Datopotamab Deruxtecan Demonstrates Promising Efficacy in Heavily Pretreated Metastatic Triple-Negative Breast Cancer with 43% ORR and 95% DCR in Phase I TROPION-PanTumor01 Trial

May 10, 2021 / BIOON -- AstraZeneca and Daiichi Sankyo recently announced at the 2021 European Society for Medical Oncology (ESMO) Breast Cancer Online Conference (ESMO Breast 21)TROP2-Targeting Antibody-Drug Conjugate (ADC) Datopotamab Deruxtecan (Dato-DXd; DS-1062)TROPION-PanTumor01 Phase I Trial: Initial Data from the Triple-Negative Breast Cancer (TNBC) Cohort Show Highly Promising Early Treatment Responses to Datopotamab Deruxtecan in Patients with Metastatic TNBC Who Experienced Disease Progression After Standard Therapy(Overall Response Rate [ORR] = 43%) and Disease Control Rate (DCR = 95%).

Triple-negative breast cancer (TNBC) accounts for approximately 10%–15% of breast cancer cases and, compared with other breast cancer subtypes, is associated with higher rates of disease recurrence and poorer prognosis. It is estimated that among patients with metastatic TNBC, the 5-year survival rate is only 12.2%, and the median overall survival (OS) is typically less than 2 years. The results presented at the conference provide proof of concept for datopotamab deruxtecan targeting TROP2 as an effective therapeutic strategy in patients with previously treated TNBC.

Cristian Massacesi, Senior Vice President and Head of Oncology R&D at AstraZeneca, stated, “It is well known that triple-negative breast cancer (TNBC) is highly aggressive and grows particularly rapidly, with faster recurrence and higher risk after treatment than any other breast cancer subtype. The preliminary results of datopotamab deruxtecan in this group of previously treated TNBC patients are very encouraging.”

TROPION-PanTumor01 is a Phase 1 trial. In the TNBC cohort, patients had received a median of 4 prior regimens (range: 1–9, including [neo]adjuvant or metastatic therapy). The majority of patients (88%) had received ≥2 prior regimens, including taxanes (83%), platinum-based chemotherapy (50%), immunotherapy (33%), the novel TROP2-directed antibody-drug conjugate Trodelvy (8%), and PARP inhibitors (4%). As of the data cutoff date of January 8, 2021, 75% of patients were still receiving datopotamab deruxtecan treatment.

Results presented at the conference showed that, among 21 evaluable patients treated with datopotamab deruxtecan, the initial objective response rate (ORR) was 43% by blinded independent central review (6 mg/kg [n=19] or 8 mg/kg [n=2]). As of the data cutoff date of January 8, 2021, five patients had confirmed complete or partial responses (CR/PR), and four additional CR/PRs were awaiting confirmation. The disease control rate (DCR) was 95%. In the triple-negative breast cancer (TNBC) cohort, the observed safety profile of datopotamab deruxtecan was consistent with that previously reported in the non-small cell lung cancer (NSCLC) cohort of this trial.

Data from the NSCLC cohort presented at the virtual 2020 World Conference on Lung Cancer (WCLC) in late January showed that, as of the data cutoff date of September 4, 2020, independent central review revealed an objective response rate (ORR) ranging from 21% to 25% among 159 patients with advanced or metastatic NSCLC treated with datopotamab deruxtecan at various doses. The disease control rates (DCR) for the three datopotamab deruxtecan dose levels ranged from 67% to 80%, and the median progression-free survival (PFS) was 4.3 to 8.2 months.

TROP2 (trophoblast cell surface antigen 2) is a transmembrane glycoprotein that is overexpressed in various solid tumors, including breast cancer. Studies have shown that high expression of TROP2 is associated with cancer cell growth and proliferation, as well as low patient survival rates. Although TROP2 is expressed in all breast cancer subtypes, it is overexpressed in approximately 80% of TNBC patients, making it a very promising molecular target for the development of new drugs.

Datopotamab deruxtecan is a TROP2-targeting antibody-drug conjugate (ADC), one of the three major ADC assets in Daiichi Sankyo’s oncology pipeline, and among the most advanced programs in AstraZeneca’s ADC science platform.

In March 2019, AstraZeneca and Daiichi Sankyo entered into an immuno-oncology collaboration valued at up to $6.9 billion to jointly develop Enhertu (trastuzumab deruxtecan, DS-8201), a HER2-targeted antibody-drug conjugate (ADC) therapy, for the treatment of patients with various cancers characterized by different levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer.

In July 2020, the two parties signed another immunooncology collaboration agreement valued at up to $6 billion to jointly develop datopotamab deruxtecan (DS-1062), a TROP2-targeting antibody-drug conjugate (ADC) therapy. This therapy is currently in Phase I clinical trials for the treatment of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

In August 2020, the two parties entered into a clinical trial collaboration to evaluate patritumab deruxtecan (U3-1402) in combination with Tagrisso (generic name: osimertinib) for the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations.

Enhertu, datopotamab deruxtecan, and patritumab deruxtecan are next-generation antibody-drug conjugates (ADCs) developed by Daiichi Sankyo using its DXd ADC technology. These agents link humanized monoclonal antibodies targeting specific antigens on the surface of tumor cells—namely, an anti-HER2 antibody [trastuzumab], an anti-TROP2 antibody, and an anti-HER3 antibody [patritumab], respectively—to a novel topoisomerase I inhibitor, the exatecan derivative DX-8951 (DXd), via a tetrapeptide linker. This design enables targeted delivery of the cytotoxic payload into cancer cells, thereby reducing systemic exposure to the cytotoxic agent compared with conventional chemotherapy.

To date, Enhertu has been approved for the treatment of two types of cancer: (1) adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least two anti-HER2 regimens; and (2) patients with HER2-positive unresectable advanced or recurrent gastric cancer. (Bioon.com)