Preliminary data from the phase I TROPION-PanTumor01 study demonstrate that the TROP2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) has promising anti-tumour activity with a manageable safety profile in patients with heavily pre-treated advanced/metastatic triple-negative breast cancer.
To date, effective treatment options for patients with advanced or metastatic triple-negative breast cancer (TNBC) with relapse or refractoriness to standard treatments are limited. The ongoing phase I TROPION-PanTumor01 study is evaluating the safety and efficacy of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) in advanced/metastatic breast cancer, non-small cell lung cancer (NSCLC) and other tumour types. Dato-DXd is an ADC consisting of a humanised anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker. Preliminary results from the TROPIONPanTumor01 study demonstrated that Dato-DXd has encouraging anti-tumour activity and a manageable safety profile in patients with NSCLC and those with TNBC. At SABCS 2021, Prof. Krop presented updated results with this agent in the TNBC cohort.
TROPION-PanTumor01 study design
TROPION-PanTumor01 is a phase I, multicentre, open-label, two-part study evaluating Dato-DXd in previously treated patients with solid tumours. Based on the dose-escalation results in patients with NSCLC, Dato-DXd is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies at a dose of 6 mg/kg intravenously every 3 weeks. All patients were unselected for TROP2 expression, had an ECOG performance status of 0 or 1 and had measurable disease per RECIST version 1.1. Stable, treated brain metastases were allowed. Safety and efficacy of Dato-DXd was assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). The HR+/HER2- breast cancer cohort of this study has recently finished enrolment but the data are still immature. Therefore, only the results of the TNBC cohort were presented during SABCS 2021.
As of the data cut-off (July 30, 2021), 44 patients with TNBC had received at least one dose of Dato-DXd. Treatment was ongoing in 13 patients (30%), while 31 patients (70%) discontinued their treatment, primarily due to disease progression (30 out of 31 patients). The median age of study participants was 53 years and patients were generally heavily pre-treated, with a median of three prior therapies in the metastatic setting. Of note, 13 patients (30%) had previously received a Topo I inhibitor-based ADC (N=10 for sacituzumab govitecan, N=2 for trastuzumab-deruxtecan and N=1 for patritumab-deruxtecan). The median follow-up was 7.6 months (range: 4-13 months). Among the 44 patients evaluable for response, the ORR by BICR was 34% (15 partial responses [PR]), with a disease control rate (DCR) of 77%. Among the 27 patients who were naive to Topo I inhibitor-based ADCs, the ORR by BICR was 52% (14 partial responses [PR]), with 13 confirmed and 1 pending confirmation). In this subgroup, the DCR was 81%. The median duration of response was not reached, with the majority of responses ongoing at the data cut-off.
Treatment-emergent adverse events (TEAEs; any grade or grade ≥3) were observed in 98% and 45% of patients, respectively. Dose reductions, treatment interruptions and treatment discontinuation due to AEs occurred in respectively 18%, 14% and 2% of patients. No treatment-related fatal TEAES were reported. The most common adverse events observed were nausea, stomatitis, vomiting, fatigue and alopecia, predominantly of grade 1 and 2. The incidence of haematological toxicity and diarrhoea was low. There were no cases of interstitial lung disease that could be adjudicated to the study drug.
In heavily pre-treated patients with TNBC, Dato-DXd demonstrated a highly encouraging and durable efficacy with an ORR of 34% in all patients with TNBC and of 52% in patients with measurable disease at baseline who are treatment-naive to Topo I inhibitor-based ADC therapies. In addition, Dato-DXd demonstrated a manageable safety profile with no new safety signals.
Krop I, et al. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study. Presented at SABCS 2021; abstract GS1-05.