Abstract
Background
The study aimed to evaluate real-world effectiveness and toxicity data of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in pretreated patients with metastatic breast cancer (mBC).
Patients and methods
A retrospective multicenter review of medical records of patients with mBC treated with T-DXd and/or SG at 24 Departments of Oncology, affiliated with the Hellenic Cooperative Oncology Group (HeCOG) was carried out. Patients with triple-negative BC (TNBC), HER2-positive, and/or hormone receptor (HR)-positive mBC who received at least one cycle of T-DXd and/or SG in any line of treatment were included. The primary endpoint was the toxicity rate of each drug.
Results
From January 2020 to April 2024, 312 patients received treatment; 226 (72.4%) received T-DXd and 60 (19.2%) SG, while 26 (8.3%) patients received both agents. Adverse events (AEs) were reported in 57.1% of patients treated with T-DXd and 56.6% of patients treated with SG. The most common AEs were nausea (28.1%) and fatigue (22.5%) among patients treated with T-DXd, and fatigue (20.7%) and neutropenia (12.6%) among those treated with SG. Toxicity-related discontinuation was reported in 12 (8.8%) and 2 (3.2%) patients, respectively, who received T-DXd and SG. Interstitial lung disease was observed in 17 (6.9%) patients treated with T-DXd. The 12-month progression-free survival (PFS) rate was 69.6 [interquartile range (IQR) 61.4-79] in patients with HER2-positive and 46.5 (IQR 28.6-46.5) in patients with HER2-low mBC receiving T-DXd. In patients with TNBC receiving SG, the 12-month PFS rate was 16.2 (IQR 8.1-32.4), whereas in patients with HR-positive/HER2-negative mBC, it was 23.6 (IQR 13.8-40.3).
Conclusions
Real-world data on the use of T-DXd and SG in patients with mBC provide significant clinical insights into the toxicity and effectiveness of each agent.
Key words: breast cancer, interstitial lung disease, HER2-low, real-world data, sacituzumab govitecan, trastuzumab deruxtecan
Highlights
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T-DXd and SG have revolutionized outcomes in advanced BC.
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Real-world data are critical for validating drug efficacy and safety.
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This was a retrospective multicenter review of patients treated with T-DXd and SG.
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Real-world efficacy was consistent with previously published results.
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Interstitial lung disease remains a critical issue for patients receiving T-DXd.
Introduction
Next-generation antibody–drug conjugates (ADCs) have revolutionized outcomes in patients with metastatic breast cancer (mBC) and have been rapidly incorporated into the treatment algorithms.1 Trastuzumab deruxtecan (T-DXd), an HER2-targeting ADC, and sacituzumab govitecan (SG), a TROP-2-targeting ADC, recently demonstrated unprecedented efficacy over standard-of-care treatments across all BC subtypes, addressing significant unmet clinical needs.2, 3, 4, 5, 6 The robust efficacy of these novel therapeutic compounds is characterized by increased target specificity, a high drug-to-antibody ratio, a hydrolyzable linker that facilitates rapid internalization and release of an efficient payload in cancer cells, and the ability of the payload to cross the cell membrane and exert its cytotoxic effect on surrounding cells (bystander effect). This partly explains their remarkable efficacy in the heterogeneous environment of mBC.7
Alongside the unprecedented effectiveness of these new agents in the setting of mBC, several unanswered questions arise. Clinicians increasingly discuss dilemmas regarding their optimal sequencing,8 resistance mechanisms after previous ADC exposure,9 effectiveness in patients with brain metastases,10 and more importantly, their toxicity profiles in real-world clinical settings.11 As randomized clinical trials with head-to-head comparisons are cumbersome and costly, alternative ways to provide answers to these critical challenges are warranted. Real-world data hold the promise of providing representative and inclusive data from patients often excluded from clinical trials (e.g. older patients, those with excessive comorbidities, or those with limited access to specialized centers). However, real-world published data are often generated from academic centers, and therefore, may not fully represent the broader treated patient population. The collection of real-world data needs to be inclusive and representative of the whole population, including minorities, to provide relevant data compared with clinical trials. To date, very scarce real-world clinical data are available about the activity and toxicity of second-generation ADCs in routine clinical practice.12, 13, 14, 15, 16, 17
Thus, our aim was to document and evaluate real-world effectiveness and toxicity data of T-DXd- and SG-pretreated patients with mBC in Greece and possibly provide some evidence on clinically relevant questions often arising in everyday practice.
Patients and methods
Patients
This retrospective data collection included patients with histologically confirmed mBC treated with T-DXd and/or SG in Departments of Oncology associated with the Hellenic Cooperative Oncology Group (HeCOG). Departments of Oncology were located in private or national hospitals across the country, covering a wide range of patients. Departments of Oncology are affiliated with HeCOG to participate in the research activities of the group, provided they meet the necessary requirements. Eligible patients were aged ≥18 years; diagnosed with triple-negative BC (TNBC), HER2-positive, and/or hormone receptor (HR)-positive mBC; and had initiated treatment with an ADC in any line. First-line was defined as the treatment of patients who had not received prior systemic therapy for advanced disease. Systemic therapies, including endocrine treatments, chemotherapy agents, targeted/biologic drugs, and ADCs were considered as a line of treatment. Surgical or radiation treatments were not considered as lines of therapy. The first-line treatment initiation was recorded at the date of the first oral or infused drug administration. In case of discontinuation of a line of therapy, irrespective of the reason, initiation of the next line of therapy would similarly be reported on the first date of the subsequent oral or infused drug.
Patients who received at least one cycle of T-DXd and/or SG between January 2020 and April 2024 were included. The end of the follow-up was October 2024. Histopathological, immunohistochemical, and in situ hybridization studies were carried out locally. HER2 was interpreted as follows: HER2-positive was defined as HER2+3 by immunohistochemistry (IHC) or HER2+2 by IHC with positive fluorescent in situ hybridization (FISH). HER2-low was defined as HER2+1 by IHC or HER2+2 by IHC with negative FISH. HER2 ultra-low categorization was not available at the time of data collection. Treatment with T-DXd and SG was administered per national guidelines.
Data collection
Clinical, pathological, treatment, and outcome data were recorded from medical records. Pathology data were recorded in detail from all available histology reports. Toxicity data were recorded from clinician documentation of patient-reported symptoms and laboratory results during scheduled clinical visits or patient hospitalizations. Toxicity rates were evaluated in all patients who received ADC, regardless of immunohistochemical BC subtype. The database was completed by experienced data managers from each Department of Oncology participating in HeCOG academic clinical trials and translational research. Data monitoring was carried out by trained HeCOG personnel. Data were anonymized and recorded in a specially formatted database with unique identification numbers. This dataset focused on specialized data to address the objectives of the study. This study was carried out according to the ESMO Guidance for Reporting Oncology real-World evidence (GROW) guidelines for real-world data reporting.18 All living patients provided informed consent, while a waiver of consent was obtained for deceased patients. The study was approved by the Institutional Review Board of ‘G. Papanikolaou’ General Hospital (protocol number: 13_28/11/2023). The trial is registered on ClinicalTrials.gov (NCT06504719).
Study objectives
The primary objective was to evaluate the toxicity rate of each ADC and the related dose reduction or treatment discontinuation. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Secondary objectives included the assessment of (i) progression-free survival (PFS), (ii) overall survival (OS), (ii) PFS in patients with central nervous system (CNS) metastases, and (iv) the 12-month PFS and 12-month OS rates. PFS was defined as the time from the start of ADC treatment (index date) to disease progression or death from any cause, and OS was defined as the time from the start of ADC treatment (index date) to death.
Statistical analysis
For descriptive statistics, frequencies and relative frequencies were derived for the categorical variables, whereas median and interquartile range (IQR) were derived for the numeric variables. In the case of censored data, the median survival time was derived through the Kaplan–Meier estimator. For data visualization, grouped barplots and Kaplan–Meier curves were constructed. Patients without an event were censored at the last contact known to be alive.
For the inferential statistics, the risk factors examined were the age at treatment initiation (<70 years versus ≥70 years), the line of treatment (first/second versus subsequent), and the performance status. Regarding the toxicity rates, the dose reduction, and the treatment discontinuation, Fisher’s exact test was applied. Concerning the PFS and OS, the log-rank test was conducted.
The significance level was set to 5% and the statistical analyses were carried out using R (version 4.3.2; R Foundation, Vienna, Austria).
Results
Study population
From January 2020 to April 2024, 312 patients (1 man and 311 women) were treated with T-DXd and/or SG across 24 major HeCOG-affiliated Oncology Departments. The median age at diagnosis was 51 years (IQR 43.75-63 years). Approximately, one-third of the patients presented with de novo metastatic disease. Brain metastatic lesions were identified in 6 patients (1.9%) at diagnosis, and in 56 patients (17.9%) at the initiation of ADC therapy.
Among the cohort, 226 patients (72.4%) initiated treatment with T-DXd, 60 patients (19.2%) with SG, and 26 patients (8.3%) were treated with both agents (Figure 1). T-DXd was administered to 128 patients (50.8%) with HER2-positive disease and to 124 patients (49.2%) with HER2-low disease. SG was administered to 38 patients (45.8%) with HR-positive/HER2-negative disease and to 45 patients (54.2%) with TNBC. Most patients received either agent as a third-line treatment or beyond (T-DXd: 174 patients, 69.3%; SG: 71 patients, 82.6%). The median number of prior treatment lines for advanced disease was 3 (IQR 2-4) for SG and 2 (IQR 1-4) for T-DXd. None of the patients had received an ADC as part of adjuvant or neoadjuvant treatment. Overall, the median number of treatment cycles was 9 (IQR 5-16) for T-DXd and 4 (IQR 2-6) for SG. Detailed patient characteristics are presented in Table 1.
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT) flowchart. HR, hormone receptor; SG, sacituzumab govitecan; T-DXd, trastuzumab deruxtecan; TNBC, triple-negative breast cancer.
Table 1.
Patient clinical characteristics
| Variable | Value | All | T-DXd | SG |
|---|---|---|---|---|
| Age at diagnosis, years | Median (interquartile range) | 51 (43.75-63) | 51 (43-61.25) | 54 (45-66) |
| Working, n (%) | No | 110 (55) | 88 (54.7) | 28 (50) |
| Yes | 90 (45) | 73 (45.3) | 28 (50) | |
| Personal history of other cancers, n (%) | No | 281 (95.3) | 226 (95) | 77 (96.2) |
| Yes | 14 (4.7) | 12 (5) | 3 (3.8) | |
| Family history of breast or ovarian cancer, n (%) | No | 233 (82) | 189 (83.3) | 64 (80) |
| Yes | 51 (18) | 38 (16.7) | 16 (20) | |
| Family history of other cancers, n (%) | No | 200 (72.2) | 160 (71.4) | 54 (72) |
| Yes | 77 (27.8) | 64 (28.6) | 21 (28) | |
| Concurrent diseases, n (%) | No | 66 (37.9) | 55 (39.6) | 15 (31.2) |
| Yes | 108 (62.1) | 84 (60.4) | 33 (68.8) | |
| Germline testing, n (%) | Mutation | 29 (30.5) | 25 (34.2) | 7 (20.6) |
| Negative | 60 (63.2) | 43 (58.9) | 24 (70.6) | |
| VUS | 6 (6.3) | 5 (6.8) | 3 (8.8) | |
| Menopausal status, n (%) | Pre-perimenopausal | 129 (42.4) | 108 (44.1) | 30 (35.7) |
| Postmenopausal | 175 (57.6) | 137 (55.9) | 54 (64.3) | |
| Breast cancer diagnosis, n (%) | De novo metastatic | 99 (31.7) | 85 (33.7) | 24 (27.9) |
| Early stage | 213 (68.3) | 167 (66.3) | 62 (72.1) | |
| Breast surgery, n (%) | No | 86 (27.7) | 72 (28.8) | 21 (24.4) |
| Yes | 224 (72.3) | 178 (71.2) | 65 (75.6) | |
| Adjuvant radiotherapy, n (%) | No | 64 (32) | 52 (32.9) | 16 (27.6) |
| Yes | 136 (68) | 106 (67.1) | 42 (72.4) | |
| (Neo)adjuvant chemotherapy, n (%) | No | 22 (10.7) | 19 (11.7) | 5 (8.5) |
| Yes | 184 (89.3) | 144 (88.3) | 54 (91.5) | |
| SG indication, n (%) | HR positive/HER2 negative | 38 (45.8) | 18 (78.3) | 38 (45.8) |
| TNBC | 45 (54.2) | 5 (21.7) | 45 (54.2) | |
| T-DXD indication, n (%) | HER2-low | 124 (49.2) | 124 (49.2) | 24 (92.3) |
| HER2 positive | 128 (50.8) | 128 (50.8) | 2 (7.7) | |
| Line of treatment, n (%) | 1 | 14 (4.5) | 13 (5.2) | 1 (1.2) |
| 2 | 70 (22.5) | 58 (23.1) | 12 (14.1) | |
| ≥3 | 227 (73) | 180 (71.7) | 72 (84.7) |
Percentages are provided for informative patients.
FISH, fluorescent in situ hybridization; HER2 low, HER2: +1 and HER2: +2/FISH negative; HER2 positive, HER2: +2 by immunohistochemistry/FISH positive and HER2+3 by immunohistochemistry; HR, hormone receptor; SG, sacituzumab govitecan; T-DXd, trastuzumab deruxtecan; TNBC, triple-negative breast cancer; VUS, variant of unknown significance.
Toxicity
AEs were reported in 139 patients (55.2%) treated with T-DXd and 47 patients (54.7%) treated with SG. The most common AEs among patients receiving T-DXd were nausea (25.8%), fatigue (28.2%), and vomiting (13.9%). In patients treated with SG, common AEs included fatigue (19.8%), neutropenia (12.8%), anemia (12.8%), and nausea (10.5%). Grade 3/4 AEs were reported in 21 patients (8.3%) receiving T-DXd and 10 patients (11.5%) receiving SG. Dose reductions due to AEs occurred in 31 patients (12.3%) receiving T-DXd and 9 patients (10.5%) receiving SG. Treatment discontinuation due to toxicity was carried out in 12 patients (8.8%) on T-DXd and 2 patients (3.2%) on SG.
Interstitial lung disease (ILD) was observed in 17 patients (6.7%) treated with T-DXd, with 3 patients (1.2%) experiencing grade 3/4 ILD. No cases of ILD were observed in patients treated with SG. Patients had received a median of four prior lines of therapy (excluding T-DXd) before the ILD diagnosis. Follow-up with computed tomography (CT) scans was conducted at a median interval of 13 weeks. The median time from treatment initiation to ILD diagnosis was 4.58 months (IQR 2.48-8 months). The majority of patients (14/17, 82.4%) were educated about the risk of ILD and its potential symptoms. Hospitalization for pneumonitis was required for nine patients (56.2%) with ILD. ILD was resolved in 15 out of 17 patients (88.2%) with corticosteroid treatment. Dose reduction was necessary for three patients (1.2%), while T-DXd was permanently discontinued in eight patients. In two patients with grade 2 ILD, T-DXd was re-administered after symptom improvement, with no subsequent ILD recurrence. There was one death possibly related to ILD in a patient receiving T-DXd. No drug-related fatal toxicities were reported among patients receiving SG. The incidence of treatment-related AEs is summarized in Table 2.
Table 2.
Adverse events
| Adverse event | Trastuzumab deruxtecan, n (%) |
Sacituzumab govitecan, n (%) |
||
|---|---|---|---|---|
| All grades | Grade 3/4 | All grades | Grade 3/4 | |
| Any adverse event | 140 (57.1) | 21 (8.3) | 47 (54.6) | 10 (11.6) |
| Fatigue | 71 (28.2) | 4 (1.6) | 17 (19.8) | 0 (0) |
| Nausea | 65 (25.8) | 4 (1.6) | 9 (10.5) | 1 (11.1) |
| Vomiting | 35 (13.9) | 4 (1.6) | 3 (3.5) | 1 (1.2) |
| Anemia | 22 (8.7) | 2 (0.8) | 11 (12.8) | 1 (1.2) |
| Leukopenia | 25 (9.9) | 4 (1.6) | 9 (10.5) | 1 (1.2) |
| Diarrhea | 21 (8.3) | 2 (0.8) | 8 (9.3) | 0 (0) |
| Neutropenia | 15 (5.9) | 4 (1.6) | 11 (12.8) | 6 (7.0) |
| Interstitial lung disease | 17 (6.7) | 3 (1.2) | 0 (0) | 0 (0) |
| Alkaline phosphatase/aspartate transaminase increased | 13 (5.2) | 1 (0.4) | 3 (3.5) | 0 (0) |
| Thrombocytopenia | 10 (4.0) | 1 (0.4) | 5 (5.8) | 1 (1.2) |
| Anorexia | 7 (2.8) | 1 (0.4) | 2 (2.3) | 0 (0) |
| Constipation | 8 (3.2) | 0 (0) | 5 (5.8) | 0 (0) |
| Abdominal pain | 8 (2.2) | 0 (0) | 1 (1.2) | 0 (0) |
| Headache | 7 (2.8) | 0 (0) | 1 (1.2) | 0 (0) |
| Arthralgia | 6 (2.4) | 0 (0) | 4 (4.6) | 1 (1.2) |
| Dyspepsia | 5 (2.0) | 0 (0) | 0 (0) | 0 (0) |
| Myalgia | 5 (2.0) | 0 (0) | 1 (1.2) | 0 (0) |
| Skin rash | 5 (2.0) | 0 (0) | 0 (0) | 0 (0) |
| Infection | 4 (1.6) | 1 (0.4) | 1 (1.2) | 0 (0) |
| Dizziness | 4 (1.6) | 0 (0) | 3 (3.5) | 0 (0) |
| Dry skin | 3 (1.2) | 0 (0) | 1 (1.2) | 0 (0) |
| Stomatitis/dry mouth | 3 (1.2) | 0 (0) | 3 (3.5) | 0 (0) |
| Changes in food taste | 1 (0.4) | 0 (0) | 0 (0) | 0 (0) |
| Fall quickly | 1 (0.4) | 0 (0) | 0 (0) | 0 (0) |
| Pruritus | 1 (0.4) | 0 (0) | 0 (0) | 0 (0) |
| Febrile neutropenia | 0 (0) | 0 (0) | 1 (1.2) | 0 (0) |
There was no significant difference in grade 3/4 toxicity between patients aged <70 years and those aged ≥70 years (T-DXd P = 0.24; SG P = 0.72), nor in dose reduction rates (T-DXd P = 0.31, SG P > 0.9) or discontinuation rates (T-DXd P = 0.13, SG P > 0.9; Supplementary Table S1, available at https://doi.org/10.1016/j.esmorw.2024.100095).
Clinical outcomes
With a median follow-up of 16.75 months (95% CI 15.4-18.07 months) after ADC treatment, 129 patients (51.2%) experienced recurrence while on T-DXd and 67 patients (77.9%) on SG. At the data cut-off, 109 patients (43.3%) were still receiving T-DXd and 19 patients (22.1%) were on SG. Primary resistance was observed in 15 patients (6%) with T-DXd and 16 patients (18.6%) with SG, defined by disease progression at the first evaluation on CT scans and/or clinical deterioration as assessed by the physician.
Treatment with T-DXd
Among patients with HER2-positive mBC receiving T-DXd, the 12-month PFS rate was 69.6% (95% CI 61.4% to 79%; Figure 2A). There was no significant difference in median PFS between patients treated with T-DXd as first-/second-line therapy and those treated as third-line or beyond [median PFS (mPFS) 17.31 months, 95% CI 11.21 months to non-estimable versus 15.27 months, 95% CI 11.79 to 22.04 months; HR 1.07, 95% CI 0.71 to 1.61; P = 0.752].
Figure 2.
Kaplan–Meier analysis in patients who received trastuzumab deruxtecan. (A) Progression-free survival (PFS) in patients with HER2-positive and (B) HER2-low disease. (C) Overall survival (OS) in patients with HER2-positive and (D) HER2-low disease.
For patients with HER2-low disease, the 12-month PFS rate was 36.5% (95% CI 28.6% to 46.5%; Figure 2B). There was a longer median PFS in patients receiving T-DXd as first-/second-line therapy compared with later lines (mPFS 11.56 months, 95% CI 9.72-17.71 months versus 6.34 months, 95% CI 4.37-17.31 months; HR 0.47, 95% CI 0.29-0.81; P = 0.006). The 12-month PFS rates were 51.3% (95% CI 39.5% to 66.8%) for first-/second-line therapy and 35.7% (95% CI 18.5% to 69.1%) for subsequent lines. The 12-month OS rates are shown in Figure 2C and D.
Treatment with SG
In patients with TNBC receiving SG, the 12-month PFS rate was 16.2% (95% CI 8.1% to 32.4%; Figure 3A), while in patients with HR-positive mBC, the 12-month PFS rate was 23.6% (95% CI 13.8% to 40.3%; Figure 3B). No significant difference in the median PFS was observed between patients treated earlier versus later with SG, either in TNBC (mPFS 3.61 months, 95% CI 2.66 months to nonestimable versus 5.02 months, 95% CI 3.12 to 10.61 months; HR 0.66, 95% CI 0.3-1.45; P = 0.302) or in HR-positive mBC (mPFS 32.49 months, 95% CI nonestimable to nonestimable versus 2.87 months, 95% CI 2.36-5.29 months). The 12-month OS rates for the two subgroups are shown in Figure 3C and D, respectively.
Figure 3.
Kaplan–Meier analysis in patients who received sacituzumab govitecan. (A) Progression-free survival (PFS) in patients with triple-negative breast cancer (TNBC) and (B) hormone receptor (HR)-positive/HER2-negative disease. (C) Overall survival (OS) in patients with TNBC and (D) HR-positive/HER2-negative disease. TNBC, triple-negative breast cancer.
Special populations
At T-DXd initiation, 59 patients (23.5%) had brain metastases, with an mPFS of 13.24 months (either extracranial or intracranial). CNS relapse occurred in 10 patients (18.5%) during T-DXd treatment, among which 7 (16.7%) had HER2-positive and 3 (25%) had HER2-low disease. At SG initiation, 19 patients (23.2%) had brain metastases, with an mPFS of 2.76 months. CNS relapse occurred in three patients (15.8%) during SG treatment: two patients (16.7%) with TNBC and one patient (14.3%) with HR-positive disease.
Sequential administration of ADCs
Overall, 26 patients received both ADCs sequentially, with T-DXd administered first in 20 patients (Figure 4). In 10 patients (38.5%), another treatment agent was used in between. In two patients, the ADC was interrupted due to excessive toxicity (one while receiving the first ADC and the other during the second one). In 16 of 21 remaining patients (76.2%), the administration of the second ADC was associated with decreased PFS compared with the first ADC, regardless of which drug was administered first. However, in selected cases (5 patients, 23.8%), the second ADC resulted in longer PFS compared with the first.
Figure 4.
Sequential administration of the two antibody–drug conjugates (ADCs). The top bar in each pair (patient) represents the ADC administered first. Ongoing treatments have been noted. In most patients, the first ADC resulted in a longer progression-free survival (PFS) compared with the second ADC. However, in selected cases, the administration of the second ADC resulted in longer PFS, regardless of the ADC sequence. One patient discontinued treatment with the second ADC due to excessive toxicity. SG, sacituzumab govitecan; T-DXd, trastuzumab deruxtecan.
Discussion
This study reported toxicity and effectiveness data of patients receiving the two approved ADCs in HeCOG-affiliated Oncology Departments in Greece over the past 4 years. Among known serious AEs, ILD appears to be a critical issue for patients receiving T-DXd and needs to be addressed cautiously. Despite the presence of AEs, discontinuation rates were low for both drugs. Importantly, the real-world effectiveness data of patients with mBC receiving T-DXd and SG were consistent with the results of published large phase III clinical trials.2, 3, 4, 5 The effectiveness data of the small number of patients receiving both drugs sequentially highlight the need to evaluate prospectively the optimal sequence in larger patient populations, while assessing for predicting biomarkers.
The administration of both ADCs was associated with previously reported AEs in our patient population. Compared with previously published clinical trials, we reported lower rates of AEs for both ADCs. Another real-world study reported similar AE rates (59%) with T-DXd.12 Lower rates of reported AEs may be attributed to less meticulous reporting of certain AEs (e.g. alopecia and myalgia) in everyday clinical practice compared with clinical trials.19 No new safety signals were reported in our study. The proportion of patients discontinuing T-DXd (10.1%) and SG (3.7%), which are always recorded in patient medical records, was similar to the rates reported in large phase III clinical trials.3, 4, 5,20 Importantly, there was no significant difference between patients <70 and ≥70 years of age in terms of grade 3/4 toxicity, dose reduction, or discontinuation rates, providing some reassurance when treating older patients.
ILD has been identified as an AE of special interest in patients receiving T-DXd. The incidence of ILD has been reported in ∼15% of patients in different clinical trials evaluating T-DXd, with the majority of events being grade 1/2, but in rare cases associated with hospitalization or even death.3,20 In our study, 15 (6%) patients were diagnosed with ILD while receiving T-DXd, while no ILD cases were reported with SG. Despite recommendations to frequently carry out CT scans, intervals between sequential CT scans varied significantly. Carrying out CT scans every 6-9 weeks is challenging in clinical practice, both for patients and for health systems. The current AE management guidelines recommend permanent discontinuation upon development of grade 2 or worse ILD. Rechallenge was reported in all patients with ILD grade 1, and in 2 of 4 patients with grade 2 ILD upon its resolution, despite expert recommendations against it. There was no recurrence of ILD or ILD-related symptoms in these patients. In a pooled analysis of nine clinical trials, 23% (45/193) of patients with grade 1 ILD were retreated with T-DXd, with 68.9% receiving retreatment without any dose reduction. Recurrence of ILD was observed in only 33.3% of patients, with all events being low-grade and easily manageable.21 As treatment with T-DXd can bring significant clinical benefit, adjustments may be made to balance the benefit-to-risk ratio.
Our findings were in alignment with those of large phase III clinical trials assessing the ADCs in mBC.6,22, 23, 24, 25, 26 Although the alignment of real-world findings with those of registrational clinical studies reinforces the effectiveness outcomes observed in these studies, real-world data speak on behalf of a broader population treated in everyday clinical practice; however, these groups remain underrepresented in clinical trials, and often possess poorer outcomes due to comorbidities, increased age, and later line of treatment. The median real-world PFS reported in several studies so far ranges from 4.9 to 16 months for patients with HER2-positive tumors treated with T-DXd and the median real-world OS ranges between 20 and 37.1 months.12,27, 28, 29 Accordingly, real-world median PFS observed for patients with TNBC treated with SG ranges from 4.7 to 5.2 months and real-world OS from 12.4 to 14 months.15,27,29, 30, 31 Notably, improved survival outcomes achieved in mBC by TDX-d and SG in our study are not confounded as anticipated by the real-world setting and stay in accordance with other published data. However, they should be interpreted with caution because they arise from completely heterogeneous mBC populations and should by no means be used to compare real-world effectiveness among the two different ADCs.
As a proportion of patients will be candidates to receive both ADCs, assessing the efficacy and toxicity of the sequential administration of the two ADCs is critical. Despite the small number of patients receiving both ADCs in our study, we reported that the second ADC was usually associated with shorted PFS compared with the first ADC, regardless of which ADC was administered first. However, we observed selected cases where the second ADC was associated with longer PFS, underscoring the need to identify biomarkers to select the optimal treatment agent for each patient with mBC. Similar results on the sequential administration of T-DXd and SG were recently published.16,32 As no head-to-head comparison of these two agents has been reported, real-world data associated with translational studies on large numbers of patients are warranted to enable the selection of the optimal treatment for each patient.
Importantly, real-world studies may be impacted by the timing of regimen approvals, often affecting the selection of participating patients and leading to selection bias. Therefore, the effect of prior treatments on the effectiveness of subsequent ones may not be reflected in the comparison of diverse treatment outcomes. Previous investigators have shown that real-world studies need to acknowledge selection biases to avoid inaccurate data interpretation, particularly regarding the optimal treatment sequencing and comparisons of treatment effectiveness.33 In our study, patients who benefited the most from the first ADC may not receive the second ADC and, therefore, may not be included in the treatment sequence analysis. Our analysis is descriptive only and our results need to be interpreted with caution.
Other biases related to the quality of our data that may have influenced our results need to be acknowledged. Missingness is a common bias in real-world data studies, where incomplete data collection of key variables may result in unbalanced data sources. In our study, missingness regarding the variables in our study may have influenced the analysis. However, no loss to follow-up was observed among the patients in this study. In addition, potential confounding factors may have affected the survival outcomes of the study patients. Multivariate analysis could not be carried out due to the small sample size. Confounding by indication bias, possibly related to the physicians’ treatment selection based on the two ADC indications, must also be considered. Patients who received even a single treatment cycle were included to avoid selectively analyzing those fit for additional treatment, who might have better outcomes compared with others who died rapidly from the disease.
The limitations of our study are its retrospective nature, short follow-up duration, and small sample size, which resulted in lower statistical power and restricted the analysis of subgroups, including patients who received both ADCs sequentially. In addition, the possibility of underestimating AEs is a significant limitation. However, underreporting of AEs possibly regarded as grade 1/2 AEs, because more serious AEs, including those leading to hospitalization or requiring special attention, are usually reported in patient medical records. Furthermore, our data did not include information about the date of each AE occurrence. Therefore, we were unable to use survival analysis methods, such as Kaplan–Meier or competing risks, which would have been more appropriate for examining safety. However, we analyzed the time to last follow-up for the two groups (AE versus no-AE) and found them to be comparable, indicating that the observed results are not influenced by differences in follow-up duration (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmorw.2024.100095). In addition, a limitation of our real-word study was the lack of application of standardized RECIST assessment criteria to assess disease progression, which may have impacted PFS evaluation.
The strengths of the study are the large number of patients who received ADCs compared with previously published studies and the inclusion of patients who received even a single cycle of an ADC. This approach allowed the analysis to account for those experiencing excessive toxicity or poor prognosis. Additionally, no patient was lost to follow-up, strengthening the outcome analysis. Finally, patients from both private and national hospitals across the country were included, enhancing the representativeness of the patient population.
In conclusion, real-world effectiveness study data for patients with mBC treated with T-DXd and SG were consistent with the results of pivotal phase III clinical trials. Despite caution, ILD remains a critical issue for patients receiving T-DXd and requires special attention. In the era of precision medicine, it is essential to identify robust biomarkers to determine the optimal use and sequencing of multiple available therapeutic agents.
Acknowledgements
The authors are indebted to all patients and their families for their trust and participation in the Hellenic Cooperative Oncology Group (HeCOG) studies. The authors also thank the data managers of the Group for data collection and Maria Moschoni and Anastasia Ntafalia for coordinating the study.
Funding
This study was supported by an internal Hellenic Cooperative Oncology Group (HeCOG) translational research grant [number HE 11ADC/23] and by a Hellenic Society of Medical Oncology (HeSMO) grant [number HE_11ADC/23]. The funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Disclosure
EF has stock ownership in GENPREX INC and Deciphera Pharmaceuticals, Inc.; reports travel grants from AstraZeneca, Merck, Pfizer, and DEMO; holds an advisory role with Amgen and LEO Pharma; and has received speaker fees from Roche, Pfizer, AstraZeneca, and Amgen. SK has received consulting fees from AstraZeneca, MSD, Novartis, Roche, Seagen, Pharmaserve – Lilly, and Gilead; received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from AstraZeneca, Genesis Pharma, Gilead, GlaxoSmithKline, MSD, Novartis, Pfizer, Pharmaserve – Lilly, Roche, Seagen, and Teva; travel support from AstraZeneca, Genesis Pharma, Gilead, GlaxoSmithKline, MSD, Novartis, Pfizer, Pharmaserve – Lilly, Roche, Seagen, and Teva; and has participated in a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Gilead, Seagen, GlaxoSmithKline, Pharmaserve – Lilly, MSD, and Roche. DT has received consulting fees from Gilead, Novartis, Pfizer, AstraZeneca, and Innovis Pharma; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Pfizer, AstraZeneca, and Novartis; travel support from AstraZeneca, Roche, and MSD. KP has received consulting fees from MSD, AstraZeneca, Integris Pharma, and Lilly. AK has served on the Advisory Board for Pierre Fabre, AstraZeneca, Gilead, Pfizer, Genesis, MSD, BMS, and Integris; has also been an invited speaker for Sanofi, Gilead, AstraZeneca, and Sandoz; and has received travel grants from Rafarm, Lilly, Ipsen, Gilead, Pfizer, Genesis, and AstraZeneca. AKo has served on the Advisory Board for MSD, AstraZeneca, and Genesis Pharma; and reports travel support from MSD, Servier, AstraZeneca, Gilead, and Merck. IB has received grants or contracts from AstraZeneca for Other Clinical Studies Agreement, and from Gilead for Other Clinical Studies Agreement; and travel support from AstraZeneca. EB has received travel support from AstraZeneca. DM has received travel support from AstraZeneca. EAF has received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Integris and Gilead. ER has received consulting fees from AstraZeneca, Servier, and Novartis; travel support from Gilead, AstraZeneca, Pfizer, MSD, Genesis Pharma, Novartis, and Servier; has participated in a Data Safety Monitoring Board or Advisory Board for AstraZeneca, Servier, and Novartis. DB has received consulting fees from Gilead, Novartis, Pfizer, AstraZeneca, and Innovis Pharma; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Pfizer, AstraZeneca, and Novartis; travel support from AstraZeneca, Roche, and MSD. AC has received consulting fees from MSD, AstraZeneca, and Pfizer. AB has received consulting fees from BMS, Pfizer, and Sandoz; payment or honoraria for lectures, presentations, speaker bureaus, or educational events from AstraZeneca, Amgen, BMS, Ipsen, MSD, and Servier; and holds a leadership or fiduciary role on the board of HESMO. NT has received travel support from LEO, Roche, and Janssen; and holds a leadership or fiduciary role on the boards of HeSMO and MASCC. SS has received travel support from Lilly. NS has received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from AstraZeneca, BMS, and Roche; and travel support from Amgen, Roche, Sandoz, and Sanofi. FZ has received consulting fees, honoraria for lectures, and has served in an advisory role for AstraZeneca, Daiichi, Eli Lilly, Merck, Novartis, MSD, Pfizer, Genesis Pharma, and Roche; received payment for expert testimony and participated on advisory boards for the same companies. AP has received consultation fees and honoraria from Amgen, Merck Serono, Roche, BMS, AstraZeneca, and MSD; and research funding from BMS, Kura Oncology, DEMO, and Roche. GF serves on the advisory board for Pfizer and Novartis; received honoraria from AstraZeneca and Novartis; and holds stock ownership in GENPREX, Daiichi Sankyo, RFL Holdings, and FORMYCON. All other authors have declared no conflicts of interest.
Supplementary data
References
- 1.Peters S., Loi S., Andre F., et al. Antibody-drug conjugates in lung and breast cancer: current evidence and future directions-a position statement from the ETOP IBCSG Partners Foundation. Ann Oncol. 2024;35(7):607–629. doi: 10.1016/j.annonc.2024.04.002. [DOI] [PubMed] [Google Scholar]
- 2.Modi S., Saura C., Yamashita T., et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610–621. doi: 10.1056/NEJMoa1914510. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Modi S., Jacot W., Yamashita T., et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9–20. doi: 10.1056/NEJMoa2203690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Bardia A., Hurvitz S.A., Tolaney S.M., et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529–1541. doi: 10.1056/NEJMoa2028485. [DOI] [PubMed] [Google Scholar]
- 5.Rugo H.S., Bardia A., Marme F., et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423–1433. doi: 10.1016/S0140-6736(23)01245-X. [DOI] [PubMed] [Google Scholar]
- 6.Curigliano G., Hu X., Dent R.A., et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy (TPC) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer (mBC) with prior endocrine therapy (ET): primary results from DESTINY-Breast06 (DB-06) J Clin Oncol. 2024;42(17) doi: 10.1200/JCO.2024.42.17_suppl.LBA1000. [DOI] [Google Scholar]
- 7.Shastry M., Gupta A., Chandarlapaty S., Young M., Powles T., Hamilton E. Rise of antibody-drug conjugates: the present and future. Am Soc Clin Oncol Educ Book. 2023;43 doi: 10.1200/EDBK_390094. [DOI] [PubMed] [Google Scholar]
- 8.Chen M., Huang R., Chen R., et al. Optimal sequential strategies for antibody-drug conjugate in metastatic breast cancer: evaluating efficacy and cross-resistance. Oncologist. 2024;29(8):e957–e966. doi: 10.1093/oncolo/oyae055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Loganzo F., Sung M., Gerber H.P. Mechanisms of resistance to antibody-drug conjugates. Mol Cancer Ther. 2016;15(12):2825–2834. doi: 10.1158/1535-7163.MCT-16-0408. [DOI] [PubMed] [Google Scholar]
- 10.Mair M.J., Bartsch R., Le Rhun E., et al. Understanding the activity of antibody-drug conjugates in primary and secondary brain tumours. Nat Rev Clin Oncol. 2023;20(6):372–389. doi: 10.1038/s41571-023-00756-z. [DOI] [PubMed] [Google Scholar]
- 11.D'Arienzo A., Verrazzo A., Pagliuca M., et al. Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations. EClinicalMedicine. 2023;62 doi: 10.1016/j.eclinm.2023.102113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Botticelli A., Caputo R., Scagnoli S., et al. Real-world outcomes of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer: the DE-REAL study. Oncologist. 2024;29(4):303–310. doi: 10.1093/oncolo/oyad308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Matsumoto T., Yamamura S., Ikoma T., et al. Real-world data of trastuzumab deruxtecan for advanced gastric cancer: a multi-institutional retrospective study. J Clin Med. 2022;11(8):2247. doi: 10.3390/jcm11082247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Cheng A.K., Frank S., Iyer P., et al. Trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK: real-world data. ESMO Open. 2023;8(1 Suppl 4) [Google Scholar]
- 15.Hanna D., Merrick S., Ghose A., et al. Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom. Br J Cancer. 2024;130(12):1916–1920. doi: 10.1038/s41416-024-02685-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Huppert L., Mahtani R., Fisch S., et al. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC): updated data and subgroup analyses by age, sites of disease, and use of intervening therapies. J Clin Oncol. 2024;42(16_suppl):1083. doi: 10.1200/JCO.2024.42.16_suppl.1083. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Poumeaud F., Morisseau M., Cabel L., et al. Abstract PS08-02: Efficacy of sacituzumab-govitecan (SG) post trastuzumab-deruxtecan (T-DXd) and vice versa for HER2low advanced or metastatic breast cancer (MBC): a French multicentre retrospective study. Cancer Res. 2024;84(9_Supplement) doi: 10.1158/1538-7445.SABCS23-PS08-02. [DOI] [Google Scholar]
- 18.Castelo-Branco L., Pellat A., Martins-Branco D., et al. ESMO Guidance for Reporting Oncology real-World evidence (GROW) Ann Oncol. 2023;34(12):1097–1112. doi: 10.1016/j.annonc.2023.10.001. [DOI] [PubMed] [Google Scholar]
- 19.Al Meslamani A.Z. Underreporting of adverse drug events: a look into the extent, causes, and potential solutions. Expert Opin Drug Saf. 2023;22(5):351–354. doi: 10.1080/14740338.2023.2224558. [DOI] [PubMed] [Google Scholar]
- 20.Cortes J., Kim S.B., Chung W.P., et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143–1154. doi: 10.1056/NEJMoa2115022. [DOI] [PubMed] [Google Scholar]
- 21.Baylon-Valdez V., Gonzalez Gonzalez L.F., Zamudio Lozoya E.J., et al. Risk assessment for systemic recurrence in HER2-low breast cancer: evaluating hormone receptors and immunohistochemical profiles. Ann Oncol. 2024;9(suppl_4):1–12. doi: 10.1016/esmoop/esmoop103324. [DOI] [Google Scholar]
- 22.Saura C., Modi S., Krop I., et al. Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01) Ann Oncol. 2024;35(3):302–307. doi: 10.1016/j.annonc.2023.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Andre F., Hee Park Y., Kim S.B., et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;401(10390):1773–1785. doi: 10.1016/S0140-6736(23)00725-0. [DOI] [PubMed] [Google Scholar]
- 24.Hurvitz S.A., Hegg R., Chung W.P., et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401(10371):105–117. doi: 10.1016/S0140-6736(22)02420-5. [DOI] [PubMed] [Google Scholar]
- 25.O’Shaughnessy J., Brufsky A., Rugo H.S., et al. Analysis of patients without and with an initial triple-negative breast cancer diagnosis in the phase 3 randomized ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer. Breast Cancer Res Treat. 2022;195(2):127–139. doi: 10.1007/s10549-022-06602-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Rugo H.S., Bardia A., Marmé F., et al. Sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2022;40(29):3365–3376. doi: 10.1200/JCO.22.01002. [DOI] [PubMed] [Google Scholar]
- 27.Schäffler H., Jakob D., Huesmann S., et al. Novel antibody-drug-conjugates in routine clinical practice for the treatment of metastatic breast cancer: adherence, efficacy and tolerability - real-world data from German breast centers. Geburtshilfe Frauenheilkd. 2024;84(9):855–865. doi: 10.1055/a-2375-5194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Niikura N., Yamanaka T., Nomura H., et al. Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM) NPJ Breast Cancer. 2023;9(1):82. doi: 10.1038/s41523-023-00584-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Raghavendra A., Wang Z., Bassett R., Tripathy D. Abstract PS08-01: Antibody-drug conjugates (ADCs) in breast cancer: real world analysis of outcomes. Cancer Res. 2024;84:PS08-01. [Google Scholar]
- 30.Reinisch M., Bruzas S., Spoenlein J., et al. Safety and effectiveness of sacituzumab govitecan in patients with metastatic triple-negative breast cancer in real-world settings: first observations from an interdisciplinary breast cancer centre in Germany. Ther Adv Med Oncol. 2023;15 doi: 10.1177/17588359231200454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Mai N., Klar M., Ferraro E., et al. Real world outcomes of sequential ADC therapy in metastatic breast cancer: patients treated with sacituzumab govitecan and trastuzumab deruxtecan. J Clin Oncol. 2024;42:1085. [Google Scholar]
- 32.Poumeaud F., Morisseau M., Cabel L., et al. Efficacy of administration sequence: sacituzumab govitecan and trastuzumab deruxtecan in HER2-low metastatic breast cancer. Br J Cancer. 2024;131(4):702–708. doi: 10.1038/s41416-024-02766-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Sanglier T., Fabi A., Flores C., et al. T-DM1 after pertuzumab plus trastuzumab: treatment sequence-induced selection bias in HER2-positive metastatic breast cancer. Cancers. 2022;14:2468. doi: 10.3390/cancers14102468. [DOI] [PMC free article] [PubMed] [Google Scholar]
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