Prof. Luo Ting: Focus on the safety management of T-DXd in the treatment of breast cancer and escort patients
Editor's note: Trastuzumab (T-DXd), as a novel antibody-drug conjugate (ADC), has greatly broadened the boundaries of anti-HER2 therapy and significantly extended the survival expectation of patients with advanced disease. With the improvement of the accessibility and scope of clinical application of T-DXd, the management of adverse reactions is constantly updated and improved, in order to provide patients with more stable treatment protection. Therefore, Professor Luo Ting from West China Hospital of Sichuan University reviewed the long-term follow-up results of T-DXd, tracked the cutting-edge progress of patients who experienced interstitial pneumonia (ILD) and re-applied T-DXd, and took stock of the adverse reactions and countermeasures of T-DXd, so as to escort patients through the treatment stage safely.
Evidence-based
T-DXd has a good safety profile
T-DXd is an ADC covalently linked to trastuzumab and topoisomerase I inhibitors by a cleavable tetrapeptide linker. Launched in the U.S. in December 2019 and in China in February 2023, it has been approved for second-line and above indications in mainland China for HER2-positive advanced breast cancer and HER2-low expression breast cancer, rewriting the pattern of anti-HER2 therapy in mainland China.
With the improvement of the accessibility of T-DXd, a large number of clinical studies and practical experience have confirmed its good safety profile (Table 1). The most common adverse effects of T-DXd are gastrointestinal and hematologic toxicity, and most are grade 1 to 2 [1].
Table 1. Incidence of common adverse events in T-DXd [2,3,4,5]
The long-term security of T-DXd applications is also positive. The median follow-up of the DESTINY-Breast03 study reached 43 months, with a median duration of 18.2 months for T-DXd and 6.9 months for trastuzumab (T-DM1). After adjusting for the time factor, the annual exposure-adjusted incidence (EAIRs) of treatment-related adverse events (TEAEs) for T-DXd and T-DM1 ranged from 0.53 versus 1.10, and the EAIRs for grade ≥3 TEAEs were 0.15 versus 0.26, which is a better safety profile than conventional ADCs (Table 2) [6].
表2. DESTINY-Breast03研究长期随访下TEAE的EAIRs
With the extension of the follow-up time for T-DXd in the DESTINY-Breast03 study from 16.2 months to 43.0 months, there was no significant improvement in treatment-related adverse reactions, treatment-related serious adverse reactions, treatment-related interruption or reduction of T-DXd, and no treatment-related deaths (Table 3), further confirming the safety of long-term use of T-DXd [6,7].
Table 3. DESTINY-Breast03 investigated the safety performance of T-DXd at different follow-up times
In addition, patients with better response to T-DXd after treatment have a better safety profile. According to a recent summary analysis of the best response in the DESTINY-Breast01, 02, and 03 studies released at the American Society of Clinical Oncology (ASCO) annual meeting this year, the median duration of T-DXd in the treatment-experienced complete response (CR), partial response (PR), and stable or progressive (SD/PD) population was 27.4 months versus 14.0 months versus 6.2 months, respectively, while the incidence of drug-related serious TEAEs was 8.0% vs. 8.0%. 12.4 versus 15.5 percent, and the incidence of ILD in CR patients also showed a trend of lower numerical values (Figure 1). Although patients with CR were treated with T-DXd for a longer period of time, there was no cumulative increase in toxicity, the incidence of serious TEAEs, including ILD, was lower, and the patients were significantly better tolerated, resulting in longer PFS and OS benefits [8].
Figure 1. Safety performance of DESTINY-Breast01, 02, 03 in the pooled analysis of optimal response
In addition, T-DXd has also demonstrated a manageable safety profile in Asian populations in the treatment of patients with low HER2 expression. Data from the DESTINY-Breast04 Asian population showed that the most common grade ≥3 serious adverse events in the T-DXd group were neutropenia (16.3%) and anemia (12.9%), both of which were lower than those in the physician-selected chemotherapy group (neutropenia 60.3% and anemia 33.3%). The overall safety profile was consistent with that of the DESTINY-Breast04 study in the whole population and in the HER2-positive population [9].
Confident
Management of adverse effects of T-DXd
For the common adverse reactions of T-DXd, there are relatively mature clinical countermeasures, and a Chinese expert consensus on the management of adverse reactions has been formed (Table 4) [10,11].
Table 4. Management of common adverse effects
ILD is a clinical concern for T-DXd-related adverse reactions, and expert consensus suggests that the monitoring of ILD should be strengthened when using T-DXd, and relevant suspicious symptoms should be reported and dealt with in a timely manner (Fig. 2). Historically, the incidence of ILD in T-DXd has been approximately 10 to 15 percent, of which approximately 80 percent are grade 1 to 2, and most recover with dose modification or symptomatic treatment [12].
Long-term follow-up of 43 months in the DESTINY-Breast03 study showed a better safety profile of T-DXd in ILD/pneumonia, which occurred within one year of treatment, and only two cases were grade 3 and no grade 4 to 5 events were observed [6]. In the DESTINY-Breast04 study, the incidence of ILD in HER2-low populations was 14.3 percent, with all but one case being grade 3, and no grade 4 to 5 events [9]. In addition, there has been a number of evidence-based studies that T-DXd-related grade 1 ILD can be restarted after recovery from treatment. This year, the European Society for Medical Oncology Annual Meeting on Breast Cancer (ESMO BC) presented a pooled analysis of the re-initiation of T-DXd therapy after patients developed grade 1 ILD. The study summarized 193 patients with grade 1 ILD in nine studies, of which 45 (23.3%) recovered and then received T-DXd therapy, 31 (68.9%) did not reduce the T-DXd dose, the median duration of retreatment was 85 days, and only 15 (33.3%) redeveloped ILD, all grade 1 to 2. This brings hope for prolonging the duration of treatment for T-DXd and further seeking patient benefits [13].
Figure 2. T-DXd treatment-related ILD/pneumonia management pathway
Looking to the future
Protecting your patients
With the popularization of the clinical application of T-DXd in HER2-positive and HER2-low breast cancer, the treatment benefits of breast cancer patients in mainland China are also rising. In order to ensure that patients can maximize the benefits of T-DXd treatment, it is important to standardize and effectively manage the adverse reactions of T-DXd and reduce the discontinuation or dose reduction caused by adverse reactions. The occurrence of common adverse reactions of T-DXd is not higher than that of traditional ADC drugs, and most of them are mild, and the clinical management experience is relatively mature, and corresponding guidelines and consensus have been formed, which brings reference for the clinical application of T-DXd.
For advanced breast cancer, prolonging PFS and OS as much as possible is the main therapeutic goal. Therefore, the long-term application of strong anti-tumor strategies should be ensured in order to achieve more benefits for patients. T-DXd has demonstrated impressive survival benefits in the subsequent line of treatment, and the newly published data of up to 43 months of follow-up also demonstrate the long-term and reliable safety profile of T-DXd. With the prolongation of continuous treatment of T-DXd, there was no significant increase in the incidence of treatment-related adverse events, dose reduction and discontinuation. In addition, pooled analyses of multiple studies of T-DXd also showed a better safety profile in the CR population. In terms of ILD, the incidence of ILD in the T-DXd group did not increase significantly and most of them were mild, and a relatively mature management strategy has been formed for the management of ILD, and most patients can recover after symptomatic treatment. In addition, the existing consensus and evidence-based evidence confirm that T-DXd therapy can be restarted after the recovery of grade 1 ILD, so as to strive for more therapeutic benefits of T-DXd for patients.
Therefore, on the road to the management of adverse reactions of T-DXd, a full understanding of the patient's condition, early monitoring, comprehensive prevention, and scientific intervention are the core elements. It is hoped that the majority of colleagues will grasp the standardized countermeasures for T-DXd adverse reactions, actively respond to them, and make sure that they can take care of patients comprehensively.
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[1] Instructions for trastuzumab, revised July 11, 2023. Available at : https://www.daiichisankyo.com.cn/Portals/0/254_0_%E6%B3%A8%E5%B0%84%E7%94%A8%E5%BE%B7%E6%9B%B2%E5%A6%A5%E7%8F%A0%E5%8D%95%E6%8A%97-%E8%AF%B4%E6%98%8E%E4%B9%A6.pdf
[2] Hurvitz SA , Hegg R , Chung WP ,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[J]. Lancet, 2023,401(10371):105-117. DOI: 10.1016/S0140-6736(22)02420-5 .
[3] Im SA , Xu BH , Kim SB ,et al. PS2-1 Trastuzumab deruxtecan vs T-DM1 in HER2+ mBC in Asian subgroup: results of the randomized phase 3 study DESTINY-Breast03[J]. Ann Oncol, 2022,33:S464-S465. DOI: 10.1016/j.annonc.2022.05.064 .
[4] Modi S , Jacot W , Yamashita T ,et al. Trastuzumab deruxtecan in previously treated HER-2-low advanced breast cancer[J]. N Engl J Med, 2022,387(1):9-20. DOI: 10.1056/NEJMoa2203690 .
[5] Tsurutani J , Modi T , Hyuk Sohn J ,et al. T-DXd vs TPC in patients with HER-2-low unresectable and/or metastatic BC in Asian subgroup: results of DESTINY-Breast04[EB/OL]. [ 2024-01-19]. https://datasourcebydaiichisankyo.com/documents/14090001/14096138/JSMO+2023_T-DXd_Tsurutani_Oral_FINAL.pdf/4e70f0a6-0af6-5b28-62d8-ea7b19244c52
[6] Cortés J, Hurvitz SA, Im SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial. Nat Med. Published online June 2, 2024. doi:10.1038/s41591-024-03021-7
[7] Cortés J, Kim SB, Chung WP, et al. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022; 386(12):1143-1154. doi:10.1056/NEJMoa2115022
[8] Cristina Saura, Javier Cortés, et al. Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03. J Clin Oncol 42, 2024 (suppl 16; abstr 1023). 2024 ASCO Ab s# 1023.
[9] Yamashita T, Sohn JH, Tokunaga E, et al. Trastuzumab deruxtecan versus treatment of physician's choice in previously treated Asian patients with HER2-low unresectable/metastatic breast cancer: subgroup analysis of the DESTINY-Breast04 study. Breast Cancer. Published online June 17, 2024. doi:10.1007/s12282-024-01600-7
[10] Consensus Expert Group on Clinical Management Pathway and Adverse Reaction Management of Trastuzumab. Chinese Expert Consensus on Clinical Management Pathway and Adverse Reaction Management of Trastuzumab (2024 Edition)[J]. Chin J Oncology,2024,46(04):304-318. DOI:10.3760/cma.j.cn112152-20231122-00319
[11] Chinese Society of Clinical Oncology Guidelines Working Committee. Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Tumor-Associated Anemia (2024). People's Medical Publishing House. 2024.
[12] Rugo HS, Bianchini G, Cortes J, Henning JW, Untch M. Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. ESMO Open. 2022; 7(4):100553. doi:10.1016/j.esmoop.2022.100553
[13] Rugo HS, et al. Pooled Analysis of Trastuzumab Deruxtecan (T-DXd) Retreatment (RTx) After Recovery From Grade (Gr) 1 Interstitial Lung Disease/Pneumonitis (ILD). Annals of Oncology (2024) 9 (suppl_4): 1-12. 10.1016/esmoop/esmoop103324. 2024 ESMO BC 267MO.
Prof. Ting Luo
Deputy Director of the Breast Disease Center of West China Hospital, Sichuan University
Chief Physician, Doctor of Medicine, Master's Supervisor
Member of the Standing Committee of the Young Expert Committee of the Chinese Society of Clinical Oncology
Member of the Breast Cancer Committee of the Chinese Society of Clinical Oncology
Young expert of the Breast Cancer Committee of the Chinese Anti-Cancer Association
Youth member of the Breast Oncology Group of the Oncology Branch of the Chinese Medical Association
Secretary-General of the Breast Cancer Integrated Prevention and Screening Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Yangtze River Academic Belt Breast Alliance
Chairman of the Breast Tumor Committee of Sichuan Association for the Promotion of International Medical Exchange
Vice Chairman of the Breast Cancer Committee of Sichuan Anti-Cancer Association
Vice President of Breast Professional Branch of Sichuan Medical Doctor Association
Member of the Standing Committee of the Breast Disease Prevention and Control Branch of the Sichuan Preventive Medicine Association and Chairman of the Youth Committee
Vice Chairman of the Breast Tumor Committee of Sichuan Oncology Society
Outstanding Contribution Award in the field of breast cancer of the 3rd "People's Good Doctor Golden Camellia Program".