Drug Therapy for Melanoma: Current Updates and Future Prospects

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents a comprehensive and timely narrative review of systemic drug therapies for melanoma, covering immune checkpoint inhibitors, molecular targeted therapies, emerging treatment modalities, biomarkers, and treatment sequencing. The manuscript is generally well written, scientifically accurate, and supported by appropriate and up-to-date references. The topic is highly relevant, and the review will be of value to clinicians and researchers.

To further strengthen the manuscript and enhance its impact as a high-level review article, several points regarding critical depth, balance, and clarity should be addressed. The comments below are intended to improve the analytical rigor and translational relevance of the review without requiring additional experimental data.

Major Comments
- Increase critical synthesis beyond descriptive summarization: While the manuscript accurately summarizes a wide range of clinical trials and therapeutic strategies, several sections remain primarily descriptive. For a review article at this level, a stronger critical synthesis is encouraged. Please clarify why certain therapeutic strategies have failed or shown limited benefit (e.g., triple combination therapies, metabolic or epigenetic targeting approaches). Where applicable, highlight lessons learned from negative or inconclusive trials and how these findings should influence future study design or clinical decision-making.

- Balance optimism with clinical and translational limitations: Some emerging therapies (e.g., novel immune checkpoint inhibitors, cytokine-based therapies, and combination regimens) are described in an optimistic tone that may not fully reflect current limitations, including toxicity, feasibility, and inconsistent efficacy across trials. Please more explicitly discuss the clinical barriers and unresolved challenges associated with these approaches to avoid potential overinterpretation. 

- Clarify melanoma subtype–specific differences: Although the review acknowledges melanoma heterogeneity, the discussion is largely centered on cutaneous melanoma. Acral, mucosal, and uveal melanomas exhibit distinct biological features and therapeutic responses. Please strengthen the discussion by clearly differentiating treatment efficacy, biomarker relevance, and immunotherapy responsiveness among melanoma subtypes, particularly where evidence diverges from cutaneous melanoma.
- Improve prioritization and structure in the biomarker section: The biomarker section is comprehensive but would benefit from clearer stratification between clinically established biomarkers and those that remain investigational. Please consider explicitly categorizing biomarkers as “clinically actionable,” “prognostic,” or “exploratory/research-stage” to improve clarity and translational relevance.
- Acknowledge limitations inherent to a narrative, single-author review: Given the breadth and complexity of the topic, a brief acknowledgment of the limitations of a narrative review—particularly one authored by a single contributor—would improve transparency and academic balance.

Minor Comments
- Please correct the typographical error in the title: “Furture Prospects” should be revised to “Future Prospects.”
- In Figure 1 and its legend, consider adding melanoma-specific context (e.g., relevance to tumor immunogenicity or immune evasion mechanisms) to strengthen its conceptual value.
- The frequent use of approximate expressions (e.g., “approximately”) could be reduced by providing specific numerical values where available.
- In sections discussing therapies with limited or negative clinical outcomes (e.g., PARP inhibitors, metabolic and epigenetic targets), consider briefly emphasizing the lack of definitive efficacy to improve balance.
- In the guideline section, a concise comparison highlighting differences or nuances among NCCN, ESMO, and ASCO recommendations may improve readability for an international audience.

 

Author Response

Major Comment 1

Comment: Increase critical synthesis beyond descriptive summarization… clarify why certain strategies failed or showed limited benefit (e.g., triple combinations, metabolic/epigenetic targeting)… highlight lessons from negative/inconclusive trials and how these inform future study design/clinical decision-making.

Response:
I thank the Reviewer for their valuable comment. Accordingly, I have strengthened the “critical synthesis” by explicitly summarizing why certain strategies have shown limited benefit and what lessons can be drawn.

• Metabolic/epigenetic targeting: I have added a more explicit statement emphasizing that, despite biological rationale, these approaches have not yet achieved clear clinical success and that future work likely requires biomarker-driven patient selection and rational combinations.
• PARP inhibitors: I have clarified that PARP inhibition remains exploratory in melanoma and is not yet established as a standard approach, emphasizing the current lack of definitive efficacy.
• Triple combination therapy / intensive combinations: I have revised the discussion to more clearly highlight the trade-off between potential efficacy and increased toxicity, and to acknowledge heterogeneous trial outcomes (supporting a more nuanced interpretation and trial design).

Major Comment 2

Comment: Balance optimism with clinical/translational limitations (toxicity, feasibility, inconsistent efficacy across trials) to avoid overinterpretation.

Response:
I agree and have revised the relevant sections to more explicitly balance promise with limitations, including feasibility and toxicity concerns. In particular, I have emphasized (i) inconsistent efficacy across trials for some emerging combinations and (ii) toxicity escalation as a key clinical barrier.

Major Comment 3

Comment: Clarify melanoma subtype–specific differences (cutaneous vs acral/mucosal/uveal) regarding efficacy, biomarker relevance, and immunotherapy responsiveness.

Response:
I thank the Reviewer for their thoughtful comment. I have added an explicit “subtype-focused” discussion to distinguish cutaneous melanoma from acral, mucosal, and uveal melanoma, including:

• differential immunotherapy responsiveness and mutational landscapes,
• subtype-specific actionable targets (e.g., KIT in acral/mucosal; GNAQ/GNA11 axis in uveal),
• distinct therapeutic constraints and unmet needs.

I have also highlighted practical treatment implications for acral/mucosal melanoma (e.g., KIT testing; clinical trial prioritization) and uveal melanoma.

Major Comment 4

Comment: Improve prioritization/structure in biomarker section by stratifying biomarkers into clinically actionable / prognostic / exploratory.

Response:
I have reorganized the biomarker section by explicitly introducing a “clinical implementation level” framework, separating:

• Clinically actionable biomarkers (treatment selection changes),
• Prognostic biomarkers (risk stratification), and
• Exploratory/research-stage biomarkers (trial enrichment/monitoring).

This revision is aimed to improve translational clarity while preserving comprehensiveness.

Major Comment 5

Comment: Acknowledge limitations inherent to a narrative, single-author review to improve transparency.

Response:
I agree and have added a dedicated “Limitation” section explicitly stating that this is a single-author narrative review (not systematic), and that study selection may be influenced by publication bias and evolving guidelines, particularly for emerging therapies.

Minor Comments

Minor Comment 1

Comment: Correct typographical error in title: “Furture” → “Future”.

Response:
I thank the Reviewer for their valuable comment. Accordingly, I have corrected the typographical error in the manuscript title to “Future Prospects” (and I have ensured that it is consistently corrected at all relevant instances).

)

Minor Comment 2

Comment: In Figure 1 and its legend, consider adding melanoma-specific context (tumor immunogenicity/immune evasion).

Response:
I thank the Reviewer for their insightful comment. Accordingly, I have strengthened the melanoma-specific immunogenicity/immune-evasion context in the relevant discussion (to better connect the conceptual figure to melanoma biology).

I have also updated the Figure 1 legend accordingly to explicitly reflect these melanoma-specific mechanisms.

Minor Comment 3

Comment: Reduce frequent approximate expressions by providing specific numerical values where available.

Response:
I agree and have added/retained concrete ranges where appropriate (e.g., primary resistance rates to PD-1–based therapy), to reduce vagueness while maintaining accuracy across studies.

Minor Comment 4

Comment: For therapies with limited/negative outcomes (PARP inhibitors, metabolic/epigenetic targets), emphasize lack of definitive efficacy.

Response:
I have revised these sections to more explicitly state the current lack of definitive efficacy and to clarify that these remain investigational strategies in melanoma.

Minor Comment 5

Comment: In guideline section, concisely compare nuances among NCCN/ESMO/ASCO.

Response:
I thank the Reviewer for their thoughtful comment. Accordingly, I have added a concise comparison paragraph summarizing shared principles and differences in presentation style/strength-of-recommendation framing across NCCN, ESMO, and ASCO, aiming to improve readability for an international audience.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This review summarizes the main types of therapies currently used in clinical practice and discusses promising novel approaches under development. But there are still some issues that need to be clarified and discussed. Major concerns are as follows:

1. Drug resistance is a major clinical challenge in melanoma. The authors should more comprehensively address molecular mechanisms underlying resistance to BRAF/MEK inhibitors and immune checkpoint blockade.
2. Combination regimens are increasingly important in melanoma treatment. Please expand on rational combinations (e.g., BRAF/MEK inhibitors with immunotherapy) and discuss both efficacy gains and toxicity trade-offs.
3. It's necessary to summarize the impact of biomarkers and corresponding therapies on patient benefits.
4. Melanoma is treated largely as a single disease entity. The authors should address heterogeneity across cutaneous, acral, mucosal, and uveal melanoma, as therapeutic responses differ substantially among these subtypes.

Author Response

Comment 1

Comment: Drug resistance is a major challenge; discuss molecular mechanisms underlying resistance to BRAF/MEK inhibitors and immune checkpoint blockade more comprehensively.

Response:
I thank the Reviewer for their valuable comment. Accordingly, I have expanded the discussion on resistance, including targeted-therapy resistance and immune checkpoint blockade resistance. In particular, I have added/expanded a dedicated “Immunotherapy Resistance” subsection describing primary vs acquired resistance and mechanistic categories (antigen presentation loss, immunosuppressive microenvironment, alternative checkpoints), and have linked these to practical next-step strategies.

Comment 2

Comment: Expand on rational combinations and discuss efficacy gains vs toxicity trade-offs.

Response:
I agree. Accordingly, I have revised the combination-therapy discussion to more explicitly address the benefit–risk balance and heterogeneous trial outcomes, emphasizing that toxicity and feasibility remain key barriers despite potential efficacy gains.

Comment 3

Comment: Summarize the impact of biomarkers and corresponding therapies on patient benefits.

Response:
I thank the Reviewer for their thoughtful comment. Accordingly, I have strengthened the biomarker section’s clinical utility by stratifying biomarkers based on implementation level and decision impact (clinically actionable vs prognostic vs exploratory) to clarify where biomarkers directly change therapy selection versus where they inform risk stratification or monitoring.

Comment 4

Comment: Address heterogeneity across cutaneous, acral, mucosal, and uveal melanoma.

Response:
I agree and have added explicit subtype-based distinctions in biology and therapeutic responsiveness, including actionable targets and practical treatment implications for acral/mucosal melanoma and the distinct systemic-therapy landscape in uveal melanoma.

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

Altogether the work presented in this manuscript by H. Kato summerizes timely contribution with interesting, important and novel data reviewing the recent treatment approaches of human melanoma. It provides also new insight into the novel potential improved therapies of this type of cancer including ongoing challenges such as drug resistance, side effectss and future research directions.

The manuscript contains a valuable collection of data which were generated from a fairly thorough scientific literature search.

In general, the manuscript is well written and provides a lot of interesting data supported by several recently published clinical studies and other novel promising approaches. In the well structured and designed manuscript several future research directions were also mentioned. Overall, the manuscript provides further support for novel therapeutic approaches and opens new avenues in drug development and therapeutic strategies of the disease.

In conclusion the manuscript is undoubtedly interesting and well written and the conceptual advance is pretty high thus it is a welcome addition to the literature.

  

Author Response

Response:

We sincerely thank the reviewer for the highly positive and encouraging evaluation of our manuscript. We appreciate the recognition of the timeliness, clinical relevance, and conceptual advancement of this narrative review, as well as the acknowledgment of our comprehensive literature search. We also appreciate the emphasis placed on ongoing challenges, such as drug resistance, adverse events, and future research directions.

In response to the reviewers’ feedback, we have strengthened the clarity and clinical applicability of the revised manuscript by refining the discussion of the following:

(i) the mechanisms and clinical implications of resistance to immune checkpoint inhibitors and targeted therapy;

(ii) the feasibility and toxicity considerations for emerging combination strategies; and

(iii) the subtype-specific differences across cutaneous, acral, mucosal, and uveal melanoma.

We have also provided a more structured presentation of clinically actionable versus exploratory biomarkers. We believe these refinements improve the balance and translational utility of the review while maintaining its comprehensive scope.

Thank you again for your thoughtful comments and for considering our work a valuable addition to the literature.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all of my concerns about this work. I suggest accepting this revision in its present form.