Targeting the Uncommon: A Case Report of Osimertinib Response in Advanced NSCLC Patient with Dual EGFR (E701fs and L702fs) Frameshift Deletions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

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Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a well-documented, clinically relevant, and timely case report describing a favorable response to osimertinib in a patient with extremely rare dual EGFR exon 18 frameshift deletions (E701fs and L702fs). The manuscript is generally well written, logically structured, and supported by appropriate imaging, laboratory trends, and literature. The case adds novel real-world evidence to a sparsely studied molecular subgroup and is particularly valuable given the patient’s enrollment in the OCELOT trial.

Abstract:

1. The abstract would benefit from explicitly stating that the observed response is radiological and biochemical (tumor marker decline) to improve clarity and clinical precision.
2. Consider briefly specifying the duration of response (11 months and ongoing) in a single phrase to highlight durability.

 

Introduction:

1. The Introduction is very strong scientifically, but slightly long for a case report. Consider modest condensation, particularly in the epidemiology paragraphs, to improve flow.
2. Ensure consistent spacing and formatting (e.g., “skipping mutations , RET translocations” → remove extra space).

3. Ensure all abbreviations are defined at first use (e.g., fs, ORR).
4. Maintain consistency in terminology (e.g., “frameshift” vs “frame-shift”).

Case Presentation:

1. “He is a lifelong non-smoker who was a professional” → please clarify the profession or remove if not clinically relevant.
2. Consider harmonizing tense usage (past vs present) throughout this section.

 

Results:

• The phrase “partial response” should ideally be defined according to RECIST or clearly stated as a radiologic assessment.

 

Discussion:

1. After the paragraph discussing limitations of EGFR-TKI efficacy in uncommon mutations, I suggest supporting with https://doi.org/10.3390/ph18040585. This review highlights the anti-angiogenic and multitargeted properties of Anlotinib, supporting its role in combination regimens for advanced NSCLC. Adding this citation strengthens the manuscript by demonstrating awareness of non-EGFR-driven targeted strategies and providing a rationale for combination approaches when molecular sensitivity is uncertain.
2. When discussing post-progression or alternative systemic therapies, I suggest supporting with this recent meta-analysis https://doi.org/10.3390/ph18050652 . This meta-analysis provides quantitative evidence for Anlotinib-based combinations after platinum failure and supports the manuscript’s discussion on future treatment options upon progression.
3. For paragraph addressing CNS disease and systemic control, I suggest discussing this recent systematic review to support your finding https://doi.org/10.3390/ph18070974. This review complements the manuscript’s emphasis on CNS penetration and disease control, a known strength of osimertinib and provides a comparative framework showing that alternative combination strategies may also offer CNS benefit.

 

Conclusion:

1. Consider explicitly stating that clinical trial enrollment remains critical for patients with rare EGFR mutations.
2. Avoid generalizing structural hypotheses without reinforcing the need for functional validation.

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

 

The manuscript presented a case report of stage IV lung adenocarcinoma with uncommon TKI mutation (701/702 fs) who have favorable response with Osimertinib treatment.

Authors carefully presented the clinic-pathological feature of the patient, with updated literature background. In general, the manuscript is well written with appropriate references with fair interpretation.

There are several issues may need attention for the clarity of the manuscript.

 

 

#1. Since Osimertinib is a kinase inhibitor this pharmacological reagent will expect to be effective for the treatment of NSCLC patient by suppressing the kinase activity of EGFR. How are the mutation of fs 701/702 would affect for the downstream amino acid sequences? Does these two consecutive amino acid mutations (fs 701/702) will expect to completely destroy the AA sequence downstream amino acid sequences which, then, how the kinase activity would turn out to be. Does the fs 701/702 mutation expecting to increase the kinase activity of TKI? Are there any evidence of the kinase activity of this mutation？ How much are known about the kinase activity of this particular mutation (fs 701/702) experimentally in vitro kinase assays or clinical samples for phosphor-immune staining or perhaps in the literature? Are there any kind of in vitro study support the kinase activity in the literature/or experimentally?

 

 

#2. Page 6, line 199, It is not clear what exactly mean by stating “two uncommon EGFR frame-shift deletions 199 (E701fs and L702fs; VAFs of 32.8% and 21.5%, respectively)”, “VAFs of 32.8% and 21.5%” need more precise explanation for the general readership for the clinician.

 

#3. Are there any possibilities of additional mutation of this particular case may have affected by the additional mutations, since this particular case has additional mutations of “NGS identified a PIK3C 198 E542K missense mutation (VAF 39%) (page 6, line 197~201).

 

#4. In the introduction section (lines between 54~57), one of the logical reasons that never smoker lung cancer is more prominent in woman would be adenocarcinoma is not influenced by the smoking, and adeno ca is more incidence of the woman, Adenocarcinoma is over 60~70 % of the lung cancer which would also affect the incidence in the dominancy of the never-smoker cancer in woman.

 

#5. Tabel 1: Which exact mutation groups/mutations listed on this table of “Anderson mutation classification” are thought/considered/subclassified to be either “common/uncommon” and/or “typical/atypical” mutation?

One could expect that TKI effectiveness can be subclassified by the TKI kinase activity, therefore among the list of these mutations, are there any information available for the alteration of the kinase activity of EGFR?  Can these mutations listed on this table be subclassified by the kinase activity and the clinical effectiveness of the TKI inhibitor treatment? What are known about the pharmacological effectiveness of TKI among these mutations in the literature?

 

#6. Fig 1: How much is known about the kinase activity and/or the clinical efficacies of TKI inhibitor(s) including Osimertinib of all the mutations listed (E701fs/702fs, EX19del, S768I, EX20ins, T790M, L861Q, and L858R) on the top of the figures.

Can these mutations (E701fs/702fs, EX19del, S768I, EX20ins, T790M, L861Q, and L858R) be subclassified by the kinase activity and the clinical effectiveness of the TKI inhibitor treatment?

 

#7. Fig 2: Authors are suggested to provide the “exact date” of chest XP and CTs were taken, but not just “pretreatment” and/or “most recent”.

 

#8. Fig 4. Authors are suggested to provide the “exact date” of chest XP and CTs were taken, but not just “base line” or “most recent”.

 

#9. Fig 5: Also, authors are suggested to provide the “exact date” of the measurement of the serum samples, but not just indicated as “recent days”.

 

#10. Authors are suggested the occupation of “professional” as more details for example no inhalation of chemicals or other relevant information would be preferable instead of just “professional”.

 

#11. Table 2:  It is not clear what “Base line” means on the right-side panel of this table. Authors are suggested to provide the normal values of this measurement in the institute, since these normal values would be different in different institute/laboratories/countries/kits available.

 

#12. In Discussion: What is the exact definition of the term “common/uncommon or typical/atypical”? Perhaps only “exon 19 deletions (Ex19del) and exon 21 (L858R) point mutations” are considered as common, and the rest of the mutations are considered as uncommon? Are there any scientific criteria of frequencies or number of incidences for subclassified as “common/uncommon or typica/atypical mutation among the different EGFR mutations?

 

#13. In the paragraph starting from page 10, lines 326~: If authors can provide any information about the correlations between clinical effectiveness and kinase activity of EGFR mutations that would be very interesting, if they are known in some extent.

 

#14. Page 20 line 355~: Since PDL-1 is negative in this particular case (page 6, line 198), how can immunotherapy be the option for the further therapy may be uncertain.

 

 

 

 

 

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Authors carefully responded my suggestions and concerns satisfactory manner.  The manuscript is acceptable for publication.

Since it would be predicted that EGFR (E701fs and L702fs) would expect/very likely to generate premature stop codon early downstream of EGFR, so that would not expect to increase the increased kinase activity of EGFR.  There is no clue of the molecular nature of the clinical effectiveness of TKI inhibitor for this particular case. It may be possible that Osimertinib may cross inhibit other kinase activity other than the kinase activity of EGFR.  In this particular case NGS identified a PIK3CA 201 E542K missense mutation, though how likely additional kinases are activated in this particular case, which possibly be inhabited by Osimertinib for the outcome of clinical effectiveness.  But certainly, further precise investigation would help to elucidate some clue for the future therapy for uncommon mutation of EGFR.