In first-in-human phase I TROPION-PanTumor01 study of datopotamab deruxtecan, encouraging antitumour activity and manageable safety profile were observed in patients with heavily pretreated advanced HR-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC). Confirmed objective response rate (ORR) was 26.8% in patients with HR-positive/HER2-negative breast cancer and 31.8% in patients with TNBC, and responses were durable.
Although patient numbers were small, the higher ORR and longer median overall survival and progression-free survival (PFS) observed in the topoisomerase I–naïve TNBC subgroup compared with those in the overall TNBC population also suggest that tumours may start to develop resistance to topoisomerase I inhibition through previous exposure.
Although no patients in the HR-positive/HER2-negative breast cancer cohort received previous topoisomerase I inhibitor–based antibody drug conjugate, patients with a ≥30% decrease in measurable tumour sum of the diameters had only 1-2 previous lines of chemotherapy, suggesting that increasing resistance to topoisomerase I inhibition may be partly due to the cumulative effect of previous treatment with DNA-damaging agents.
Together, these results provide rationale for further evaluation of datopotamab deruxtecan in earlier lines of treatment for patients with HR-positive/HER2-negative breast cancer and TNBC according to Prof. Funda Meric-Bernstam of the Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues who published the findings on 23 April 2024 in the JCO.
Approximately 10% of patients with HR-positive metastatic breast cancer show primary resistance to CDK4/6 inhibitors, and secondary or acquired endocrine resistance is inevitable in most patients. For patients with advanced/metastatic TNBC who have disease progression or are refractory to standard therapies, treatment options remain limited. Antibody drug conjugates aim to address this unmet need by potentially reducing systemic toxicity and improving response rates through selective payload delivery to tumours.
TROP2 is a transmembrane protein sporadically expressed in healthy tissue, but broadly expressed and associated with poor prognosis in HR-positive/HER2-negative breast cancer and TNBC, making TROP2 an attractive tumour-associated antigen for treatment of these breast cancer subtypes. Datopotamab deruxtecan is a TROP2-directed antibody drug conjugate comprising a humanised anti-TROP2 immunoglobulin G1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor, a derivative of exatecan, via a plasma-stable, tumour-selective, tetrapeptide-based cleavable linker, resulting in reduced systemic exposure and off-target adverse effects. Internalisation of datopotamab deruxtecan into TROP2-expressing cells leads to death of target tumour cells and bystander killing of neighbouring cells in the tumour microenvironment.
TROPION-PanTumor01 is a phase I, dose-escalation, and dose-expansion study evaluating datopotamab deruxtecan in patients with previously treated solid tumours. The primary study objective was to assess the safety and tolerability of datopotamab deruxtecan. Secondary objectives included evaluation of antitumour activity and pharmacokinetics.
At data cut-off of 22 July 22 2022, 41 patients with HR-positive/HER2-negative breast cancer and 44 patients with TNBC had received datopotamab deruxtecan. The rate of ORR by blinded independent central review was 26.8% (95% confidence interval [CI] 14.2 to 42.9) for patients with HR-positive/HER2-negative breast cancer and 31.8% (95% CI 18.6 to 47.6) for patients with TNBC. The median duration of response was not evaluable in the HR-positive/HER2-negative breast cancer cohort and 16.8 months in the TNBC cohort. The median PFS in patients with HR-positive/HER2-negative breast cancer was 8.3 months and 4.4 months for TNBC.
All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR-positive/HER2-negative breast cancer and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR-positive/HER2-negative breast cancer (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts.
Cataracts were observed in patients across both cohorts, with treatment-emergent grade 1 to 2 events reported in 14.6% and 9.1% patients in the HR-positive/HER2-negative breast cancer and TNBC cohorts. While these incidences are notable, most events were not considered drug-related by the investigator, and known risk factors for cataract development were enriched in the study population on the basis of age, sex, and treatment history. Development of cataracts and other ocular events continues to be monitored in ongoing trials of datopotamab deruxtecan.
One case of grade 3 adjudicated interstitial lung disease (ILD) was observed in the HR-positive/HER2-negative breast cancer cohort. Toxicity management guidelines for ILD/pneumonitis were implemented at the start of the conduct of the trial.
The safety and efficacy profiles of datopotamab deruxtecan appear to be favourable compared with those of the current standards of care for metastatic HR-positive/HER2-negative breast cancer and TNBC. The authors commented that although their payloads have similar mechanisms of action, sacituzumab govitecan and datopotamab deruxtecan have demonstrated distinct AE profiles in similar but not identical patient populations.
The mode of action of datopotamab deruxtecan may contribute to its safety profile compared with other TROP2-directed antibody drug conjugates. The selective payload delivery of datopotamab deruxtecan, which is enabled by the selectively cleavable plasma-stable linker that releases deruxtecan after proteolytic processing by tumour cell–enriched lysosomal enzymes, reduces systemic exposure while achieving a sustained response, resulting in an improved benefit-risk profile. This may account for the comparatively low incidences of neutropenia and diarrhoea in this study compared with sacituzumab govitecan.
Study limitations include the relatively small number of patients in each cohort and the single-arm open-label study design without a comparator. However, the findings from this study provide rationale for further investigation of datopotamab deruxtecan as a treatment option for advanced/metastatic HR-positive/HER2-negative breast cancer and TNBC, which is ongoing in several phase III trials.
In patients with advanced/metastatic HR-positive/HER2-negative breast cancer, datopotamab deruxtecan is being compared with single-agent chemotherapy as second- or third-line therapy in the randomised, phase III TROPION-Breast01 trial, which recently met its primary PFS endpoint with median PFS of 6.9 months and confirmed ORR of 36.4%. In patients with advanced/metastatic TNBC, datopotamab deruxtecan is being investigated as first-line therapy compared with chemotherapy in the randomised, phase III TROPION-Breast02 trial. Additional studies investigating datopotamab deruxtecan in combination with durvalumab in patients with TNBC are also underway, including the phase III TROPION-Breast03, TROPION-Breast04, TROPION-Breast05, and the BEGONIA phase Ib/II trials.
The study was supported by Daiichi Sankyo, Inc. In July 2020, AstraZeneca entered into a global development and commercialisation collaboration agreement with Daiichi Sankyo for datopotamab deruxtecan.
Reference
Bardia A, Krop IE, Kogawa T, et al. Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study. JCO; Published online 23 April 2024: DOI: https://doi.org/10.1200/JCO.23.01909