Datopotamab Deruxtecan Shows Encouraging Preliminary Safety, Efficacy in TNBC

The differentiated TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (DS-1062a) was found to have promising antitumor activity with a manageable safety profile in heavily pretreated patients with triple-negative breast cancer (TNBC), according to preliminary results from the TNBC cohort of the phase 1 TROPION-PanTumor01 trial (NCT03401385) presented during the ESMO Breast Cancer Virtual Congress 2021.

Among 21 evaluable patients, the objective response rate with datopotamab deruxtecan was 43% (n = 9) per blinded independent central review (BICR); this included a confirmed complete response (CR)/partial response (PR) rate of 24%; 19% of patients had a CR/PR that was pending confirmation. The disease control rate was 95% by BICR. Moreover, only 1 patient experienced disease progression, and no patients discontinued treatment due to adverse effects (AEs).

“Further study [of this agent] in breast cancer is needed, and the hormone receptor (HR)–positive cohort [of this study] is now enrolling,” lead study author Aditya Bardia, MD, director of Precision Medicine at the Center for Breast Cancer and founding director of the Molecular and Precision Medicine Metastatic Breast Cancer Clinic at Massachusetts General Hospital Cancer Center, said during an oral presentation on the data.

Patients with relapsed/refractory advanced or metastatic TNBC continue to have poor clinical outcomes. Datopotamab deruxtecan is a TROP2-directed ADC with 3 components: a humanized anti-TROP2 IgG1 monoclonal antibody, a topoisomerase 1 inhibitor payload, and a tetrapeptide-based cleavable linker.

Previously, the ADC demonstrated encouraging antitumor activity with acceptable safety in the non–small cell lung cancer (NSCLC) cohort of this trial. Based on those efficacy results, 6 mg/kg has been selected as the dose for expansion in other advanced tumor types.

TROPION-PanTumor01 is an ongoing, phase 1, first-in-human basket trial that includes multiple cohorts, including NSCLC, TNBC, and soon, HR-positive breast cancer. At the ESMO Breast Cancer Virtual Congress 2021, Bardia shared results from the TNBC cohort.

To be eligible for enrollment to the cohort, patients had to have advanced or metastatic HR-/HER2-negative TNBC and have relapsed or progressed on at least 1 standard treatment. Measurable disease per RECIST v1.1 criteria was required, and patients needed to be unselected for TROP2 expression.

In the TNBC cohort, 24 patients were treated with intravenous datopotamab deruxtecan every 3 weeks, 22 of whom received the 6-mg/kg dose, while 2 patients received an 8-mg/kg dose. Of those patients, 18 remain on treatment and 6 have discontinued due to disease progression.

The primary end point of the study is safety and tolerability, while secondary end points include efficacy and pharmacokinetics.

The median age of study participants was 57 years (range, 32-82), and the majority were from the United States (75%). Most patients had an ECOG performance status of 1 (67%), and 38% presented with de-novo metastatic disease. Additionally, this was a heavily pretreated population, with a median of 4 prior lines of therapy received (range, 1-9). Eighty-eight percent of patients had received at least 2 prior therapies. Previous treatment included taxanes (83%), platinum-based chemotherapy (50%), immunotherapy (33%), sacituzumab govitecan (Trodelvy; 8%), and a PARP inhibitor (4%).

In terms of safety, treatment-emergent AEs (TEAEs) of any grade were experienced by all patients, while grade 3 or higher TEAEs were only reported in 8 patients (33%). Treatment-related toxicities that were grade 3 or higher in severity were experienced by 17% of patients (n = 4). Serious TEAEs occurred in 3 patients (13%), but none of them were determined to be associated with the study drug.

Additionally, dose reductions due to AEs were needed in 6 patients (25%) and were mostly due to stomatitis (13%; n = 3) or mucosal inflammation (8%; n = 2). No fatal TEAEs were reported.

Most of the AEs reported were grade 1 or 2, the most common of which included stomatitis (63%), nausea (63%), fatigue (42%), vomiting (42%), and alopecia (25%). Grade 3 or higher TEAEs included stomatitis (13%), fatigue (4%), and anemia (4%). No cases of grade 3 or higher diarrhea or neutropenia were observed, and no cases adjudicated as drug-related interstitial lung disease were reported.

Reference

1. Bardia A, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): Preliminary results from an ongoing phase 1 trial. Presented at: ESMO Breast Cancer Virtual Congress 2021; May 5-8, 2021; Virtual. Abstract LBA4.