Promising Antitumor Activity for Datopotamab Deruxtecan in TNBC

Aditya Bardia, MD, MPH

Encouraging findings from the phase 1 TROPION-PanTumor01 trial revealed a positive response and safety profile for the antibody-drug conjugate (ADC) datopotamab deruxtecan (DS-1062a) in patients with triple-negative breast cancer (TNBC). The preliminary findings were presented during the European Society for Medical Oncology (ESMO) Breast Cancer Virtual Congress 2021.

Among 21 evaluable patients in the trial (NCT03401385), the objective response rate with datopotamab deruxtecan was 43% (n = 9) per blinded independent central review (BICR); this included a confirmed complete response/ partial response (CR/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 events (AEs).

“Further study [of this agent] in breast cancer is needed, and the hormone receptor [HR]-positive cohort [of this trial] is now enrolling,” said lead study author Aditya Bardia, MD, MPH, 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, during an oral presentation.

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 with multiple cohorts, including NSCLC, TNBC, and soon, HR-positive breast cancer. At the ESMO congress, Bardia shared results from the TNBC cohort.

To be eligible for enrollment to the cohort, patients had to have advanced or metastatic HR-negative/human epidermal growth factor receptor 2 (HER2)-negative TNBC and have relapsed or progressed on at least 1 standard treatment. Measurable disease per RECIST 1.1 criteria was required, and patients needed to be unselected for TROP2 expression.

In the TNBC cohort, investigators treated 24 patients with intravenous datopotamab deruxtecan every 3 weeks; 22 received the 6-mg/kg dose and 2 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, and 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 who had received a median of 4 prior lines of therapy (range, 1-9), with 88% having 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, all patients experienced treatment-emergent AEs (TEAEs) of any grade, whereas grade 3 or higher TEAEs were reported in only 8 patients (33%). Seventeen percent of patients (n = 4) experienced treatment-related toxicities that were grade 3 or higher in severity. Serious TEAEs occurred in 3 patients (13%), but none were determined to be associated with the study drug.

Additionally, 6 patients (25%) needed dose reductions due to AEs, which were mostly due to stomatitis (13%; n = 3) or mucosal inflammation (8%; n = 2). The trial investigators reported no fatal TEAEs.

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%). Investigators observed no cases of grade 3 or higher diarrhea or neutropenia, and reported no cases determined as drug-related interstitial lung disease.

_References:

_{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. Ann Oncol. 2021;32(suppl 2):S60. doi:10.1016/j.annonc.2021.03.213}