Managing the Risk of Lung Toxicity with Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective

Round 1

Reviewer 1 Report

Dear Authors,

 

I have thoroughly reviewed your work on multidisciplinary clinical guidance for trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis. Your comprehensive analysis sheds light on the importance of proactive monitoring, diagnosis, and management of DI-ILD, particularly in the context of novel anticancer agents.

 

Your paper effectively highlights the significant clinical challenge posed by DI-ILD, which has been associated with various chemotherapeutic and targeted antineoplastic therapies. The compilation of data regarding the incidence and mortality rates of DI-ILD in different drug classes provides valuable insights into the potential risks and consequences associated with these treatments

 

In light of the intriguing findings presented in your work, I would like to pose a few questions:

1,Regarding the pathogenesis of DI-ILD, which is currently poorly understood, do you have plans to further investigate the cytotoxic and immune-related mechanisms involved in DI-ILD? Exploring these mechanisms could provide a better understanding of the underlying processes and potentially aid in the development of preventive strategies.

2,The identification and monitoring of patients at risk of DI-ILD are crucial for timely intervention. Are there any known methods or strategies that have demonstrated efficacy in identifying and monitoring DI-ILD in clinical practice? Additionally, do these strategies have universality and apply to ILD induced by multiple drugs?

 

3,Early diagnosis and management of DI-ILD are essential for improving patient outcomes. You mentioned various strategies for the proactive management of DI-ILD, but has there been further research or clinical evaluation to assess the effectiveness and feasibility of these strategies? Have any studies explored the impact of these strategies on reducing the incidence of DI-ILD and enhancing patient safety?

 

I believe addressing these questions would further enrich the knowledge surrounding DI-ILD and contribute to improving patient care and safety. I appreciate the insights provided in your work and encourage the publication of a unified article that encompasses your findings and addresses the raised questions. Please note that keeping the review concise and focused will enhance its impact.

 

Thank you for your valuable contributions to the field of DI-ILD research. I look forward to seeing your continued efforts in this area.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate used for the treatment of certain HER2-positive breast cancer and other HER2-positive solid tumors. Like many cancer treatments, T-DXd can have side effects, and one of the potential adverse reactions associated with its use is interstitial lung disease (ILD). In the case of T-DXd-related ILD, the drug may cause direct toxicity to the lung tissue or trigger an immune-mediated reaction, leading to inflammation and damage with high risk of evolution to serious illness (grade 3-4 72 ILD). The diagnosis of DI-ILD is challenging and requires a thorough evaluation by a healthcare professional.

 

In this review, the authors conducted a comprehensive analysis of the current multidisciplinary clinical recommendations regarding T-DXd-related ILD in the United States and Europe. They aimed to adapt these guidelines to suit the specific context of the Canadian healthcare system. The ultimate objective was to create a practical and effective strategy that maximizes the therapeutic advantages of T-DXd for patients in Canada. This review holds promise for the field of oncology, offering potential benefits and valuable insights.

 

Following are suggestions to strengthen the impact of the manuscript:

 

Minor:

1.     Table 1, title needs to be changed since no data of “incidence of interstitial lung disease (ILD)/pneumonitis” is provided in this table.

2.     Line 109, “In oncology” is not accurate. This section is talking about a wide range of factors that has been associated with DI-ILD, including but not limited to oncology drugs.

3.     I think the Sections can be reorganized for a better structure. For example, Section 2 can be combined with Section 5 and Table 1 and Table 4 can be merged into one table.

4.     Figure 2, can the authors summarize how the guidelines were tailored for Canadian health care environment? Which part is simplified, and which part is essential?

Author Response

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Author Response File: Author Response.docx

Reviewer 3 Report

The authors report on Trastuzumab deruxtecan (T-DXd), its safety and efficacy from a Canadian perspective. Trastuzumab is an antibody-drug conjugate targeting human 25 epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer 26 setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an ad- 27 verse event of special interest associated with T-DXd with potentially fatal consequences if left un- 28 treated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd–re- 29 lated ILD can be monitored and treated effectively with the possibility of treatment continuation. 30 Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are therefore needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes. Several guidance documents have been developed regarding strategies for the early identification and management of T-DXd–related ILD, although none have been within the context of the Canadian healthcare environment. A Canadian multidisciplinary steering committee was therefore convened to evaluate existing recommendations and adapt them for application in Canada. A multidisciplinary approach involving collaboration among medical oncologists, radiologists, respirologists, and allied health care professionals is needed to ensure the proactive identification and management of T-DXd–related ILD and DI-ILD associated with other agents with similar toxicity profiles.

The paper is well-written and it's very clear that a multidisciplinary team is needed to diligently and proactively assess toxicity and whether to continue this drug in a clinical setting.

I would recommend the publication of this paper. 

Author Response

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Author Response File: Author Response.docx

Reviewer 4 Report

The authors of the manuscript have proposed strategies for identifying and managing drug-induced interstitial lung disease (DI-ILD) caused by trastuzumab deruxtecan (T-Dxd) in cancer patients. They conducted a comprehensive study of DI-ILD cases in T-Dxd clinical trials, as well as in other treatments involving molecular targeting and immune checkpoint inhibitors. Moreover, the authors examined the different symptoms associated with varying levels of DI-ILD severity and offered diagnostic and treatment approaches specifically designed for each stage of the condition. The manuscript is well-written and contains all the necessary information for the identification and management of DI-ILD. However, I have some suggestions to further improve the manuscript:

1.       The authors should have included information about the adverse effects of unbound, if available in previous studies, to better understand the toxicological profile of characteristics of trastuzumab.

2.       In section 6.1.1 (Medical history), it is important for the authors to mention that the prior medical history of patients is essential, regardless of the patient's age.

3.       It would be helpful to annotate the figures representing CT images so that readers having non-clinical background can easily differentiate between normal and abnormal lung conditions.

4.       There are a few sentences, such as line numbers 62 and 304, that do not seem to convey meaningful information and may need to be revised.

5.       Instead of using "AEs" (line number 251), the authors should write "adverse events" for clarity.

6. As an optional suggestion, the authors could recommend clinicians to create a repository or database to record DI-ILD events for future research purposes.

There are a few sentences, such as line numbers 62 and 304, that do not seem to convey meaningful information and may need to be revised.

Author Response

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Author Response File: Author Response.docx