‘Targeting’ Improved Outcomes with Antibody-Drug Conjugates in Non-Small Cell Lung Cancer—An Updated Review
Round 1
Reviewer 1 Report
This review manuscript by Saurav et al. addresses the timely topics of the ADC in cancer immunotherapy with focus on NSCLC.
The abstract promises to discuss the recent evidence including targets, efficacy, and safety of newer ADC candidates in NSCLC, and specific toxicities, novel biomarkers, overcoming resistance mechanisms, challenges, and the way forward, as these new ADCs and combinations find way into the clinical practice. The manuscript touches on many of these vast aspects but fails to convey a comprehensive picture of the field, specifically “specific toxicities, novel biomarkers, overcoming resistance mechanisms”. The manuscript should be either significantly expanded for each of the aspects or limit itself to a more specific focus.
Specific Points.
1) It is unclear who is the target audience. The authors do not provide background information on NSCLC. Readers with no background NSCLC will not get sufficient usefulness of the ADCs without the biological context. Additional section(s) should be added to provide background NSCLC, their types, biomarkers, and challenges in current stander of care.
2) Authors need significantly to expand the novel biomarkers discovery, antibody development against novel antigens, overcoming resistance mechanisms sections with extensive primary references.
3) The authors may want to consider organizing the tables and the subsequent description of individual ADCs by type of payloads.
4) Line 47: A schematic diagram depicting each of the components for this section would be useful.
5) Line 87, 90: Table 1, 2, and 3 are redundant. A single consolidated table will be more useful.
6) Line 38: Define all the acronyms at their first use in the text.
Author Response
Comment 1: This review manuscript by Saurav et al. addresses the timely topics of the ADC in cancer immunotherapy with focus on NSCLC. The abstract promises to discuss the recent evidence including targets, efficacy, and safety of newer ADC candidates in NSCLC, and specific toxicities, novel biomarkers, overcoming resistance mechanisms, challenges, and the way forward, as these new ADCs and combinations find way into the clinical practice. The manuscript touches on many of these vast aspects but fails to convey a comprehensive picture of the field, specifically “specific toxicities, novel biomarkers, overcoming resistance mechanisms”. The manuscript should be either significantly expanded for each of the aspects or limit itself to a more specific focus.
Reply 1: We thank you for taking the time to review our manuscript and the feedback. We appreciate your suggestions to improve the manuscript. Since this manuscript is a part of special edition on ‘ADCs in Cancer’, we kept the description of some topics brief, where data is relatively immature in the field of lung cancer. We have expanded on toxicities by including a paragraph on strategy to decrease the toxicities. We have also elaborated more on biomarkers and added examples to explain the resistance mechanisms.
Comment 2: It is unclear who is the target audience. The authors do not provide background information on NSCLC. Readers with no background NSCLC will not get sufficient usefulness of the ADCs without the biological context. Additional section(s) should be added to provide background NSCLC, their types, biomarkers, and challenges in current stander of care.
Reply 2: We thank the reviewer for the valuable comment. The primary audience is oncologists and the researchers in the field of oncology. The focus is primarily on evidence, safety, and efficacy of ADCs in NSCLC (contributing to 85% of lung cancer), with a brief overview on other aspects. The first paragraph is providing a context to NSCLC, mentioning the available therapeutic arsenal, mainly chemotherapy, immunotherapy, and targeted therapy, as the ADCs pave there way in 2nd line treatment, and with ongoing trials in 1st line setting. A comprehensive elaboration of treatment is out of the scope of this review. We have further elaborated the 1st paragraph based on your suggestion.
Comment 3: Authors need significantly to expand the novel biomarkers discovery, antibody development against novel antigens, overcoming resistance mechanisms sections with extensive primary references.
Reply 3: We thank the reviewer for the valid comment. We have expanded these sections with primary references and highlighted changes in red.
Comment 4: The authors may want to consider organizing the tables and the subsequent description of individual ADCs by type of payloads.
Reply 4: We have organized the description of 10 most developed ADCs in text in the order from the one with most clinical data (TDXd, f/b TDM1 and henceforth) to least clinical data, in order of importance in the field of lung cancer, rather than target. We have categorized by the target in the tables.
Comment 5: Line 47: A schematic diagram depicting each of the components for this section would be useful.
Reply 5: We have included a diagram for structure and mechanism of action.
Comment 6: Line 87, 90: Table 1, 2, and 3 are redundant. A single consolidated table will be more useful.
Reply 6: Thank you for the viewpoint. However, our idea is to present the available evidence (Table 2) and ongoing clinical trials (Table 3) in two separate tables. Table 1 is provided as a snapshot of the range of ADCs in clinical and preclinical development in the rapidly evolving field.
Comment 7: Define all the acronyms at their first use in the text.
Reply 7: This was corrected as suggested.
Reviewer 2 Report
Antibody-drug conjugates (ADCs) are a relatively new class of drugs with an extremely interesting mechanism of action and relatively high clinical efficacy. Preliminary published data suggest that selected patients diagnosed with non-small cell lung cancer may also benefit. Therefore, the topic taken up by the authors is important and interesting.
The paper is a valuable review of the data published to date. It is carefully prepared and I have no significant comments on the content of the manuscript.
However, the authors might consider supplementing the manuscript with a figure that provides an overview of the conjugate structure and mechanism of action of this class of drugs?
Author Response
Comment: Antibody-drug conjugates (ADCs) are a relatively new class of drugs with an extremely interesting mechanism of action and relatively high clinical efficacy. Preliminary published data suggest that selected patients diagnosed with non-small cell lung cancer may also benefit. Therefore, the topic taken up by the authors is important and interesting.
The paper is a valuable review of the data published to date. It is carefully prepared, and I have no significant comments on the content of the manuscript.
However, the authors might consider supplementing the manuscript with a figure that provides an overview of the conjugate structure and mechanism of action of this class of drugs.
Reply: We thank you for taking the time to review our manuscript and the positive feedback. Since this manuscript is a part of special edition on ‘ADCs in Cancer’, we kept the description of structure of ADC and its mechanism of action very basic, and did not elaborate, to eliminate repetition. We appreciate your suggestion to improve the manuscript and have elaborated structure and mechanism of action a bit more. We have also included a diagram for structure and mechanism of action.
Reviewer 3 Report
1. The structure of this study is relatively complete, focusing on the development and application of ADC in NSCLC, but the three components of ADC and the mechanism of action are not enough. The author may consider making a graph to show it more clearly and intuitively. It is suggested to refer to the literature [PMID: 36631624].
2. In this paper, the mechanism of drug resistance is rarely explained, probably because the application of ADC in the field of lung cancer is relatively immature, the author can give a fuller description through examples;
3. Whether there is overlap between NSCLC and LC in the key words, just write one.
Author Response
Comment 1: The structure of this study is relatively complete, focusing on the development and application of ADC in NSCLC, but the three components of ADC and the mechanism of action are not enough. The author may consider making a graph to show it more clearly and intuitively. It is suggested to refer to the literature [PMID: 36631624].
Reply 1: We thank you for taking the time to review our manuscript and the positive feedback. Since this manuscript is a part of special edition on ‘ADCs in Cancer’, we kept the description of structure of ADC and its mechanism of action very basic, and did not elaborate, to eliminate repetition. We appreciate your suggestion to improve the manuscript and have elaborated structure and mechanism of action a bit more. We have also included a diagram for structure and mechanism of action.
Comment 2: In this paper, the mechanism of drug resistance is rarely explained, probably because the application of ADC in the field of lung cancer is relatively immature, the author can give a fuller description through examples.
Reply 2: Thank you for this suggestion and we have incorporated more details under section 6, ‘Resistance mechanisms, highlighted in red.
Comment 3: Whether there is overlap between NSCLC and LC in the key words, just write one.
Reply 3: We have removed lung cancer and included NSCLC in keywords (line 24) as suggested.
Reviewer 4 Report
Overall excellent review
Also, mention the current drawbacks of T-Dxd. For example, microphage-related toxicity remains a challenge.
Should mention SSC to improve ADC TI. The appropriate citation is also needed.
The section explaining ADC toxicity is a very important insight. Please add a brief summary of current approaches to avoid toxicity problems. Improved linker technology should be one of the topics.
Author Response
Comment 1: Overall excellent review.
Reply 1: We thank you for taking the time to review our manuscript and the positive feedback. We appreciate your thoughtful suggestions to improve the manuscript.
Comment 2: Also, mention the current drawbacks of T-DXd. For example, macrophage-related toxicity remains a challenge.
Reply 2: Thank you for the suggestion. We have included the possible mechanism of macrophage mediated ILD due to TDXd under the section 4, ‘Toxicity’, 1st paragraph, highlighted in red.
Comment 3: Should mention SSC to improve ADC TI. The appropriate citation is also needed.
Reply 3: We have included site specific conjugation and it’s resulting improvement in Therapeutic Index under the section 7, ‘Future’, 1st paragraph, highlighted in red, with citation.
Comment 4: The section explaining ADC toxicity is a very important insight. Please add a brief summary of current approaches to avoid toxicity problems. Improved linker technology should be one of the topics.
Reply 4: We have added a paragraph on current approaches to decrease toxicity (under section 4, ‘Toxicity’, last paragraph, highlighted in red.
Round 2
Reviewer 1 Report
The manuscript has been sufficiently improved to warrant publication in Current Oncology.
Reviewer 3 Report
The study focuses on the development and application of ADCs in the treatment of non-small cell lung cancer. It includes the targets, efficacy and safety of novel ADC candidates in NSCLC, as well as specific toxicity, novel biomarkers, mechanisms to overcome drug resistance, challenges and the way forward.
