Fluctuation of Acquired Resistance Mutations and Re-Challenge with EGFR TKI in Metastatic NSCLC: A Case Report

Round 1

Reviewer 1 Report

In this case report, the authors successfully treated a young EGFR-mutated Stage IV NSCLC patient by using various anti-tumor drugs and monitoring with liquid biopsies. This manuscript is well written and can give useful information to readers. But I have some comments should be addressed.

1.       Abstract: The authors mentioned a lot about Osimertinib. In contrast, there are very little information about this patient. Therefore, they should shorten the description of osimertinib, and add more information about the patient.

2.       They analyzed six liquid biopsies in total. I can understand these information could be useful to select the drugs. I just wonder multiple liquid biopsies can be covered by insurance. Was it okay?

3.       Between erlotinib and carboplatin/pemetrexed, they chose a cobas® EGFR mutation test although the other ctDNA analyses were conducted by NGS. Why? They should address.

4.       Minor

-         Introduction section: line 5; afatinib is 2^nd. generation. Please correct.

-        Figure 1.: This patient received on course cisplatin/pemetrexed chemotherapy before 1^st. line erlotinib. This chemotherapy was not included. Why?

Author Response

We thank Reviewer 1 for the very valid suggestions:

• Abstract: The authors mentioned a lot about Osimertinib. In contrast, there are very little information about this patient. Therefore, they should shorten the description of osimertinib, and add more information about the patient.

Within the abstract, we shortened the section about osimertinib and instead added more detailed information about the patient.

 

• They analyzed six liquid biopsies in total. I can understand these information could be useful to select the drugs. I just wonder multiple liquid biopsies can be covered by insurance. Was it okay?

Unfortunately, German health care providers do generally not cover the sequential use of liquid biopsies as a tool for therapy monitoring. However, some select health insurance companies, as part of the German network “national Network of Genomic Medicine, nNGM”, do reimburse NGS liquid biopsies, in case disease progression of NSCLC under targeted therapy requires a change of therapy.

 

• Between erlotinib and carboplatin/pemetrexed, they chose a cobas® EGFR mutation test, although the other ctDNA analyses were conducted by NGS. Why? They should address.

Cobas® test was performed instead of NGS because ctDNA concentration did not pass quality criteria, we added this explanation in the result section on page two, and in the discussion on page four.

 

• Introduction section: line 5; afatinib is 2nd. generation. Please correct.

Thank you, we corrected that mistake.

 

• Figure 1.: This patient received on course cisplatin/pemetrexed chemotherapy before 1st. line erlotinib. This chemotherapy was not included. Why?

Cisplatin/pemetrexed was merely used as bridging, due to significant therapeutic pressure until primary NGS diagnosis with driver mutation status was available. We therefore regarded cis/pem as only minor relevant to the overall therapeutic course and excluded it from figure 1.

Reviewer 2 Report

Manuscript ID:CO-2599617
Title: Disappearance of acquired resistance mutations and re-challenge with TKI in EGFR mutated NSCLC monitored with liquid biopsies: a case report

Date:20230907

Reviewer's report:
This is an interesting manuscript as its a study of the detection of disappearance of acquired resistance mutations and re-challenge with TKI in EGFR mutated NSCLC monitored with liquid biopsies thru a single case study. Targeted therapy has led to a profound extension of overall survival (OS) in patients with stage IV NSCLC. Since 2009, several EGFR TKI have been approved for first line and second linetreatment, which increases the survival rate and control rate of advance NSCLC. However, resistance and mutation frequently occur with T790M as the most common resistance mutation to these generations of TKI. Recently, with the success of the FLAURA trial, osimertinib complemented the portfolio of first-line TKI and at the same time diminished the relevance of sequential TKI therapy due to superior survival data compared to other TKI Resistance to osimertinib limits therapeutic success . Genetic re-assessment of the tumor DNA should be performed at re-lapse under TKI therapy. Liquid biopsy has become an important alternative in this situation .It has further been observed that ctDNA analysis can predict resistance prior to imaging techniques and is more sensitive

This MS was a case study of an advance stage NSCLC at diagnosis with a seven-year therapeutic course including different generations of EGFR TKI which succesfully prolong the survival rate of this patient. I'm sure the result of this MS could help in the decision-making process and guide towards an optimal future management of NSCLC. The MS is well prepared . Although, there remain some limitation. Nevertheless, it was still well written. However, a few issue should be clarify prior publication.

     1. What was the ctDNA sequencing platform use on the course of treatment ?

2. What was the common adverse effect found during the whole course of treatment?

3. How does the patient tolerate the entire course of treatment ?

Author Response

We thank Reviewer 2 for addressing these legitimate and helpful aspects:

• What was the ctDNA sequencing platform use on the course of treatment?

We used the Illumina platform NextSeq500 for sequencing analysis. We thank you for the reminder and added this relevant information to the result section on page 2.

• What was the common adverse effect found during the whole course of treatment?

Side effects were in all lines of therapy not higher than CTC (common toxicity criteria) grade 2 and therefore, were not reported in detail. In addition, there were no new side effects described by the patient that have not been already mentioned in the approval studies.

• How does the patient tolerate the entire course of treatment?

The lines of therapy were all well tolerated by the patient. There had been no delays due to side effects or poor tolerance. Therefore, this was not reported in the text.

Reviewer 3 Report

Journal of Current Oncology

Case Report;

The article entitled “Disappearance of acquired resistance mutations and re-challenge with TKI in EGFR mutated NSCLC monitored with liquid biopsies: a case report’’. The authors tried their best to report that Osimertinib has become the preferred first-line therapy for EGFR mutation-positive metastatic NSCLC in recent years, based on the FLAURA trial. Originally it became approved for second-line treatment after EGFR tyrosine kinase inhibitors (TKI) of the first and second generation had failed and EGFR T790M had emerged as a mode of resistance. As osimertinib itself provokes a wide array of on- and off-target molecular alterations, oncologists need to consider sequential versus best first TKI treatment for the individual patient and close monitoring for emerging resistance.

I carefully read the manuscript and found it suitable for publication in the journal. The author describe in wonderful way about the Osimertinib, which will help in future therapy of NCSLC metastasis. I accept this article for possible publication. There are some common mistakes in the manuscript which should be corrected by the authors. After the correction of all the mistakes, the report could be considered for publication in the prestigious Current Oncology Journal.

Comments for Authors

Ø  The author needs to revise the title of the manuscript.

Ø  Write the keywords in alphabetical order.

Ø  The author needs to revise the introduction section. Include more references and revise in more detail with NSCLC background.

Ø  EGFR, NSCLC, abbreviation stand for? Revised all the abbreviation.

Ø  “DOI: 10.1093/jjco/hyy179” could the study is just the repeating of the same case? What is the novelty to show in this case?

Ø  The author needs to include the survival rate and include the image taken during the study.

Cite the following references;

v  https://doi.org/10.1038/s41419-021-03771-z

Author Response

Dear reviewer 3, we appreciate and thank you for your valid comments and would like to address each point step by step.

 

• The author needs to revise the title of the manuscript.

We re-phrased the title to a more concise version: “Fluctuation of acquired resistance mutations and re-challenge with EGFR-TKI in metastatic NSCLC: a case report”

 

• Write the keywords in alphabetical order.

We put the keywords in alphabetical order as suggested

 

• The author needs to revise the introduction section. Include more references and revise in more detail with NSCLC background.

We revised the introduction section, included several references and elaborated more on NSCLC background (prevalence, histology, frequency of driver mutations and implication on human health)

 

• EGFR, NSCLC, abbreviation stand for? Revised all the abbreviation.

We included missing abbreviations.

 

• “DOI: 10.1093/jjco/hyy179” could the study is just the repeating of the same case? What is the novelty to show in this case?

We thank you for pointing out the paper “DOI: 10.1093/jjco/hyy179” to us. The referenced publication is describing a study in a subset of the FLAURA trial, including 120 Japanese patients. EGFR positive patients were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy.   The main conclusion of this study was that first line osimertinib was more effective than gefitinib in this Japanese population. Our case indeed differs from this study in some aspects. At the time our patient was diagnosed with EGFR positive NSCLC, osimertinib was not approved in Germany for first line treatment, hence Erlotinib was preferred as (at that time) standard of care treatment. Later, our patient developed T790M and osimertinib was administered as second line TKI. T790M disappeared under osimertinib treatment providing clinical rationale for erlotinib re-challenge. Apart from this, the diagnostic approach differed from the cited publication, in that we used liquid biopsy testing though out the course of disease for the management of further line therapy.

We therefore consider our data as clinically relevant “patient-case based” addition to the concept followed in the paper you reference.

 

• The author needs to include the survival rate and include the image taken during the study.

Since we focus on describing a single case study we were not able to define a survival rate in the classical sense. However, we show an astonishingly long survival benefit of the patient with more than seven years from the time of primary diagnosis. At the time of writing, the patient is still in good overall health.

We appreciate your suggestion to include imaging data of the patient. However, given the extraordinarily long course of therapy, together with a multitude of images being taken at several time points, it is difficult to provide representative figures in a way that would concisely support the presented figure 1.

 

• Cite the following references https://doi.org/10.1038/s41419-021-03771-z

The manuscript entitled “Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer” is of high interest in the field of lung cancer, however since this article, in our mind, does not fit smoothly into our manuscript, since it is not dealing with EGFR-directed therapy. Therefore, we cannot cite this paper.