.

Furthermore, at a median follow-up of 8.8 months (range, 4-13), the ORR was 52% in patients with TNBC who did not receive prior treatment with a Topo I inhibitor-based ADC (n = 27), which included 13 patients (48%) with confirmed CRs or PRS, plus 1 patient (4%) with a CR/PR pending confirmation. Nine patients (33%) had SD, 1 patient (4%) was NE, and 4 patients (15%) had PD. The DCR was 81%.

Additional data showed that the median duration of response was not reached (range, 2.7 to 7.4+ months); the majority of responses were ongoing at the data cutoff.

"There are clear responses or clear tumor regressions in those patients who had prior Topo-based ADCs with at least 1 confirmed PR," lead study author Ian E. Krop, MD, PhD, of Dana-Farber Cancer Institute, 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) ADC, 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 1 of these prior ADCs."

There are currently very limited standard treatments for patients with advanced or metastatic TNBC that considered relapsed/refractory. TROP2 is highly expressed in various malignancies, including breast cancer. In the TROPION-PanTumor01 study, investigators are evaluating the safety and efficacy of the TROP2-directed ADC datopotamab deruxtecan in patients with advanced or metastatic breast cancer, non–small cell lung cancer (NSCLC), and other tumor types.

At the 2021 SABCS, Krop, who is an associate chief in the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, clinical research director of the Breast Oncology Center, and associate professor of medicine at Harvard Medical School, presented on the data from the TNBC cohort.

Patients enrolling in the trial were required to have relapsed/refractory advanced or metastatic solid tumors, an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1. 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. Those with stable, treated brain metastases were permitted.

In the TNBC cohort, 42 of 44 patients received datopotamab deruxtecan intravenously (IV) at 6 mg/kg every 3 weeks, and the other 2 patients received the ADC IV 8 mg/kg every 3 weeks. The decision to use the 6-mg/kg dose, which was selected for expansion across other tumors, 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.

The primary end points of the trial were safety and tolerability; secondary end points included efficacy, pharmacokinetics, and anti-drug antibodies.

In the TNBC cohort, the median age was 53 years (range, 32-82), and 31 patients (70%) were based in the United States vs 13 patients (30%) in Japan. The majority of patients had an ECOG performance status of 1 (59%) and did not have de novo metastatic disease (68%). Eleven percent of patients had brain metastases.

Furthermore, the median number of prior therapies in the metastatic setting was 3 (range, 1-10), and 68% of patients had at least 2 prior lines of therapy. Previous treatments included taxanes (91%), platinum-based chemotherapy (52%), immunotherapy (43%), PARP inhibitors (16%), and Topo I inhibitor-based ADC (30%).

At the data cutoff date of July 30, 2021, 31 patients (70%) discontinued treatment, including 30 due to disease progression, and 1 patient due to an adverse event (AE). Thirteen patients (30%) remained on treatment at the time of the presentation.

Furthermore, datopotamab deruxtecan showed a manageable safety profile with no new safety signals. The most frequent treatment-emergent adverse events (TEAEs) included nausea, stomatitis, vomiting, and fatigue. However, neutropenia and diarrhea were both uncommon. No cases adjudicated as treatment-related interstitial lung disease were observed.

Ninety-eight percent of patients had at least 1 TEAE, 45% of which were considered to be of grade 3 or higher; 23% experienced grade 3 or higher treatment-related TEAEs. Dose reductions due to AEs were required in 18% of patients, and 14% of patients experienced treatment interruption due to AE. One patient discontinued treatment due to AEs, and no fatal AEs were reported.

Krop added that the HR-positive, HER2-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 durvalumab (Imfinzi) as a first-line treatment for patients with metastatic TNBC.²

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 said. "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."

_Reference

_{1. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.}

_{2. Schmid P, Nunes AT, Dry H, et al. BEGONIA: phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): Addition of arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062). J Clin Oncol. 2021;39(15_suppl). doi:10.1200/JCO.2021.39.15_suppl.TPS1105}