Trastuzumab deruxtecan in HER2-positive and low breast cancer: Real-world outcomes from the Indian perspective (TREAD-IN study)

INTRODUCTION

Breast cancer (BC) is the most prevalent cancer in women and the second leading cause of cancer-related deaths globally.^[1] Approximately 20% of breast cancer cases exhibit overexpression of the human epidermal growth factor Receptor 2 (HER2) protein and/or amplification of the HER2 gene. Notably, HER2-positive (HER2+) breast cancer is a particularly aggressive form of the disease, associated with a worse prognosis and higher rates of recurrence.^[2,3]

In recent years, the development of effective anti-HER2 therapies has significantly improved the prognosis for patients with HER2+ breast cancer, both in early and advanced stages. In the context of advanced disease, the CLEOPATRA trial showed that adding pertuzumab to trastuzumab and docetaxel in untreated HER2+ breast cancer patients led to consistent improvements in progression-free survival (PFS) and overall survival (OS).^[4,5] Based on these findings, the combination of pertuzumab, trastuzumab, and taxane-based chemotherapy has become the first-line treatment for advanced HER2+ breast cancer. For the past decade, trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC), has been the standard second-line treatment, having demonstrated improved PFS and OS compared to capecitabine plus lapatinib in patients with metastatic HER2+ breast cancer who had previously been treated with trastuzumab and a taxane.^[6]

Recently, the treatment landscape for patients with HER2+ metastatic breast cancer (MBC) has been transformed with the introduction of a new antibody-drug conjugate (ADC), Trastuzumab deruxtecan (T-DXd). This innovative therapy combines an anti-HER2 monoclonal antibody (MoAb) with a potent topoisomerase inhibitor, Trastuzumab deruxtecan, to target and deliver treatment directly to cancer cells.^[7]

In the phase II DESTINY-Breast01 (DB-01) trial, T-DXd showed remarkable efficacy in heavily pretreated HER2+ MBC patients, with a median PFS of 19.4 months and a median response duration of 20 months.^[8,9] Furthermore, the phase III DESTINY-Breast03 (DB-03) trial confirmed that T-DXd offers superior PFS and OS compared to T-DM1 as a second-line therapy for patients who have progressed after first-line taxane-trastuzumab-pertuzumab treatment.^[10,11] Based on the DB-03 trial results, T-DXd is now the standard second-line therapy for HER2+ MBC. In the DESTINY-Breast02 trial, T-DXd demonstrated a significant and clinically meaningful improvement in both PFS and OS when compared to the physician's choice of treatment for patients with HER2+ unresectable or metastatic breast cancer who had previously been treated with T-DM1.^[12] In the recent Destiny Breast 6 study, among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; p <0.001).^[13]

Despite these impressive clinical advancements and the growing role of T-DXd in treating HER2+ breast cancer, real-world data on its safety and efficacy in routine clinical practice are still lacking from India and the Southeast Asian region. There is an urgent need for real-world evidence to better understand how to manage this new treatment and its actual effectiveness in a broader, unselected patient population.

This analysis presents the results of a retrospective study, which assessed the safety, anti-tumour activity, and efficacy of T-DXd in a real-world cohort of patients with HER2+ metastatic breast cancer.

MATERIAL AND METHODS

RESULTS

Outcomes

All 24 patients had measurable disease; among these, the observed ORR was 66.7%. Of these patients, 1 (4.2%) achieved a complete response (CR), while 15 (62.5%) had a partial response (PR) during T-DXd therapy [Table 1]. Another 20.8% of patients (n = 5) reported a stable disease (SD), while primary resistance to T-DXd was detected in 12.5% of cases (n = 3) [Figure 1]. The DCR registered in our population was 87.5% (4.2% CR, 62.5% PR, and 20.8% SD). With a median follow-up of 6 months (range, 3 to 8), the median progression-free survival time was not reached. The estimated 1-year progression-free survival rate of the cohort was 72.7±12.5% [Figure 2]. The estimated 1-year progression-free survival for HER2-neu (1-2) and HER2-neu (3+) were 66.7±27.2% and 78.4±11.2%, respectively (using log-rank test, p = 0.939) [Figure 3]. The estimated 1-year progression-free survival for the 2^nd -3^rd line of treatment and 4^th+ line of treatment was 78.8±13.4% and 59.3±25.2%, respectively [Figure 4].

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Figure 1: Waterfall plot showing the changes in percentages of RECIST based on the line of treatment (2nd vs. 3rd vs. 4th+). RECIST: Response Evaluation Criteria in Solid Tumors

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Figure 2: The estimated progression-free survival curve obtained from the Kaplan-Meier method shows the survival of the cohort.

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Figure 3: Progression-free survival curve using Kaplan-Meier estimation for patients based on HER2-neu (1-2 vs. 3+). HER2: Human epidermal growth factor receptor 2

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Figure 4: Progression-free survival curve using Kaplan-Meier estimation for patients based on line of treatment (2nd vs. 3rd vs. 4th+).

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The 1-year PFS rates for patients with CNS metastases and those without were 70.3 ± 14.8% and 80.0 ± 17.9%, respectively [Figure 5]. The ORR was comparable between patients who experienced any-grade toxicity and those who did not (67% vs. 68%, p = 0.74). Likewise, there was no significant difference in ORR between patients with low-grade (Grade 1-2) toxicities and those with high-grade (Grade 3-4) toxicities (68% vs. 66%, p = 0.63). Furthermore, no notable difference in ORR was found between patients receiving T-DXd as second or third-line therapy and those receiving it in later lines (72% vs. 67%, p = 0.88).

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Figure 5: Progression-free survival curve using Kaplan-Meier estimation based on Mets (CNS vs. Non-CNS). CNS: Central nervous system

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Table 2 summarises the incidence of treatment-related AEs reported in the study. Of the 24 patients treated with T-DXd, 79% experienced at least one adverse event (n = 19). Overall, 62% of patients (n = 15) experienced low to moderate grade toxicities (Grade 1/2). Nausea was the most common AE, occurring in 45.8% of patients (n = 11). Fatigue was reported in 33% (n = 8), while neutropenia occurred in 25% of cases (n = 6, any grade). All patients reporting fatigue/asthenia experienced Grade 1/2 toxicity. Severe AEs (SAEs) were observed in 16.6% of patients receiving T-DXd (n = 4/24). Severe nausea was reported in 8.33% of cases (n = 2), and 8.33% of patients with neutropenia experienced Grade 3/4 toxicity.

Table 2: Adverse events experienced by all the patients enrolled in the study

Adverse event	Incidence, (%) any grade	Grade 1–2 (%)	Grade 3–4 (%)
Patients with AES	79% (n=19)	62% (n=15)	16.6% (n=4)
Nausea	45.8% (n=11)	37.5% (n=9)	8.33% (n=2)
Vomiting	20.8% (n=5)	20.8% (n=5)	-
Fatigue	33% (n=8)	33% (n=8)	-
Neutropenia	25% (n=6)	16.7% (n=4)	8.33% (n=2)
Thrombocytopenia	8.33% (n=2)	8.33% (n=2)	-
ILD	12.5% (n=3)	12.5% (n=3)	None

AES: Adverse events, ILD: Interstitial lung disease.

Interstitial lung disease (ILD) was documented in 3 out of 24 patients (12.5%). Among these, 1 patient had Grade 1 ILD, while 2 patients experienced Grade 2 ILD, which developed after 10 cycles of T-DXd. AEs led to treatment discontinuation in 8.3% (n = 2) of patients and necessitated a dose reduction in another 8.3% (n = 2/24). Notably, no drug-related fatalities were reported in our analysis [Table 2].

DISCUSSION

T-DXd has demonstrated unparalleled efficacy in metastatic HER2-positive and low breast cancer patients who have previously been exposed to standard anti-HER2 therapies.^[8,9] Despite T-DXd being integrated into clinical practice based on the excellent results from prospective clinical trials, its safety, feasibility, and antitumour efficacy in a real-world population of patients with HER2-positive MBC remain largely unknown. This study aims to address this knowledge gap by gathering information on the real-world safety and efficacy of T-DXd in patients with HER2-positive and low MBC who do not meet the stringent criteria typically employed in the DESTINY-Breast clinical trials.^[10-12]

We reported the results of a single-centre, retrospective study that investigated the safety and efficacy of T-DXd in a real-world population of patients with HER2-positive and low MBC. Our findings indicate that T-DXd is both safe and effective in this patient cohort, demonstrating robust activity across various lines of therapy and regardless of HR status. These results further validate the clinical relevance of T-DXd as a novel option for patients with HER2-positive/low MBC, reinforcing its efficacy in a real-world setting [Table 1 and Figure 2]. Notably, the safety and efficacy outcomes observed in our study align closely with those reported in clinical trials. For example, the randomised phase III DB-02 trial reported a median PFS of 17.8 months and an ORR of 70% in heavily pretreated patients receiving T-DXd. Additionally, the DB-03 trial demonstrated a significant improvement in PFS with T-DXd compared to TDM-1 for patients pretreated with trastuzumab and taxane (28.8 months versus 6.9 months, 95% CI: 22.4-37.9).

Patients enrolled in the DB-02 trial had received a median of 2 lines of systemic therapy prior to receiving Trastuzumab Deruxtecan (T-DXd), whereas in the DB-03 trial, 65% of patients received T-DXd as first or second-line treatment.^[10-12] In contrast, our study included patients with a median of 6 prior lines of therapy, and the median progression-free survival (PFS) time was not reached. The estimated 1-year PFS rate for our cohort was 72.7 ± 12.5%, which is lower than that reported in the DB-01 and DB-02 trials, where T-DXd was administered after fewer lines of systemic therapy.

Notably, only a small proportion of our population (6 patients, approximately 24%) received T-DXd in a second-line setting, allowing for a limited comparison with the DB-03 trial. When comparing survival outcomes based on treatment lines (second/third vs. fourth or higher), the estimated 1-year PFS rates were 78.8 ± 13.4% for second/third-line treatment and 59.3 ± 25.2% for fourth-line or later treatment [Figure 3]. These results, combined with data from DB-03, suggest that T-DXd remains effective regardless of the treatment line, indicating that the sensitivity of HER2-positive MBC to T-DXd may not be significantly affected by the number of prior anti-HER2 therapies. This could reflect either intrinsic tumour sensitivity or resistance to T-DXd.

Furthermore, the estimated 1-year PFS rates for HER2-neu (1-2) and HER2-neu (3+) were 66.7 ± 27.2% and 78.4 ± 11.2%, respectively (using the log-rank test, p = 0.939). In comparison, the 1-year PFS in the DB-06 study was around 60%.^[15] These findings suggest that the efficacy of T-DXd may be influenced by the ability of tumour cells to bind to the drug, which is likely determined by HER2 expression levels on tumour cell membranes, as well as the intrinsic sensitivity of the tumour cells to the T-DXd payload.

However, differences in the study population that could have influenced the results should be critically considered. First, patients enrolled in our study had a higher median number of previous treatment regimens when compared to patients included in a real-world cohort and patients enrolled in DB-02 were less heavily pretreated. In addition, patients enrolled in our study were younger than the patient population in a real-world study, and those enrolled in both clinical trials (66y vs 55y in DB-01 and 54y in DB-02, respectively) [Table 1].^[8,9,12]

Overall, any-grade treatment-related AEs were reported in 19 patients (79%). Nausea emerged as the most common AE, affecting 45.3% of patients, followed by asthenia at 25%. Additionally, 4 out of 24 patients (16%) experienced grade 3 or 4 AEs, and 7 patients (23%) required secondary dose adjustments. These findings align with those from the REAL study, which reported nausea in 37% of cases and asthenia in 18% as common toxicities. Another single-centre experience indicated a 13% incidence of severe AEs.^[16]

Our cohort demonstrated lower non-haematologic toxicities, such as diarrhoea, nausea, and fatigue, with minimal rates of grade ≥3 events, as detailed in Table 2. Notably, we observed a lower incidence of nausea and vomiting compared to what was reported in the registration trials. This discrepancy may be attributed to improved antiemetic prophylaxis practices adopted across treatment centres, likely in response to the high rates of nausea and vomiting noted in the DESTINY-Breast trials.^[8-12,17,18]

In terms of interstitial lung disease (ILD), three patients developed any-grade ILD; one case was classified as grade 1 and the other two as grade 2, which necessitated treatment discontinuation. Details regarding ILD and other toxicities are summarised in Table 2. Both patients with grade 2 ILD developed the condition after 10 cycles of T-DXd and were successfully managed with steroids, with symptoms resolving within one week. The patient with grade 1 ILD continued treatment with T-DXd, while the patients with grade 2 ILD did not undergo rechallenge with the therapy.

In our real-world study, we observed a lower rate of all-grade and severe haematological toxicities compared to those reported in controlled randomised trials. This could be attributed to the younger median age of our patient population, which may have contributed to lower rates of bone marrow toxicity, such as anaemia and decreased neutrophil counts, compared to the rates observed in published clinical trials.^[8-12]

Several factors may explain this finding: (1) Retrospective analyses often suffer from under-reporting of the incidence and grading of adverse events (AEs), reflecting the limitations inherent in the retrospective collection of safety data.^[18] (2) The growing experience in the prevention and management of T-DXd-related toxicities in clinical practice may have led to a reduction in the incidence of typical severe AEs associated with T-DXd, such as nausea and interstitial lung disease (ILD). (3) In real-world analyses, dose reductions tend to occur more frequently, often due to less stringent treatment protocols, which may subsequently result in lower incidences of both haematological and non-haematological toxicities. Additionally, subjective assessments of toxicity in real-world cohorts may be affected by underreporting in medical records, as highlighted in previous literature.^[19-23] This underreporting further complicates the evaluation of toxicity profiles in real-world settings, emphasising the need for careful interpretation of our findings in the context of existing literature.^[24]

TAKE HOME MESSAGE

T-DXd demonstrated comparable efficacy while maintaining a reasonable safety profile in our real-world study. This suggests that all patients, including those who do not meet the strict inclusion criteria outlined in the DESTINY trials, are likely to benefit from this highly effective treatment.