Adjuvant Therapy for High-Risk Stage II Cutaneous Melanoma: Insights and Future Directions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for providing this excellent summary of the available studies results and ongoing studies. It fully covers the topic of EBM in perioperative treatment in melanoma stage II patients. I would consider adding some more recommendations, for example in bullet points, for clinicians, and adding more recommendations for observation in case the patients are not treated perioperatively. Generally despite safety profile is shortly described, I would add more detailed information to show that despite of interesting results there is still a risk of toxicities which may impact the patients life. Not required but recommended. 

Author Response

Comments 1: "I would consider adding some more recommendations, for example in bullet points, for clinicians, and adding more recommendations for observation in case the patients are not treated perioperatively"

Response 1: We thank the reviewer for this valuable suggestion. In response, we expanded the Conclusions section by adding a brief discussion on the importance of long-term clinical and radiologic surveillance in patients who are not selected for adjuvant systemic therapy, emphasizing the role of follow-up strategies for early detection of disease recurrence.

Comments 2: "despite safety profile is shortly described, I would add more detailed information to show that despite of interesting results there is still a risk of toxicities which may impact the patients life. Not required but recommended."

Response 2: We thank the reviewer for this important observation. In the revised manuscript, we further emphasized the importance of appropriate prognostic stratification in order to avoid unnecessary exposure to adjuvant immunotherapy and its potentially irreversible toxicities (pages 9–10). A detailed description of treatment-related and immune-related adverse events associated with adjuvant anti-PD-1 therapy was already included in the sections describing the KEYNOTE-716 and CHECKMATE-76K trials (pages 3–4), and these considerations are also recalled in the Conclusions section.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Adjuvant Therapy for High-Risk Stage II Cutaneous Melanoma: Insights and Future Directions” by Federico Pravisano et al. provides an update on clinical trials assessing adjuvant therapy of cutaneous melanoma (SKCM) patients, with emphasis on immunotherapy-based approaches for stage II patients. The manuscript is adequately organized, with sections describing current trials (section 2), future perspectives (section 3), the use of BRAF/MEK inhibitors (section 4) and the tools for reliable risk stratification and identification of responders to adjuvant approaches (section 5). The interest of the topic is clear, since, as the authors highlight, almost 50 % SKCM-related deaths occur in patients diagnosed at early stage II, even though this stage comprises only about 15 % of all diagnosed SKCM. Therefore, a significant fraction of stage II melanomas should be classified as high-risk, and the authors propose extending adjuvant treatment to these patients, while emphasizing the need for careful selection of potential responders due to the inherent risks of these therapies. The manuscript describes in detail the clinical trials protocols, the adverse effects and the overall results achieved, in terms of objective clinical benefits for patients. Although these are interesting topics, their novelty is limited and short-lived. On the other hand, the coverage of the highly relevant matter of identifying optimal candidates for adjuvant therapy and useful biomarkers for risk stratification is incomplete and less convincing. This may compromise the citability of the work.

Major points

1- To increase the readability of the manuscript, the current criteria for SKCM staging should be clearly presented before proceeding to the description of clinical trials. This is important because readers interested in SKCM from more basic perspectives may not be familiar with subtle differences within stage II. In particular, the authors should clearly establish the criteria to distinguish high-risk versus low-risk stage II, since selection of high-risk stage II SKCM patients is a key factor in determining their eligibility for (neo)adjuvant therapies.

2- Section 5 of the manuscript is highly relevant, as it describes how the best profiles of high-risk stage II SKCM patients could be identified. This part of the manuscript should be a major focus of the manuscript, owing to its title, and, consequently, should be strengthened, since, the current version it is basically restricted to ctDNA and implement platforms. Therefore, the authors should supplement it with clear descriptions of the clinical characteristics, on one hand, and potential emerging molecular signatures as biomarkers for risk stratification of low-grade SKCM patients, on the other. In particular, the studies by Dixon et al (J Eur Acad Dermatol Venereol 2025); Sánchez-Beltrán et al (Int J Mol Sci, 2025); Garg et al (Nat Commun 2021) and Karin van den Hurk et al (J Invest Dermatol 2026) should be at least briefly mentioned.

Minor points

1- To improve readability, paragraph breaks should be used more extensively, particularly in long sections such as section 5.

2- The authors mention an apparent inconsistency related to the risk of patients diagnosed as stage II compared to stage III SKCM, in terms of outcome rates. Indeed, they report that the outcomes are worse for patients bearing tumors, a priori considered less advanced or aggressive. This apparent paradox should be discussed, and possible explanations, even if speculative, should be provided.

3- Page 3, line 99, the authors mention “melanoma subtypes” but do not specify the criteria. Are they considering molecular, anatomical or other subtypes? Please specify.

Author Response

Comments 1: "To increase the readability of the manuscript, the current criteria for SKCM staging should be clearly presented before proceeding to the description of clinical trials. This is important because readers interested in SKCM from more basic perspectives may not be familiar with subtle differences within stage II. In particular, the authors should clearly establish the criteria to distinguish high-risk versus low-risk stage II, since selection of high-risk stage II SKCM patients is a key factor in determining their eligibility for (neo)adjuvant therapies" 

Response 1: We thank the reviewer for this valuable suggestion. In the revised Introduction section (page 2), we clarified the AJCC 8th edition staging criteria for stage II melanoma and more clearly detailed the differences between low-risk and high-risk stage II disease. In particular, we specified the clinicopathological features defining stage IIB/IIC melanoma and their relevance for patient selection for (neo)adjuvant treatment strategies.

Comments 2: "Section 5 of the manuscript is highly relevant, as it describes how the best profiles of high-risk stage II SKCM patients could be identified. This part of the manuscript should be a major focus of the manuscript, owing to its title, and, consequently, should be strengthened, since, the current version it is basically restricted to ctDNA and implement platforms. Therefore, the authors should supplement it with clear descriptions of the clinical characteristics, on one hand, and potential emerging molecular signatures as biomarkers for risk stratification of low-grade SKCM patients, on the other. In particular, the studies by Dixon et al (J Eur Acad Dermatol Venereol 2025); Sánchez-Beltrán et al (Int J Mol Sci, 2025); Garg et al (Nat Commun 2021) and Karin van den Hurk et al (J Invest Dermatol 2026) should be at least briefly mentioned."

Response 2: We thank the reviewer for this insightful comment. In the revised manuscript, Section 5 was substantially expanded (pages 8–9) in order to strengthen the discussion on patient selection for adjuvant therapy in stage II melanoma. In addition to ctDNA-based approaches, we incorporated a broader overview of emerging clinicopathological, molecular, and epigenetic prognostic models that may improve risk stratification and help identify patients most likely to benefit from adjuvant treatment. Specifically, we added discussion of the studies by Dixon et al., Sánchez-Beltrán et al., Garg et al., and van den Hurk et al., as suggested by the reviewer.

Comments 3: " We thank the reviewer for this suggestion. To improve readability, the manuscript was revised with additional paragraph breaks and clearer subdivision of concepts, particularly within Section 5."

Response 3: We thank the reviewer for this suggestion. To improve readability, the manuscript was revised with additional paragraph breaks and clearer subdivision of concepts, particularly within Section 5.

Comments 4: "The authors mention an apparent inconsistency related to the risk of patients diagnosed as stage II compared to stage III SKCM, in terms of outcome rates. Indeed, they report that the outcomes are worse for patients bearing tumors, a priori considered less advanced or aggressive. This apparent paradox should be discussed, and possible explanations, even if speculative, should be provided."

Response 4: We thank the reviewer for this important observation. In the revised Introduction section, we expanded the discussion regarding the apparent prognostic paradox between stage IIB/IIC and stage IIIA melanoma. Specifically, we discussed the potential role of the biological heterogeneity of melanoma and the limitations of a purely anatomy-based staging system. We also highlighted that patients with stage IIIA melanoma may have a relatively low nodal tumor burden and more favorable primary tumor characteristics, whereas some patients classified as stage II may harbor occult micrometastatic disease not detected at diagnosis, potentially contributing to their unexpectedly poor outcomes.

Comments 5: "Page 3, line 99, the authors mention “melanoma subtypes” but do not specify the criteria. Are they considering molecular, anatomical or other subtypes? Please specify"

Response 5: We thank the reviewer for this observation. In the revised manuscript, we clarified that the term “melanoma subtypes” referred to histopathologic melanoma subtypes.

Reviewer 3 Report

Comments and Suggestions for Authors

Overall a very nice review on the current status of therapy for melanoma patients with stage II disease.  The authors have organized the review well and covered important topics.  This is well written and overall my comments are minor.

For the future perspectives section I would consider starting with the V940 data since there is promising phase II data for stage III and a trial that did complete enrollment and will have a readout in this space.  Would include TIGIT and Lag3 next.

In the neoadjuvant space there is some interests in looking at injectable drugs (TLR9 for example) in thick primary melanomas that should be mentioned although the data remains pretty thin in this space.

The authors bring up SLN biopsy and the continued need for this at the end of the conclusions without really including a section discussing this.  I would consider moving this earlier with a little expansion and using the end of the conclusions to discuss future directions and next steps for the field.

Author Response

Comments 1: "For the future perspectives section I would consider starting with the V940 data since there is promising phase II data for stage III and a trial that did complete enrollment and will have a readout in this space.  Would include TIGIT and Lag3 next."

Response 1: We thank the reviewer for this valuable suggestion. In the revised manuscript, we modified the structure of Section 3 by reordering the discussion of future therapeutic strategies. Specifically, we now begin with the description of the KEYNOTE-942 study evaluating the V940 mRNA vaccine plus pembrolizumab, given the promising results in this setting. The discussion of TIGIT- and LAG-3–targeting strategies was subsequently presented.

Comments 2: "In the neoadjuvant space there is some interests in looking at injectable drugs (TLR9 for example) in thick primary melanomas that should be mentioned although the data remains pretty thin in this space."

Response 2:  We thank the reviewer for this insightful suggestion. In the revised manuscript, we expanded the section on neoadjuvant approaches (page 6) by including discussion of the INTRIM trial evaluating the intradermal TLR9 agonist tilsotolimod in patients with resectable pT3–T4 cN0 melanoma. We highlighted the reduction in sentinel lymph node positivity and the encouraging relapse-free survival results observed with this injectable neoadjuvant strategy.

Comments 3: "The authors bring up SLN biopsy and the continued need for this at the end of the conclusions without really including a section discussing this.  I would consider moving this earlier with a little expansion and using the end of the conclusions to discuss future directions and next steps for the field."

Response 3: We thank the reviewer for this important suggestion. In the revised manuscript, we moved and expanded the discussion regarding the role of sentinel lymph node biopsy (SLNB) from the "Conclusions" section to Section 5 (“Identifying the Optimal Candidate for Adjuvant Therapy in Stage II Melanoma”). Specifically, we discussed the current prognostic value of SLNB in high-risk stage II melanoma and its role in therapeutic decision-making, particularly in patients with BRAF-mutated melanoma who may become eligible for adjuvant targeted therapy if occult nodal involvement is detected. We also highlighted in the Conclusions section, as suggested by the reviewer, that ongoing clinicopathological and molecular models may in the future help identify selected low-risk patients in whom SLNB could potentially be omitted.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors addressed adequately most of the objections raised in the first revision round. Accordingly, the current version is significantly improved.