Real-world outcomes of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer: Turkish oncology group multicenter study

Abstract

Background:

Trastuzumab deruxtecan (T-DXd) has transformed the treatment landscape of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC), with significant improvements in survival reported in clinical trials. However, limited data exist regarding its performance in real-world settings, particularly in lower-middle-income countries (LMICs).

Objectives:

To evaluate the real-world effectiveness and safety of T-DXd in patients with HER2+ mBC in Türkiye.

Design:

A multicenter retrospective cohort study.

Methods:

This multicenter, retrospective cohort study, conducted by the Turkish Oncology Group, evaluated the real-world outcomes and tolerability of T-DXd in patients with HER2+ mBC across 27 oncology centers in Türkiye. The primary endpoints were real-world progression-free survival (rwPFS) and overall survival (rwOS). Secondary endpoints included response rate, safety (with adverse events (AEs) graded according to CTCAE v5.0), and evaluation of the first post-T-DXd treatments.

Results:

A total of 269 patients were included. The median age was 49 years (interquartile range: 42–59), and the median follow-up was 12.9 months. The median rwPFS was 17.9 months (95% confidence interval: 13.3–22.5), and the median rwOS was 35.7 months (95% confidence interval: 27.8–43.6). The objective response rate was 71.4%, and the disease control rate was 95.2%. Patients receiving T-DXd in the second line experienced significantly longer rwPFS compared with those treated in later lines (p < 0.001). Treatment-related AEs of any grade occurred in 68.4% of patients. Interstitial lung disease was reported in 21 patients (7.8%), with 4 cases being grade ⩾3.

Conclusion:

In this large national real-world cohort from an LMIC, T-DXd demonstrated robust antitumor activity and a manageable safety profile in patients with HER2+ mBC. These findings are consistent with prior clinical trial data and support the applicability of T-DXd in broader clinical settings.

Plain language summary

Real-world use of trastuzumab deruxtecan for HER2-positive metastatic breast cancer

HER2-positive metastatic breast cancer is an aggressive form of breast cancer that often requires multiple lines of treatment. Trastuzumab deruxtecan is a targeted cancer medicine that combines an antibody with a chemotherapy drug, allowing treatment to be delivered directly to cancer cells. Clinical trials have shown that this treatment can be very effective, but patients enrolled in trials may not fully represent those treated in everyday clinical practice. In this study, we examined how trastuzumab deruxtecan performed in real-world settings across Turkiye. We collected and analyzed data from 269 patients treated at 27 cancer centers. This allowed us to understand how well the drug worked and how safe it was outside of clinical trials. We found that many patients experienced meaningful disease control, with most patients showing tumor shrinkage or stabilization. Patients who received trastuzumab deruxtecan earlier in their treatment course tended to benefit the most. Overall survival and the time patients lived without cancer progression were similar to, or better than, results previously reported in clinical trials. Side effects were generally manageable. A small number of patients developed lung inflammation, a known risk of this treatment, highlighting the importance of careful monitoring. In summary, our findings show that trastuzumab deruxtecan is an effective and reasonably safe treatment for HER2-positive metastatic breast cancer in routine clinical care. These results support its use beyond clinical trials and provide valuable evidence from a middle-income country setting, helping doctors and patients make informed treatment decisions.

Introduction

Breast cancer (BC) remains a leading cause of cancer-related morbidity and mortality among women worldwide, necessitating ongoing therapeutic strategies.^1–3 Human epidermal growth factor receptor 2-positive (HER2+) BC is characterized by an aggressive nature and accounts for approximately 15%–20% of all cases. ⁴ HER2+ metastatic breast cancer (mBC) historically carried a poor prognosis, but clinical outcomes of patients with HER2+ mBC have been significantly improved with the advent of HER2-targeting monoclonal antibodies and subsequent development of antibody-drug conjugates (ADCs). ⁵

Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed ADC consisting of a trastuzumab backbone covalently linked to a potent topoisomerase I inhibitor cytotoxic payload. ⁶ The DESTINY-Breast01 and Breast02 trials initially established the efficacy of T-DXd in third- or later-line setting for HER2+ mBC, leading to its accelerated approval.^7,8 Subsequently, the pivotal DESTINY-Breast03 trial demonstrated the superiority of T-DXd over trastuzumab emtansine (T-DM1) as second-line therapy. ⁹ The DESTINY-Breast04 trial further expanded the clinical use of T-DXd to HER2-low mBC. ¹⁰ Regarding safety, T-DXd exhibits an overall manageable toxicity profile characterized mainly by low-grade gastrointestinal and hematological adverse events (AEs); however, interstitial lung disease (ILD) may occur and can be severe in some patients. ¹¹ Most recently, the DESTINY-Breast09 study demonstrated that the combination of T-DXd with pertuzumab has, for the first time, challenged long-standing trastuzumab, pertuzumab, and taxane regimen in the first-line setting, suggesting a paradigm shift in the management of HER2+ mBC. ¹²

Despite the impressive clinical trial results, data from randomized controlled trials may not fully capture the heterogeneity of patients encountered in daily practice. Consequently, real-world evidence has become indispensable in validating trial outcomes, identifying safety signals, and informing subsequent treatment strategies. ¹³ Recent real-world observational studies from Europe and North America have confirmed the clinical efficacy of T-DXd in more heterogeneous, unselected populations, albeit with generally shorter progression-free survival (PFS) than reported in pivotal clinical trials.^14–17 Moreover, most published real-world data come from high-income settings; evidence from lower- and middle-income countries (LMICs) is scarce. Therefore, we conducted a multicenter study to assess the real-world effectiveness and safety of T-DXd in patients with HER2+ mBC across 27 oncology centers in Türkiye.

Methods

Patient population and enrollment criteria

We conducted a multicenter, observational, real-world study. The enrolled patients were those who received T-DXd for the treatment of mBC between January 2021 and January 2025, and the study was carried out at 27 tertiary oncology centers across Türkiye (Supplemental Table 1). Eligible patients were aged ⩾18 years with pathologically confirmed mBC who demonstrated HER2 positivity. HER2 positivity was determined locally and defined as immunohistochemistry (IHC) 3+ or IHC 2+ with amplification confirmed by fluorescence in situ hybridization test (FISH). Patients were required to receive at least one cycle of T-DXd in the metastatic setting with adequate clinical documentation. Patients with insufficient clinical data, unknown or indeterminate HER2 status, or concurrent enrollment in clinical trials were excluded (Supplemental Figure 1).

Demographic, clinicopathological, and treatment-related variables, including age, menopausal status, Eastern Cooperative Oncology Group (ECOG) performance status, prior systemic therapies, metastatic disease sites, and first treatments after T-DXd progression, were systematically extracted from institutional electronic health records. The reporting of this study conforms to the Strengthening the reporting of observational studies in epidemiology (STROBE) statement (Supplemental Table 2). ¹⁸

Planning schedule

Patients received T-DXd (5.4 mg/kg) every 3 weeks, until progression or unacceptable toxicity. The date of T-DXd initiation was designated as the index date. Patients were followed until death, last available clinical documentation, or the prespecified data cutoff of June 30, 2025. Radiological response was locally evaluated, and the tumor assessment was performed every 2–4 months.

Study objectives and endpoint definitions

The primary objectives of the study were to evaluate real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) in patients treated with T-DXd. rwPFS was defined as the time interval between the initiation of T-DXd therapy and the earliest occurrence of either radiologically confirmed disease progression or death from any cause. rwOS was defined as the time from treatment initiation to death due to any cause.

Secondary objectives included the assessment of objective response rate (ORR), disease control rate (DCR), safety profile, and rwPFS with the immediate post-T-DXd regimen. Post-T-DXd rwPFS was defined as the time from initiation of the first systemic therapy administered after T-DXd discontinuation due to disease progression to the earliest occurrence of radiologically confirmed progression or death from any cause. The ORR was defined as the proportion of patients who achieved a complete response (CR) or partial response (PR), while the DCR was defined as the proportion of patients who achieved CR, PR, or stable disease (SD). Time to best response was defined as the interval from initiation of T-DXd therapy to the date of the first documented best overall response, as assessed by local radiologic evaluation. Safety monitoring was performed throughout treatment exposure, and AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. ¹⁹

Statistical analysis

Baseline demographic and clinical characteristics were summarized using descriptive statistics. Continuous variables were reported as medians with interquartile ranges, while categorical variables were presented as frequencies and percentages. Survival outcomes including rwPFS and rwOS were estimated using the Kaplan–Meier method, and differences between groups were compared using the log rank test. Subgroup analyses were performed according to line of therapy, hormone receptor status, ECOG performance status, HER2 immunohistochemical expression, and the presence of brain metastases. Analyses were performed using IBM SPSS Statistics version 24.0 (IBM Corporation, Armonk, NY, USA). Schematic illustrations were created using BioRender (BioRender.com). A two-sided p value less than 0.05 was considered statistically significant.

Results

Patient characteristics

A total of 269 patients with HER2-positive mBC who received T-DXd were included in this multicenter cohort. All patients were female, with a median age of 49 years (interquartile range (IQR): 42–59). Most patients were <65 years (84.4%), and 55.8% were pre-/perimenopausal. ECOG performance status was 0 in 178 patients (66.2%) and 1–2 in 91 patients (33.8%). Regarding disease presentation, 136 patients (50.6%) had de novo metastatic disease, while 133 (49.4%) had a history of early-stage BC. Hazard ratio (HR) positivity was observed in 173 patients (64.3%), whereas 96 patients (35.7%) were HR-negative. HER2 status was IHC 3+ in 197 patients (73.2%) and IHC 2+/FISH+ in 72 patients (26.8%). The main comorbid conditions at baseline included hypertension (15.2%), diabetes (9.7%), and cardiovascular diseases (5.6%).

The majority had received prior anti-HER2 therapy, including trastuzumab (100%), pertuzumab (91.4%), and T-DM1 (63.9%). T-DXd was administered as second therapy in 79 patients (29.4%), as third in 82 patients (30.5%), and as fourth line or later in 108 patients (40.1%). The median number of prior lines of treatment was 2. Sites of metastatic involvement included bone (56.9%), lung (40.9%), liver (33.8%), and brain (21.6%; Table 1).

Table 1.

Baseline characteristics of patients with HER2-positive metastatic breast cancer receiving T-DXd.

Characteristics	All patients (n = 269)
Female, n (%)	269 (100)
Median age, years (IQR)	49 (42–59)
Age group, n (%)
<65 years	227 (84.4)
⩾65 years	42 (15.2)
Menopausal status, n (%)
Pre-perimenopausal	150 (55.8)
Postmenopausal	119 (44.2)
ECOG performance status, n (%)
0	178 (66.2)
1–2	91 (33.8)
Comorbidities, n (%)
No	193 (71.7)
Yes	76 (28.3)
Hypertension	41 (15.2)
Diabetes	26 (9.7)
Cardiovascular disease	15 (5.6)
Breast cancer diagnosis, n (%)
De novo metastatic	136 (50.6)
Early stage	133 (49.4)
Hormone receptor status, n (%)
Positive	173 (64.3)
Negative	96 (35.7)
HER2 status, n (%)
IHC3+	197 (73.2)
IHC2+ and ISH+	72 (26.8)
Prior anti-HER2 therapy, n (%)
Trastuzumab	269 (100)
Pertuzumab	246 (91.4)
T-DM1	172 (63.9)
Line of therapy at which T-DXd was administered in metastatic setting, n (%)
2	79 (29.4)
3	82 (30.5)
4 or more	108 (40.1)
Metastatic sites, n (%)
Bone	153 (56.9)
Lung	110 (40.9)
Liver	91 (33.8)
Brain	58 (21.6)

ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; IQR, interquartile range; ISH, in situ hybridization; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.

Efficacy outcomes

After a median follow-up of 12.9 months, disease progression had been observed in 100 patients (37.2%), while death occurred in 61 patients (22.7%). The median rwPFS was 17.9 months (95% confidence interval (CI): 13.3–22.5). Regarding milestone rwPFS, 86% and 66% of patients remained progression-free at 6 and 12 months, respectively. The median rwOS was 35.7 months (95% CI: 27.8–43.6). At 12 and 24 months, the OS rates were 83% and 62%, respectively (Figure 1).

Figure 1.

Kaplan–Meier curve of real-world overall survival (a) and real-world progression-free survival (b) in patients treated with T-DXd.

T-DXd, Trastuzumab deruxtecan.

In the subgroup analysis, median rwPFS differed significantly according to line of therapy, favoring second-line treatment over later use (p < 0.001; Figure 2). rwPFS also differed significantly by ECOG performance status, with a median of 20.4 months (95% CI: 9.1–31.9) in patients with ECOG 0 and 14.9 months (95% CI: 9.6–20.1) in those with ECOG ⩾1 (p = 0.029) and was significantly shorter in patients with prior T-DM1 exposure (p = 0.004). By contrast, median rwPFS did not vary substantially across age, hormone receptor status, HER2 status, menopausal status, and presence of brain metastases, and these data were consistent with the overall patient population. After adjustment for potential confounders, treatment line of T-DXd (⩾4 vs <4) remained the only independent predictor of rwPFS (HR 2.23, 95% CI: 1.41–3.53; p = 0.001; Table 2). Median rwOS was not reached in patients treated in the second or third line and was 19.7 months (95% CI: 14.4–25.0) in those treated in the fourth line or beyond (p < 0.001). rwOS did not differ significantly by ECOG performance status, age, hormone receptor status, and HER2 status. In contrast, median rwOS was significantly shorter in patients with brain metastases compared with those without, at 29.2 months (95% CI: 13.1–45.3) versus not reached (p = 0.004; Figure 3).

Figure 2.

Kaplan–Meier estimates of rwPFS by LOT for patients with HER2-positive metastatic breast cancer.

LOT, line of therapy; rwPFS, real-world progression-free survival.

Table 2.

Univariable and multivariable Cox regression analyses for PFS.

Variable	Univariable			Multivariable
	HR	95% CI	p Value	HR	95% CI	p Value
Age (⩾ 65 vs <65)	0.829	0.471–1.460	0.516
ECOG status ( > 0 vs 0)	1.561	1.043–2.336	0.029	1.444	0.962–2.165	0.076
Menopausal status (pre/peri vs postmenopausal)	1.023	0.690–1.517	0.908
Comorbidities (yes vs no)	0.870	0.558–1.355	0.538
Hormone receptor status (positive vs negative)	1.049	0.695–1.584	0.819
HER2 status (IHC 3+ vs IHC 2+/ISH+)	0.677	0.437–1.049	0.081
Treatment line of T-DXd (⩾4 vs <4)	2.615	1.744–3.919	<0.001	2.228	1.407–3.528	0.001
Prior pertuzumab exposure (Yes vs no)	1.106	0.537–2.279	0.784
Prior T-DM1 exposure (yes vs no)	2.020	1.253–3.254	0.004	1.353	0.791–2.316	0.270
Timing of metastasis (de novo vs recurrent)	0.806	0.537–1.209	0.297
Brain metastasis (yes vs no)	1.437	0.923–2.238	0.108

CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridization; PFS, progression-free survival; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan.

Figure 3.

Subgroup analysis of survival outcomes in patients with mBC receiving T-DXd.

mBC, metastatic breast cancer; T-DXd, trastuzumab deruxtecan.

In the response-evaluable population (n = 256), the ORR was 71.4%, with CR in 40 patients (14.9%) and PR in 152 patients (56.5%). An additional 46 (17.1%) patients had SD, resulting in a DCR of 95.2%. When stratified by line of T-DXd therapy, response rates were highest in the second- and third-line settings (ORR 85.9% and 80.5%, respectively) and declined in later lines (ORR 62.4% in ⩾4th line), with DCRs showing a similar trend (98.7%, 93.5%, and 88.1%, respectively; Supplemental Table 3). Primary resistance to T-DXd, defined as progressive disease at the first radiological assessment, was documented in 18 patients (6.7%; Table 3). The median number of T-DXd cycles administered was 13 (IQR: 7–19). The median time to best response was 3.9 months (IQR: 1.9–7.9).

Table 3.

Response rates to T-DXd (n = 256).

Responses	n (%)
CR	40 (14.9)
PR	152 (56.5)
SD	46 (17.1)
PD	18 (6.7)
ORR	71.4%
DCR	95.2%
Median time to best response, months (IQR)	3.9 (1.9-7.9)

CR, complete response; DCR, disease control rate; IQR, interquartile range; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; T-DXd, trastuzumab deruxtecan.

Safety

Table 4 summarizes the incidence of treatment-related AEs reported in the study. A total of 184 patients (68.4%) experienced any grade toxicity. Grade 3 or higher toxicities occurred in 39 patients (14.5%). The most common AEs were nausea (all grade, 39.8%; grade ⩾3, 4.1%), neutropenia (all grade, 33.1%; grade ⩾3, 6.3%), anemia (all grade, 31.2%; grade ⩾3, 0.7%), and alopecia (all grade, 30.5%). A decrease in ejection fraction was reported in two patients (0.7%), with one case reported as grade 3. ILD was reported in 21 patients (7.8%), with 4 cases graded as 3 or higher (3 patients had grade 3 events, and1 had grade 5 event). Among the 12 patients with grade 1 ILD eligible for rechallenge, 83.3% (10/12 patients) were rechallenged, and 2 (20%) developed a subsequent ILD. During T-DXd treatment, dose reductions were required in 39 patients (14.4%), and permanent treatment discontinuation due to AEs occurred in 9 patients (3.3%). Of note, the rwPFS and rwOS rates were not affected by dose reduction (p = 0.668 and p = 0.854, respectively).

Table 4.

Summary of adverse events observed during T-DXd treatment, stratified by grade.

Adverse event	All grades, n (%)	Grade ⩾3
Any adverse event	184 (68.4)	40 (14.5)
Nausea	107 (39.8)	11 (4.1)
Neutropenia	89 (33.1)	17 (6.3)
Anemia	84 (31.2)	2 (0.7)
Alopecia	82 (30.5)	–
Leukopenia	78 (29.0)	8 (3)
Alkaline phosphatase/aspartate transaminase increased	56 (20.8)	0 (0)
Vomiting	54 (20.1)	5 (1.9)
Thrombocytopenia	49 (18.2)	6 (2.3)
Diarrhea	19 (7.1)	1 (0.4)
Interstitial lung disease	21 (7.8)	4 (1.5)
Heart failure	2 (0.7)	1 (0.4)

T-DXd, trastuzumab deruxtecan.

Post-T-DXd outcomes

Among the 100 patients who experienced a disease progression, 51 patients (51%) received subsequent systemic therapy following progression on T-DXd. In 26 patients, T-DXd was continued beyond radiologic progression due to asymptomatic or indolent disease at the discretion of the treating physician. Eighteen patients experienced rapid clinical deterioration or death before initiation of further systemic therapy, while in five patients additional treatment was not pursued due to toxicity or poor clinical condition. The most frequently administered regimens were chemotherapy (n = 13, 25.5%) and chemotherapy combined with anti-HER2 agents (n = 13, 25.5%). Chemotherapy plus HER2-TKI was given to five patients (9.8%) and consisted of lapatinib or neratinib-based combinations. Anti-HER2 monoclonal antibodies with or without a TKI were used in four patients (7.8%). Tucatinib was reported as a separate category and was administered in combination with trastuzumab and capecitabine in four patients (7.8%). Endocrine therapy was given to six patients (11.8%), and both T-DM1 and sacituzumab govitecan were used in three patients each (5.9% for both; Figure 4).

Figure 4.

First post-T-DXd treatment progression-free survival in patients receiving subsequent therapy.

T-DXd, trastuzumab deruxtecan.

In the overall population, the median rwPFS was 6 months (95% CI: 3.9–8.2 months), and rwPFS outcomes with these post-T-DXd regimens were heterogeneous (Figure 4). When subsequent therapies were categorized as anti-HER2-based versus non-anti-HER2 regimens, post-T-DXd rwPFS did not differ significantly between the two groups (p = 0.802; Supplemental Figure 2). Moreover, post-T-DXd rwPFS did not differ significantly between patients who achieved an objective response to T-DXd and those who did not (p = 0.389).

Discussion

This large multicenter study provides robust evidence on the effectiveness and safety of T-DXd in a real-world population of patients with HER2+ mBC. The efficacy outcomes observed in our cohort were comparable to those reported in pivotal clinical trials and were numerically higher than those described in previously published real-world series, despite differences in patient characteristics and treatment settings. T-DXd showed a favorable and manageable safety profile. To our knowledge, this is one of the largest national real-world cohorts evaluating T-DXd outside of high-income settings.

The median rwPFS of 17.9 months and rwOS of 35.7 months observed in this study are consistent with the outcomes reported in pivotal clinical trials such as DESTINY-Breast01 and DESTINY-Breast03, which demonstrated median PFS values ranging from 16.4 to 28.8 months and prolonged OS in heavily pretreated and second-line populations, respectively.^7,9 Notably, 70.6% of patients in our cohort received T-DXd in the third line or beyond, paralleling the late-line setting of DESTINY-Breast01, yet achieving similar PFS and numerically higher OS compared with that trial. ²⁰ The median age of our patients was 49 years, which is younger than in DESTINY-Breast01 (55 years), ⁷ DESTINY-Breast02 (54 years), ⁸ and DESTINY-Breast03 (54 years). ²¹ Although younger age may have contributed to improved tolerance and treatment exposure, it is important to note that nearly one-third of our cohort had baseline comorbidities such as hypertension, diabetes, or cardiovascular disease, which were less common in the clinical trials. Interestingly, the efficacy outcomes in our cohort were numerically higher than those reported in several published real-world studies from Europe and North America, where median rwPFS was generally in the range of 12–14 months, and rwOS was approximately 24–30 months.^14–17

Several factors may have contributed to the favorable outcomes observed in our cohort compared with other real-world datasets. First, the proportion of patients who received T-DXd in earlier lines of therapy was relatively high. Prior analyses from both pivotal trials and real-world registries have shown that earlier use of T-DXd is associated with superior clinical outcomes. ¹⁶ In our cohort, patients treated in the second-line setting experienced significantly longer rwPFS than those treated in later lines, consistent with these prior observations. Second, the performance status of patients in this study was generally favorable, with approximately two-thirds of patients having an ECOG performance score of 0. Third, the median age of our patient population was 49 years, which is younger than in most Western real-world studies, where median ages often exceed 55 years.^15,22 Additionally, although brain metastases were present in 21.6% of patients, this proportion is comparable to or slightly lower than that reported in French and U.S. real-world cohorts.^14,22 Collectively, these factors may help explain why our observed survival outcomes were at least as favorable as, and in some cases exceeded, those seen in other real-world populations.

The safety profile of T-DXd in our study was in line with data from both clinical trials and real-world cohorts.^8,9,14,15,20 The majority of AEs were low-grade hematologic and gastrointestinal toxicities, which were manageable in routine practice. ILD occurred in 7.8% of patients, including four grade ⩾3 events (1.5%) and one fatal event. This incidence is within the lower end of the reported range in the literature, where ILD rates vary between 7% and 15% depending on the population and diagnostic vigilance.^8,9,14,15,20 Notably, most patients with grade 1 ILD in our cohort were successfully rechallenged after resolution, supporting the emerging view that carefully selected patients can safely resume T-DXd with close monitoring. These findings underscore the importance of structured ILD surveillance programs, multidisciplinary management involving oncologists and pulmonologists, and early radiologic assessment to enable prompt diagnosis and intervention.

Post-T-DXd treatment strategies remain an evolving and clinically relevant area. In our cohort, 19% of patients received subsequent systemic therapies after T-DXd, with a median rwPFS of 6 months. This outcome is slightly longer than the post-T-DXd PFS reported in recent Japanese and U.S. cohorts, where median values ranged between 4.1 and 4.6 months.^23,24 The regimens used were heterogeneous, reflecting the absence of a clear standard of care in this setting. Treatment selection in routine practice was influenced by multiple factors, including hormone receptor status, loss of HER2 expression, prior treatment exposure, patient performance status, and access or reimbursement considerations. There was no significant difference in rwPFS between anti-HER2-based and non-anti-HER2 regimens. However, this analysis was exploratory in nature and limited by the small sample size and treatment heterogeneity. These findings mirror emerging real-world data suggesting that sequential HER2-targeted therapies may still provide clinical benefit, although the optimal sequencing of T-DXd relative to other ADCs and HER2-TKIs remains undefined.^25–27 Ongoing research is evaluating tucatinib-based combinations, alternative ADCs, bispecific antibodies, and novel sequencing approaches to overcome resistance (e.g., NCT06100874, NCT06533826, NCT06263543, NCT06774027, and NCT06686394). Understanding the mechanisms of primary and acquired resistance will be essential to inform rational treatment selection in this setting.

Our study had several limitations. First, it was designed as an observational retrospective analysis, which inherently introduces the possibility of bias, including heterogeneity in baseline patient characteristics and treatment patterns. Second, certain subgroups of patients were underrepresented, which warrants caution in interpreting the subgroup analyses. Third, the relatively limited number of patients per institution may have affected the robustness and reliability of the findings. In addition, neither HER2 status nor radiologic response assessments were centrally reviewed, and systematic biomarker reassessment at disease progression was not performed. Information regarding the tissue source used for HER2 assessment (primary tumor vs metastatic site) and the use of repeat biopsies at metastatic relapse was not systematically captured. Finally, supportive care strategies may have varied across participating centers. Despite these limitations, this study provides one of the first comprehensive real-world evaluations of T-DXd in an LMIC, thereby filling a critical gap in the literature and offering valuable insights for the global oncology community.

Conclusion

Taken together, this multicenter study confirms that T-DXd achieves real-world outcomes that are highly consistent with clinical trial data, including in an LMIC setting. Earlier use is associated with greater benefit, and T-DXd retained activity across key subgroups, including patients with brain metastases. The safety profile was manageable with appropriate monitoring, particularly for ILD, and no new safety signals emerged. These findings provide robust real-world evidence supporting the integration of T-DXd into standard clinical practice, highlight the need to refine sequencing strategies, and optimize post-progression treatment options.