Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

There are current clinical trials about this treatment?

Author Response

Comment 1: There are current clinical trials about this treatment?

Response: We appreciate the reviewer’s interest in the ongoing development of this agent. As noted in the "Future Perspectives" section (Section 5) of our manuscript, clinical trials are currently underway to evaluate the efficacy of cemiplimab in the adjuvant and neoadjuvant settings (e.g., NCT06931717, NCT06449313, NCT06465329). In the revised manuscript, we have added the registration number for the ongoing clinical trial             . We believe these ongoing studies will further clarify the utility of cemiplimab in earlier stages of the disease.

Action: (p.10 line 38-39) Clinical trials are currently underway to evaluate its efficacy in the adjuvant and neo-adjuvant settings for NSCLC (e.g., NCT06931717, NCT06449313, NCT06465329).

Reviewer 2 Report

Comments and Suggestions for Authors

I have only minor suggestions for revision.

1. Section 2.2, pgh2, sentence 1, and Section 4.2, Last pgh, line 6 -  should be data "indicate" -grammar issue.

2. Section 4.1 - first sentence - cemiplimab should be lower case

3. Table 1  - write out "chemo" in full (chemotherapy).  Jargon issue

Author Response

Comment 1: Section 2.2, pgh2, sentence 1, and Section 4.2, Last pgh, line 6 - should be data "indicate" -grammar issue.

Response: We thank the reviewer for pointing out this grammatical error. We have corrected "data indicates" to "data indicate" in the specified sections to ensure grammatical accuracy.

Action: (p.4 line 1-4) In the context of ICIs, data indicate that cemiplimab may possess a favorable immunogenicity profile, with a lower incidence of ADA production compared to other existing ICIs. Clinical data indicate a remarkably low incidence of treatment-emergent ADAs, ranging from approximately 0% to 2.6%.

(p.10 line 8-11) Although the specific Kaplan-Meier curves and detailed histology-stratified data for the PD-L1 1-49% subgroup are not fully detailed in the provided materials, the available data indicate that this regimen represents a promising therapeutic option for this specific intermediate expression group.

 

Comment 2: Section 4.1 - first sentence - cemiplimab should be lower case.

Response: We have corrected the capitalization. "Cemiplimab" has been changed to "cemiplimab" in the middle of the sentence in Section 4.1.

Action: (p.8 line 24-26) A compelling opportunity for cemiplimab to penetrate the current standard of care lies within the "ultra-high" expression population defined as PD-L1 TPS ≥ 90%, a subgroup which was pre-specified for exploratory analysis in EMPOWER-Lung1.

 

Comment 3: Table 1 - write out "chemo" in full (chemotherapy). Jargon issue.

Response: We agree with the reviewer that full terminology is preferable for clarity. We have updated Table 1 to spell out "Chemotherapy" instead of using the abbreviation "Chemo."

 

Reviewer 3 Report

Comments and Suggestions for Authors

1. Across the EMPOWER-Lung 1 trial as well as other clinical trials and real-world datasets, what proportion of patients are classified as having “ultra-high” PD-L1 expression (TPS ≥90%), particularly within squamous cell carcinoma? In EMPOWER-Lung 1, this subgroup accounted for approximately 35% of the study population, which is substantially higher than typically reported in large phase III NSCLC trials and raises concerns regarding the representativeness of the cohort. Please clarify how this population enrichment may limit the comparability of EMPOWER-Lung 1 with other trials and affect the generalizability of the reported subgroup benefits.
2. While reference 22 reports a cemiplimab-induced ADA incidence of 2.6% (1/39 patients), the manuscript describes an ADA incidence range of 0–2.6%. Please clarify the origin of the 0% value and indicate the specific studies or populations on which this estimate is based.
3. Do the authors consider drug-specific properties or tumor histology to be the predominant determinant of anti-drug antibody (ADA) formation? Please clarify which factor is considered more influential and provide supporting evidence for this interpretation.
4. The authors suggest that the efficacy of other ICIs is limited in squamous cell carcinoma; however, given the absence of head-to-head comparisons, can this claim be generalized? Additionally, have potential differences in tumor histology across studies been adequately considered, or might this statement overinterpret the available data? Please clarify the scope and limitations of this claim.
5. Regarding pneumonitis, should the authors report the absolute number of events (n) and explicitly discuss this safety concern? Given that patients with squamous cell carcinoma often have compromised background lung conditions, is pneumonitis truly not a relevant concern, particularly in Asian populations where its incidence has been reported to be higher? Please clarify how the authors interpret and contextualize this risk.
6. We would appreciate clarification on whether all efficacy outcomes reported in Table 2 are fully aligned with those described in the text, especially for histology- and PD-L1–based subgroup analyses. Please address any inconsistencies if present.

Author Response

Comment 1: Across the EMPOWER-Lung 1 trial as well as other clinical trials and real-world datasets, what proportion of patients are classified as having “ultra-high” PD-L1 expression (TPS ≥90%), particularly within squamous cell carcinoma? In EMPOWER-Lung 1, this subgroup accounted for approximately 35% of the study population, which is substantially higher than typically reported in large phase III NSCLC trials and raises concerns regarding the representativeness of the cohort. Please clarify how this population enrichment may limit the comparability of EMPOWER-Lung 1 with other trials and affect the generalizability of the reported subgroup benefits.

Response: We sincerely thank the reviewer for this insightful comment regarding the proportion of patients with “ultra-high” PD-L1 expression (TPS ≥90%) in the EMPOWER-Lung 1 trial. We agree that the prevalence of this subgroup (approximately 35% of the study population) warrants careful consideration regarding the representativeness and generalizability of the data. Regarding the proportion, it is important to note that the EMPOWER-Lung 1 trial specifically enrolled patients with PD-L1 expression ≥50%. Within this pre-selected “high expression” population, real-world data and other cohorts suggest that the proportion of patients with TPS ≥90% is indeed substantial. For instance, in the study by Ricciuti et al. (cited as Ref. [40] in our manuscript), which analyzed patients with PD-L1 ≥50%, a significant subset fell into the ≥90% category, supporting the notion that this is a distinct and not uncommon biological entity within the high-expression landscape. However, we fully acknowledge the reviewer's concern that the specific enrichment in EMPOWER-Lung 1—potentially influenced by the exclusion of EGFR/ALK alterations and the specific assay used—may limit direct comparisons with other trials that did not report or stratify for this specific cut-off. The high proportion in EMPOWER-Lung 1 provided the necessary statistical power to identify the unique benefit in this subgroup, but it implies that the magnitude of benefit observed in the overall population is heavily driven by this "ultra-high" group. To address this and clarify the limits of generalizability as suggested, we have added a sentence in Section 4.1 acknowledging that the proportion of TPS ≥90% patients in this trial may be enriched compared to broader real-world populations, and that this necessitates caution when interpreting cross-trial comparisons.

Action: (p.9 line 8-14) Although these cross-trial comparisons should be interpreted with caution due to differences in study design and the potential enrichment of the "ultra-high" subgroup in EMPOWER-Lung 1 (accounting for ~35% of the study population), cemiplimab demonstrates a strong potential to outperform the established standard in the context of PD-L1 ≥ 90% tumors where high immunogenicity and ADA risks intersect. While this specific population distribution may limit direct generalizability to cohorts with different PD-L1 profiles, the data clearly identify a therapeutic niche where cemiplimab excels.

 

Comment 2: While reference 22 reports a cemiplimab-induced ADA incidence of 2.6% (1/39 patients), the manuscript describes an ADA incidence range of 0–2.6%. Please clarify the origin of the 0% value and indicate the specific studies or populations on which this estimate is based.

Response: We appreciate the reviewer for carefully checking the data sources. The stated range of "0–2.6%" was intended to encompass the spectrum of ADA incidence reported across different clinical trials of cemiplimab. Specifically, the 0% incidence refers to the results from the Japanese Phase 1 study (Sato Y, et al. Jpn J Clin Oncol. 2025 Oct 29:hyaf160. cited as Reference [38] in our original manuscript), where no anti-drug antibodies were detected in the evaluated cohort. The 2.6% incidence refers to the data reported in Reference [22] (1/39 patients). We have rearranged the reference numbers and added the following to the body text.

Action: (p.4 line 3-4) Clinical data indicate a remarkably low incidence of treatment-emergent ADAs, ranging from approximately 0% to 2.6% [22, 23].

 

Comment 3: Do the authors consider drug-specific properties or tumor histology to be the predominant determinant of anti-drug antibody (ADA) formation? Please clarify which factor is considered more influential and provide supporting evidence for this interpretation.

Response: We appreciate the reviewer for raising this critical question regarding the determinants of ADA formation. Our interpretation is that while tumor histology creates the predisposition for immunogenicity, the drug-specific molecular properties are the predominant determinant of actual ADA formation. Tumor histology, particularly squamous cell carcinoma with its high tumor mutation burden and neoantigen load, provides a highly immunogenic environment ("high-risk soil") that facilitates immune recognition. However, clinical evidence shows that ADA incidence varies dramatically across different checkpoint inhibitors (e.g., up to ~30-50% for atezolizumab vs. ~0-2.6% for cemiplimab) even when treated in similar disease settings. This significant inter-drug variability suggests that a drug's structural stability (such as the S228P mutation in cemiplimab) is the decisive factor that determines whether this potential risk translates into actual ADA production. To clarify this distinction, we have added a sentence in Section 2.2 explicitly stating that drug design is the primary factor in mitigating the immunogenic risk posed by histology.

Action: (p.4 line 25-27) This implies that while squamous histology provides the immunogenic substrate, the drug's structural stability is the predominant determinant in limiting ADA formation.

 

Comment 4: The authors suggest that the efficacy of other ICIs is limited in squamous cell carcinoma; however, given the absence of head-to-head comparisons, can this claim be generalized? Additionally, have potential differences in tumor histology across studies been adequately considered, or might this statement overinterpret the available data? Please clarify the scope and limitations of this claim.

Response: We respectfully agree with the reviewer that, in the absence of head-to-head comparisons, claims regarding the limited efficacy of other ICIs in squamous cell carcinoma must be made with caution. We recognize that generalizing the "attenuated benefit" observed in certain subgroup analyses to all standard therapies may overinterpret the available data. Our intention was not to definitively assert that other ICIs are ineffective, but rather to highlight a potential mechanistic rationale—specifically regarding PD-1 glycosylation—where Cemiplimab might possess a structural advantage. However, we acknowledge that differences in patient populations and study designs (e.g., prevalence of squamous histology) confound these comparisons. To address this concern and clarify the scope of our claim, we have revised the text in Section 2.3 to soften the language regarding other ICIs. We have rephrased the statement to present it as a mechanistic hypothesis rather than a clinical conclusion, and we have explicitly acknowledged the lack of head-to-head data as a limitation.

Action: (p.4 line 47-52) These findings collectively suggest that in tumors exhibiting hyper-glycosylation of PD-1, such as squamous cell carcinomas, standard checkpoint inhibitors might encounter specific resistance mechanisms related to the strengthened PD-1/PD-L1 inter-face. While this hypothesis requires validation in head-to-head clinical studies, cemiplimab, by virtue of its ability to target these glycosylated variants, may fill a critical therapeutic gap, offering potential efficacy in patient populations that are intrinsically resistant to other agents.

 

Comment 5: Regarding pneumonitis, should the authors report the absolute number of events (n) and explicitly discuss this safety concern? Given that patients with squamous cell carcinoma often have compromised background lung conditions, is pneumonitis truly not a relevant concern, particularly in Asian populations where its incidence has been reported to be higher? Please clarify how the authors interpret and contextualize this risk.

Response: We sincerely thank the reviewer for highlighting this important safety consideration. We fully agree that pneumonitis is a critical adverse event, particularly in patients with squamous cell carcinoma and in Asian populations.In response to your suggestion, we have amended the text in Section 3.3 to include the absolute number of events (n) and to better contextualize this risk. Regarding the interpretation: While the pneumonitis incidence in the monotherapy cohort (Cohort A) was 21.7% (13/60), we observed a notably lower incidence of 10.0% (5/50) in the combination cohort (Cohort C) within the same study. The fact that the combination arm—which typically carries a higher toxicity burden—showed a lower incidence suggests that the high rate in the monotherapy arm likely reflects statistical variation inherent to small sample sizes, rather than a definitive pharmacological signal. Therefore, while we acknowledge the class effect of ICIs in Japanese patients, we consider the safety profile to be manageable and emphasize the need for larger real-world datasets to draw firm conclusions.

Action: (p.7 line 28-34) While pneumonitis occurred in 21.7% (13/60; Grade ≥3: 5.0%, 3/60) of patients receiving monotherapy, the incidence was notably lower at 10.0% (5/50; Grade ≥3: 2.0%, 1/50) in the combination cohort (Cohort C). This variability suggests that the higher rate in the monotherapy cohort may be attributable to statistical fluctuations in a small sample size rather than a unique safety signal. Nevertheless, given the known susceptibility of East Asian patients to interstitial lung disease, careful monitoring is required, and further accumulation of real-world data is warranted.

 

Comment 6: We would appreciate clarification on whether all efficacy outcomes reported in Table 2 are fully aligned with those described in the text, especially for histology- and PD-L1–based subgroup analyses. Please address any inconsistencies if present.

Response: We appreciate the reviewer for their diligence in ensuring data accuracy. We have carefully cross-referenced all efficacy outcomes reported in Table 2 with the descriptions in the main text (specifically Sections 3.1 and 4.1) and the primary source data from the EMPOWER-Lung 1 5-year update. We confirm that the values are fully aligned and consistent. For instance, the Overall Survival (OS) Hazard Ratio (HR) of 0.51 for the squamous subgroup and 0.59 for the overall population in Table 2 strictly correspond to the values cited in the text and the referenced literature. To prevent any potential ambiguity regarding the specific dataset used, we have added a footnote to Table 2 explicitly stating that these results are based on the Modified Intention-to-Treat (mITT) population (patients with confirmed PD-L1 ≥ 50%) from the 5-year follow-up analysis. We believe this addition clarifies the source of the data and ensures full transparency.

Action: (Table 2, Footer section.) Note: Data for EMPOWER-Lung 1 refer to the 5-year update analysis in the modified intention-to-treat population (confirmed PD-L1 ≥ 50%).