ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy

Round 1

Reviewer 1 Report

The manuscript presents data in a very comprehensive way, There are only some minor remarks:  

Is figure 1 originally prepared by the authors or was implemented from reference 14?

 Table 1 each data should be supplemented by a relative reference

I would suggest making short summary of availableROS1  drugs and clinical trials in Table 2

The term “ Lung non-small cell lung cancer (NSCLC)” is incorrect, non-small cell lung cancer (NSCLC) is used by the community

Type page 1 lane 16 – should diseases?  Page 1 lane 20 – acts?

Page 1 lane 41 LUAD used the first time – please explain it

Author Response

Reply to referee 1

1. The Figure 1 was implemented from reference 14 and this was now stated in the legend of this Figure.
2. Table 1 was supplemented by a relative reference.
3. A short summary of available drugs and relative clinical trials was now reported in Tbles 2 and 3.
4. The term Lung non-small cell lung cancer (NSCLC) was corrected with non-small cell lung cancer (NSCLC).
5. Typos on page 1 were now corrected, as suggested.

Reviewer 2 Report

I would like to thank the handling editor for offering me the opportunity to review the manuscript entitled “ROS1-rearranged lung adenocarcinoma: from molecular genetics to target therapy” authored by Testa and colleagues, which is currently under consideration for publication in Onco. I would also like to commend the authors for their scholarly work, which presents a comprehensive review that discusses ROS1-rearranged lung adenocarcinoma. Overall, the review covers the prevalence, molecular biology, and clinical features of ROS1-rearranged lung cancers. It also summarizes the development of ROS1-targeted TKIs, their efficacy in early trials, and known resistance mechanisms that are still being elucidated. The authors highlight the need for continued research to optimize treatment and overcome resistance in this molecular subtype of NSCLC.

This thorough review provides a timely overview of the current state of research on ROS1-rearranged lung cancers. While ROS1 fusions represent a relatively rare molecular subtype of NSCLC, there has been rapid progress in understanding the biology and developing targeted therapies against these genomic alterations over the past decade. The review offers a valuable synthesis of findings from key studies characterizing the prevalence, molecular genetics, signalling pathways, and clinical behaviour of ROS1-positive lung adenocarcinomas.

The authors have compiled an extensive literature review, including most of the major clinical trials of ROS1 inhibitors published to date. The discussion of the mechanisms of resistance to crizotinib and the emergence of next-generation ROS1 inhibitors is particularly useful, as this is a fast-moving area of research. Although the topic of targeted therapy for ROS1 fusions has been reviewed previously, this manuscript provides an ample and current update on the state of the field.

The level of detail included in summarizing the signalling pathways and drug resistance mechanisms makes this review stand out. The authors' expertise is evident through the nuanced synthesis of preclinical and clinical data. The limitations of current ROS1 inhibitors are acknowledged, highlighting the ongoing need for new therapeutic approaches to overcome resistance. Overall, this is a well-written and scholarly overview that could make a meaningful contribution to the literature once finalized. The comprehensive and up-to-date nature of the information presented would make it a valuable reference for researchers and clinicians focused on lung cancer precision medicine.

While the manuscript provides valuable insights, there are several areas that could be refined to further augment the quality and impact of the work. Here are some respectful suggestions:

1.      The authors could provide more details on their literature search methodology: databases used, search terms and dates, and screening/exclusion criteria. This would enhance the robustness and reproducibility of the review.

2.      The authors could consider including a table summarizing the key clinical trials of ROS1 inhibitors to date, including response rates, PFS, and safety profiles. This would give readers a quick overview of the evolving therapeutic landscape.

3.      More details on the prevalence and patterns of brain metastases in ROS1+ patients could further contextualize the need for CNS-active drugs.

4.      Expanding the discussion of mechanisms of resistance beyond kinase domain mutations (e.g., EMT, SCLC transformation, off-target bypass signalling) may be useful for the readers.

5.      A discussion of gaps in the current literature and limitations of the available clinical data would add helpful context. For example, how sufficient are the data on rare ROS1 fusion variants?

6.      When discussing response rates, it would be useful to also report the disease control rates and duration of responses.

7.      The authors may consider further discussing the lack of head-to-head trials comparing ROS1 TKIs, the limitations of cross-trial comparisons, and the need for data maturity, since most of the clinical data come from early phase trials with short follow-up.

8.      The authors could consider utilising more figures. Figures summarizing key concepts could further engage readers and reinforce important points.

In conclusion, I would like to reiterate my appreciation to both the editor and the authors for the opportunity to review this intriguing and informative manuscript. I trust that my suggestions will help enhance the clarity, credibility, and relevance of this important work. I look forward to seeing the revised version of the manuscript and wish the authors success in their ongoing research endeavours.

The quality of English language is satisfactory. The writing is clear, concise, and uses academic terminology appropriately.

Author Response

Reply to review reptort 2

1. This review was based on a literature search according to Publi Med and to the search of data based on the most relevant international Meeting on Lung Cancers and screened a lapse of time from 2000 to the present time. Case reports or studies based on the analysis of only few ROS1-rearranged LUADs were usually excluded from the present analysis.
2. Two Tables were now included, summarizing key clinical trials of ROS1-positive patients, including response rates, PFS and safety profiles.
3. More details on the prevalence and patterns of brain metastases in ROS1-positive patients were now provided. See the chapter on Intracranial failure, the analysis of the study LORLATU [37], the results of the study of Wu et al. using crizotinib [27].
4. The discussion on EMT, SCLC transformation and off-target bypass signalling was now expanded.
5. The main limitation of clinical studies related to the rarity of the disease was now outlined at the end of conclusions. It was evidenced that this limitation is particularly relevant for rare ROS1 fusion variants.
6. Disease control rates and duration of responses were now reported for the trials involving various ROS1 TKIs (see Table 2 and Table 3).
7. It was now briefly outlined in a brief dedicated section the lack of head-to-head trials comparing different ROS1 TKIs, the limitations of cross-trial comparisons and the limited maturity of the clinical data of many clinical trials due to the short follow-up.

We would thank this referee for his/her helpful comments that have contributed to improve our manuscript.

Round 2

Reviewer 2 Report

I want to express my appreciation for the attention and consideration you have devoted to my suggested revisions for your manuscript. It is evident that a significant amount of effort and thought has been directed towards the refining of your work, integrating the feedback provided during the peer review process. The resulting modifications demonstrate a thorough and thoughtful approach, and significantly enhance the rigor and overall quality of your manuscript. I look forward to witnessing the impact your research will undoubtedly have on the academic community.

The manuscript is well-written, with appropriate academic language and tone. The prose is clear, direct, and impactful.