Melanoma Treatment Plateau: Why LAG-3 is Now the Key to Unlocking Immunotherapy’s Full Potential
Despite the remarkable advances in immunotherapy, a significant portion of melanoma patients still face recurrence even after successful surgery. Recent data from the RELATIVITY-098 trial, presented at ASCO 2025 and ESMO Congress 2025, revealed that adding relatlimab to nivolumab didn’t significantly improve recurrence-free survival in stage III/IV resected melanoma. This isn’t a setback, but a crucial turning point – one that highlights the critical role of LAG-3 and signals a new era of precision in cancer treatment.
The Relatlimab Results: A Deeper Dive
The RELATIVITY-098 trial aimed to build on the success of anti-PD-1 therapies like nivolumab by combining it with relatlimab, an anti-LAG-3 antibody. The rationale was sound: blocking both PD-1 and LAG-3, two immune checkpoints, should unleash a more robust anti-tumor response. However, the trial’s outcome was unexpected. While generally well-tolerated, the combination didn’t demonstrate a statistically significant benefit in recurrence-free survival compared to nivolumab alone. This outcome underscores a critical point: simply adding more immune checkpoint inhibitors isn’t a guaranteed path to success. The absence of tumor-infiltrating LAG3+ T cells appears to be a key factor in why some patients don’t respond.
Why LAG-3 Matters: Beyond PD-1
PD-1 and LAG-3 are both immune checkpoints, but they operate differently. PD-1 primarily regulates T cell activity after they’ve been activated, preventing them from attacking healthy cells. LAG-3, however, acts earlier in the process, influencing T cell activation and proliferation. It’s often expressed on regulatory T cells (Tregs), which suppress the immune response. Blocking LAG-3 can therefore not only boost T cell activity but also potentially reduce the suppressive effects of Tregs. This makes LAG-3 a particularly attractive target, but only in patients whose tumors actually have these LAG3+ T cells present.
The Biomarker Breakthrough: Identifying the Right Patients
The most significant takeaway from RELATIVITY-098 isn’t the lack of overall benefit, but the correlative data showing that patients lacking tumor-infiltrating LAG3+ T cells didn’t respond to the relatlimab combination. This points to a clear need for a biomarker-driven approach. Instead of a one-size-fits-all strategy, future treatment decisions will likely hinge on identifying patients who are most likely to benefit from LAG-3 blockade. This is a paradigm shift towards personalized immunotherapy.
New Diagnostic Tools on the Horizon
Developing reliable and accessible assays to detect LAG3+ T cells within tumors is now a top priority. Several companies are already working on advanced immunohistochemistry (IHC) techniques and potentially even liquid biopsies to identify these biomarkers. Expect to see these diagnostic tools becoming increasingly available in clinical practice over the next 2-3 years. Furthermore, research is expanding to understand the specific characteristics of LAG3+ T cells – are all LAG3+ T cells equal, or are there subtypes with different predictive power?
Future Directions: Beyond Relatlimab
While relatlimab didn’t pan out as hoped in RELATIVITY-098, it doesn’t invalidate the LAG-3 target. Several other anti-LAG-3 antibodies are in development, some with potentially improved properties. Moreover, researchers are exploring novel combination strategies. For example, combining LAG-3 blockade with other immunotherapies, such as oncolytic viruses or adoptive cell therapies, could synergistically enhance anti-tumor immunity. The focus is shifting towards identifying the optimal combinations and patient populations for these approaches. Learn more about immunotherapy at the National Cancer Institute.
The Role of Neoantigens and Tumor Mutational Burden
The presence of LAG3+ T cells isn’t the whole story. Tumor mutational burden (TMB) and the number of neoantigens (mutated proteins that the immune system can recognize) also play crucial roles in immunotherapy response. Future studies will likely integrate LAG-3 biomarker data with TMB and neoantigen analysis to create even more refined predictive models. This multi-omic approach will be essential for maximizing the benefits of immunotherapy.
The RELATIVITY-098 trial, while initially appearing disappointing, has illuminated a critical path forward in melanoma treatment. The future of immunotherapy isn’t about simply adding more drugs; it’s about understanding the complex interplay between the tumor, the immune system, and individual patient characteristics. What are your predictions for the role of LAG-3 in future cancer treatments? Share your thoughts in the comments below!
