Datopotamab Deruxtecan as First-Line Treatment for Advanced Triple-Negative Breast Cancer: Full Interpretation of the Phase III TROPION-Breast02 Trial

　　Triple-negative breast cancer(TNBC)is one of the most aggressive subtypes of breast cancer.Although its treatment landscape has advanced in recent years,significant unmet clinical needs remain.For patients with metastatic TNBC who are PD-L1 positive or harbor germline BRCA mutations,first-line treatment options have increased.However,approximately 70%of patients are ineligible for immunotherapy,and standard first-line chemotherapy for this population still faces challenges of low response rates and short duration of response.Additionally,about half of patients with metastatic TNBC do not receive further treatment after first-line therapy,highlighting the urgent need for more effective first-line strategies to improve long-term survival outcomes.

　　Datopotamab deruxtecan is a next-generation TROP2-targeted antibody-drug conjugate(ADC).Based on the results of the Phase III TROPION-Breast01 trial,it has been approved for the treatment of adult patients with unresectable or metastatic hormone receptor-positive,HER2-negative breast cancer who have received prior endocrine therapy and chemotherapy.Meanwhile,the Phase I TROPION-PanTumor01 trial also demonstrated encouraging antitumor activity and a manageable safety profile in previously treated patients with metastatic TNBC.

　　The Phase III TROPION-Breast02 trial is an international,open-label,randomized controlled study designed to evaluate the efficacy and safety of datopotamab deruxtecan monotherapy versus investigator's choice of chemotherapy in previously untreated patients with locally recurrent inoperable or metastatic TNBC who are ineligible for immunotherapy.A total of 644 patients were enrolled and randomly assigned in a 1:1 ratio to receive either datopotamab deruxtecan(6mg/kg intravenously every 3 weeks,n=323)or chemotherapy(n=321).Randomization was stratified by geographic region,disease-free interval,and PD-L1 status.The dual primary endpoints were progression-free survival(PFS)and overall survival(OS)as assessed by blinded independent central review(RECIST v1.1).Efficacy analyses were performed in the intention-to-treat population,and safety analyses included all patients who received at least one dose of study treatment.

　　Core Efficacy Results:Significant Benefits in Both Primary Endpoints

　　The study results showed that datopotamab deruxtecan achieved statistically significant and clinically meaningful improvements in both primary endpoints.In terms of progression-free survival,the median PFS in the datopotamab deruxtecan group was 10.8 months(95%confidence interval 8.6-13.0),significantly superior to 5.6 months(95%CI 5.0-7.0)in the chemotherapy group,representing a 43%reduction in the risk of disease progression or death(hazard ratio 0.57,99%CI 0.44-0.73;p<0.0001).

　　For overall survival,the median OS in the datopotamab deruxtecan group was 23.7 months(95%CI 19.8-25.6),an extension of 5 months compared to 18.7 months(95%CI 16.0-21.8)in the chemotherapy group,with a 21%reduction in the risk of death(HR 0.79,95.01%CI 0.64-0.98;p=0.029).At data cutoff,65%of patients in the datopotamab deruxtecan group and 72%of patients in the chemotherapy group received post-progression or post-discontinuation anticancer therapy,with 21%and 41%of these patients,respectively,receiving subsequent ADC therapy.

　　Secondary Efficacy and Safety Profile

　　In terms of secondary efficacy endpoints,the confirmed objective response rate(ORR)in the datopotamab deruxtecan group was 63%,significantly higher than 29%in the chemotherapy group;complete response rates were 9%and 2%,respectively.The improvement in ORR was consistent across all predefined subgroups.For duration of response(DoR),the median DoR in the datopotamab deruxtecan group was 12.3 months(95%CI 9.1-15.9),an extension of 5.2 months compared to 7.1 months(95%CI 5.6-8.9)in the chemotherapy group,demonstrating more durable antitumor activity.Additionally,the median duration of treatment was significantly longer in the datopotamab deruxtecan group than in the chemotherapy group.

　　Regarding safety,the incidence of grade≥3 treatment-related adverse events(TRAEs)was 33%in the datopotamab deruxtecan group and 29%in the chemotherapy group,with similar overall rates.The proportion of patients who discontinued treatment due to TRAEs was 4%in the datopotamab deruxtecan group,lower than 7%in the chemotherapy group.After adjusting for differences in treatment exposure between the two groups,the incidence of all-grade,grade≥3,serious,and treatment-discontinuing TRAEs was lower in the datopotamab deruxtecan group than in the chemotherapy group.No treatment-related deaths occurred in either group,and the overall safety profile was manageable.

　　Patient-Reported Outcomes and Comparison with Similar Studies

　　Patient-reported outcome(PRO)data further supported the clinical benefit of datopotamab deruxtecan.All measures,including time to first and confirmed deterioration of pain,physical function,global health status/quality of life,and breast and arm symptoms,numerically favored the datopotamab deruxtecan group(HR<1),indicating that the drug also offers advantages in improving patients'quality of life.

　　The study authors also compared the results with the Phase III ASCENT-03 trial of another TROP2-targeted ADC,sacituzumab govitecan.Both studies demonstrated that TROP2-targeted ADCs improve efficacy outcomes compared to chemotherapy as first-line treatment for metastatic TNBC,but there are key differences in study design:ASCENT-03 only enrolled patients with a disease-free interval>6 months,while TROPION-Breast02 enrolled patients regardless of disease-free interval;chemotherapy options also differed between the two studies,although more than 50%of patients in both control groups received taxane monotherapy.Furthermore,ASCENT-03 allowed crossover to sacituzumab govitecan for patients in the chemotherapy group upon disease progression,while in TROPION-Breast02,patients could receive any appropriate subsequent treatment at the investigator's discretion,more closely reflecting real-world clinical practice.

　　Study Limitations and Conclusion

　　This study has certain limitations.First,the treatment landscape for TNBC is evolving rapidly.(Neo)adjuvant chemotherapy combined with pembrolizumab was first approved in the United States in July 2021,less than a year before TROPION-Breast02 began enrollment,with later approvals in other regions.As a result,the proportion of patients who had received prior PD-(L)1 inhibitor therapy in the study was low(approximately 5%in each group).Second,although the study achieved trial diversity goals globally and implemented multiple measures to recruit a diverse patient population,only about 4%of enrolled patients were Black.Given that Black women have a significantly higher incidence of TNBC than other racial and ethnic groups,continued efforts are needed to ensure representation of this population in clinical research in this field.

　　Overall,the results of the TROPION-Breast02 trial confirm that datopotamab deruxtecan significantly prolongs progression-free survival and overall survival compared to chemotherapy as first-line treatment for patients with locally recurrent inoperable or metastatic TNBC who are ineligible for immunotherapy,with a manageable safety profile and superior patient quality of life.These data support datopotamab deruxtecan as a new first-line standard treatment option for this patient population.