Nature Medicine | Application of Tobemstomig in Resectable Stage II Melanoma

This article explores the efficacy and safety of Tobemstomig compared to existing standard therapies in resectable stage II melanoma, offering a potential personalized neoadjuvant treatment strategy.

 

Literature Overview
The article, titled 'Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial,' published in the journal Nature Medicine, reviews and summarizes the application of neoadjuvant therapies in resectable melanoma. The study compares the efficacy and safety of Tobemstomig (anti-PD-1/anti-LAG-3 bispecific antibody), Tobemstomig plus tiragolumab (anti-TIGIT monoclonal antibody), atezolizumab plus tiragolumab, and nivolumab plus ipilimumab. Results indicate that Tobemstomig demonstrates similar pathological response rates to nivolumab plus ipilimumab but with lower toxicity, providing a safer neoadjuvant treatment option for melanoma patients.

Background Knowledge
Melanoma is a highly malignant form of skin cancer, with patients in stage III facing a high risk of recurrence. In recent years, neoadjuvant immune checkpoint inhibitor (CPI) therapies have demonstrated superior clinical outcomes in melanoma compared to adjuvant treatments. PD-1 and LAG-3 are immune checkpoint molecules frequently co-expressed on tumor-infiltrating lymphocytes (TILs). Bispecific antibodies targeting these molecules may enhance anti-tumor immune responses by simultaneously blocking multiple inhibitory signals. While nivolumab plus ipilimumab has shown high major pathological response rates (MPR) in neoadjuvant settings, their toxicity is also considerable. Therefore, identifying safer and effective neoadjuvant treatment strategies has become a focal point of current research.

 

 

Research Methods and Experiments
This study is an open-label, multicenter, randomized phase II umbrella clinical trial that enrolled 102 treatment-naïve patients with stage III melanoma. Patients were randomly assigned to receive Tobemstomig, Tobemstomig plus tiragolumab, atezolizumab plus tiragolumab, or nivolumab plus ipilimumab. The primary endpoint was the pathological response rate (pRR) assessed by independent pathological evaluation, while secondary endpoints included locally assessed pRR, RECIST-defined overall response rate (ORR), and safety. The study also evaluated the relationship between baseline tumor microenvironment (TME) biomarkers and pathological response.

Key Conclusions and Perspectives

• The pRR in the Tobemstomig group was 80.0% (32/40), compared to 77.3% (17/22) in the nivolumab plus ipilimumab group, with no statistically significant difference observed.
• The major pathological response rate (MPR) in the Tobemstomig group was 62.5% (25/40), which was lower than the 72.7% (16/22) in the nivolumab plus ipilimumab group.
• The pRR for the Tobemstomig plus tiragolumab and atezolizumab plus tiragolumab groups were 60.0% and 45.0%, respectively, both lower than the nivolumab plus ipilimumab group.
• In terms of safety, the incidence of grade 3 or higher treatment-related adverse events (TRAEs) was 2.5% (1/40) in the Tobemstomig group, compared to 22.7% (5/22) in the nivolumab plus ipilimumab group.
• Baseline CD8+ and CD3+ tumor-infiltrating T-cell density, IFNγ pathway and effector T-cell gene expression, tumor mutational burden (TMB), and preoperative circulating tumor DNA (ctDNA) were found to correlate with pathological response.
• Despite the more inflammatory TME at baseline in the nivolumab plus ipilimumab group, the Tobemstomig group demonstrated a stronger association between pathological response and biomarkers, suggesting potential applicability in specific patient populations.

Research Significance and Prospects
This study provides preliminary efficacy signals for Tobemstomig as a neoadjuvant therapy and highlights its advantage in reducing TRAE incidence. Future research is needed to validate these findings and explore how biomarker-guided personalized treatment strategies can be optimized. Additionally, the research team recommends single-cell RNA sequencing to enhance the identification of treatment-specific biomarkers.

 

 

Conclusion
In summary, Tobemstomig shows comparable pathological response rates to nivolumab plus ipilimumab in resectable stage III melanoma, but with reduced toxicity, supporting its potential as a neoadjuvant treatment option. The study also emphasizes the role of baseline TME biomarkers in predicting pathological responses, though larger studies are needed for validation. Furthermore, the research team notes that while Tobemstomig has mechanistic advantages, its clinical application still requires further optimization and validation. Future research should focus on the development of personalized treatment strategies and how biomarkers and gene expression data can be combined to enhance therapeutic efficacy.

 

Georgina V Long, Nitya Nair, Daniel Marbach, Christoph Markert, and Christian Blank. Neoadjuvant PD-1 and LAG-3-targeting bispecific antibody and other immune checkpoint inhibitor combinations in resectable melanoma: the randomized phase 1b/2 Morpheus-Melanoma trial. Nature Medicine.