Datopotamab deruxtecan showed promising responses as monotherapy and in combination with Imfinzi in patients with metastatic triple-negative breast cancer in two early trials

Datopotamab deruxtecan showed promising responses as monotherapy and in combination with Imfinzi in patients with metastatic triple-negative breast cancer in two early trials

Updated results from the TROPION-PanTumor01 Phase I trial showed datopotamab deruxtecan (Dato-DXd) continued to demonstrate encouraging responses in patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) and disease progression following standard treatment. Results were presented today at the 2022 San Antonio Breast Cancer Symposium (SABCS) (abstract #P6-10-03).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

Approximately 15% of breast cancers are considered triple-negative and are associated with higher disease recurrence and worse prognosis compared to other breast cancer subtypes.1,2 It is estimated that only 12% of patients with metastatic TNBC survive five years after diagnosis and median overall survival is between 12 to 18 months.1,3

In the TNBC cohort of TROPION-PanTumor01 (n=44), datopotamab deruxtecan demonstrated an objective response rate (ORR) of 32%, including one complete response (CR), 13 partial responses (PRs) and 18 cases of stable disease (SD) as assessed by blinded independent central review (BICR). In a subgroup of 27 patients who had not been treated with topoisomerase I inhibitor-based ADCs, the ORR was 44%, including one CR, 11 PRs and 10 cases of SD. The median duration of response (DoR) was 16.8 months across patient groups.  

In the overall cohort, datopotamab deruxtecan demonstrated median progression-free survival (PFS) of 4.4 months (95% confidence interval [CI], 3.0-7.3) and median overall survival (OS) of 13.5 months (95% CI, 10.1-16.3). In the subgroup of patients who had not been treated with a topoisomerase I inhibitor, median PFS and OS were 7.3 months (95% CI, 3.0-18.0) and 14.3 months (95% CI, 10.5-NE), respectively. The disease control rate (DCR) was consistent across the overall cohort and previously untreated subgroup at 80% and 81%, respectively.

Patients in the TROPION-PanTumor01 trial were heavily pretreated, receiving a median of three prior regimens in the metastatic setting (range 1-10). Prior treatments included taxanes (93%), anthracyclines (75%), capecitabine (61%), platinum-based chemotherapy (52%), immunotherapy (45%), topoisomerase I inhibitor-based ADCs (32%) and PARP inhibitors (18%). As of data cut-off on 22 July 2022, three patients remained on study treatment.

The safety profile of datopotamab deruxtecan was consistent with previously reported data with no new safety signals identified. The most common Grade 3 or higher treatment-emergent adverse events (TEAEs) were stomatitis (11%), decreased lymphocyte count (7%), fatigue (7%), vomiting (5%), anaemia (2%), decreased neutrophil count (2%) and nausea (2%). Serious TEAEs were reported in nine patients (20.5%). Treatment discontinuation occurred in one patient (2%) due to Grade 1 pneumonitis, which was adjudicated as not treatment-related interstitial lung disease (ILD). No cases of febrile neutropenia or Grade 3 or higher diarrhoea were observed.

Aditya Bardia, Director, Breast Cancer Research Program, Mass General Cancer Center and Associate Professor of Medicine, Harvard Medical School, and investigator in the TROPION-PanTumor01 trial, said: “Triple-negative breast cancer is the most aggressive subtype of breast cancer with the average survival rate of less than 18 months for patients with pretreated metastatic disease. The durable tumour response and disease control seen with datopotamab deruxtecan in patients with pretreated triple-negative breast cancer are encouraging, particularly in those patients who had not received previous treatment with topoisomerase I inhibitor-based antibody drug conjugate.”

Datopotamab deruxtecan plus Imfinzi (durvalumab) showed 73.6% ORR in 1st-line treatment of metastatic TNBC
Updated results from the BEGONIA Phase Ib/II trial (n=61) showed datopotamab deruxtecan in combination with Imfinzi demonstrated an ORR of 73.6% (95% CI, 59.7-84.7) in patients with previously untreated, unresectable, locally advanced or metastatic TNBC as assessed by investigator. Among the 53 evaluable patients, there were four CRs and 35 PRs. Responses were observed regardless of PD-L1 expression (low and high tumours) with 82% of patients continuing to respond at the time of data cut-off on 22 July 2022. These data were presented at SABCS on 8 December (abstract #PD11-09).

Twenty-five patients (41.0%) had not received prior treatment for metastatic TNBC. Prior treatments for patients with early-stage disease included radiotherapy (49.2%), anthracyclines (45.9%), taxanes (41.0%), platinum-based chemotherapy (14.8%), hormonal therapy (14.8%) and targeted therapy (4.9%). Seven (11.5%) patients had high PD-L1 expression (tumour area positivity [TAP]≥10%) and 53 (86.9%) patients had low PD-L1 expression (TAP<10%). At data cut-off, 45 patients remained on study treatment.

The safety profile of datopotamab deruxtecan in combination with Imfinzi was consistent with the known safety profiles of both agents. The most common all-Grade TEAEs occurring in 20% or more of patients were nausea (57.4%), stomatitis (55.7%), alopecia (45.9%), fatigue (39.3%), constipation (39.3%), rash (27.9%) and vomiting (21.3%). Serious TEAEs were observed in 10 patients (16.4%). Treatment discontinuations due to an adverse event occurred in four patients (6.6%). No dose-limiting toxicities were reported. Two cases (3.3%) were adjudicated as treatment-related Grade 1 ILD.

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “The median duration of response of nearly 17 months seen in the TROPION-PanTumor01 trial in these patients reinforces the potential of datopotamab deruxtecan to treat this persistent disease. These results, along with the promising clinical response in combination with Imfinzi seen in the BEGONIA trial, underscore the potential role of this TROP2-directed antibody drug conjugate for patients with triple-negative breast cancer as both a monotherapy and in combinations.”

Mark Rutstein, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: “Five-year survival rates for previously treated metastatic triple-negative breast cancer are significantly lower than other subtypes of breast cancer, underscoring the need for new, durable therapies. We are working with urgency and care to evaluate datopotamab deruxtecan in multiple treatment settings in Phase III trials, including the TROPION-Breast02 1st-line trial in patients with locally recurrent inoperable or metastatic triple-negative breast cancer not candidates for anti-PD-L1 therapy.”

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