Melanoma management in 2025: from immunotherapy to pregnancy

The melanoma session at EADV 2025 highlighted both consolidated practices and the next frontiers in care.

Immunotherapy and targeted therapy

Prof. Dr. Nikolas Haas (Woolloongabba, Australia) reminded the audience how radically melanoma therapy has changed since 2011. Before the approval of immune checkpoint inhibitors (ICIs) and targeted agents, dacarbazine provided minimal benefit, with median survival of only months. The discovery of BRAF mutations (Davies et al., Nature, 2002) led to the development of BRAF inhibitors, later combined with MEK inhibitors, which produced rapid responses but were hindered by resistance and characteristic cutaneous toxicities such as squamous cell carcinoma and keratoacanthoma.

The advent of immune checkpoint blockade transformed outcomes. Anti-CTLA-4 (ipilimumab) and PD-1 inhibitors (nivolumab, pembrolizumab) introduced the concept of the “tail of the survival curve,” with subsets of long-term survivors. More recently, adjuvant and neoadjuvant applications of ICIs have delivered event-free survival (EFS) rates approaching 70% in selected cohorts, underscoring the curative potential of immune modulation.

Yet challenges remain. Many patients relapse due to primary or acquired resistance. Prof. Haas underlined the importance of tumor microenvironment heterogeneity, the contrast between “hot” inflamed tumors and “cold” immune-excluded ones. Experimental strategies are exploring how to re-sensitize resistant tumors. Preclinical data with proteasome inhibitors such as bortezomib combined with ICIs suggest that immune evasion may be reversible, although translation into the clinic is still pending.

Adjuvant and neoadjuvant therapies

MD, PhD Simone Ribero (Turin, Italy) focused on how timing of systemic therapy can reshape outcomes. Neoadjuvant immunotherapy is gaining traction, offering both tumor shrinkage and immune priming before surgery.

The SWOG S1801 trial with pembrolizumab compared neoadjuvant plus adjuvant treatment versus adjuvant alone, showing an EFS of 72% vs 49%. The NADINA trial tested nivolumab plus ipilimumab in the neoadjuvant setting, reporting EFS 83% vs 57% compared to standard therapy, with major pathological responses (MPR) around 60%. In some cases, patients achieving complete response were spared adjuvant therapy altogether.

Other approaches include intralesional immunotherapy. The DARUMUN study reported a 1-year relapse-free survival of 61% vs 46%, suggesting that local therapy can enhance systemic control. Conversely, the NEO-TIM trial failed to meet its primary endpoint, underlining that not all neoadjuvant combinations translate into clinical benefit.

In the adjuvant space, the evidence base continues to expand:

Stage IIIA remains a grey zone, with marginal benefit from adjuvant therapy. ESMO guidelines recommend careful selection rather than routine treatment, pointing to a future role for biomarkers in patient stratification.

Cellular therapy

Prof. Dr. Lukas Flatz (Tübingen, Germany) provided a forward-looking overview of cellular therapies. The pioneering concept of tumor-infiltrating lymphocytes (TILs) dates back to Rosenberg’s NEJM paper in 1988. Today, lifileucel, an autologous TIL therapy, has been approved by the FDA and EMA for advanced melanoma after progression on checkpoint blockade. Phase III trials have demonstrated superiority over ipilimumab in progression-free survival, re-establishing enthusiasm for cell-based strategies.

Beyond TILs, engineered T-cell receptor (TCR) therapies targeting melanoma antigens such as PRAME and gp100 have entered early clinical trials (Nat Med, 2024), showing safety and preliminary efficacy. Even more personalised approaches using neoantigen-specific T cells have shown proof-of-concept activity, though technical complexity remains high.

CAR-T cells, so successful in hematologic malignancies, are still in preclinical development for melanoma. Early work targeting TRP1 has shown promise in rare melanoma subtypes. Flatz highlighted that the future lies in combinations—integrating checkpoint inhibitors with TILs, TCRs or CAR-Ts—to exploit synergy between systemic immune activation and antigen-specific responses.

Special focus: melanoma in pregnancy

Finally, MD Marek Pásek (Prague, Czech Republic) addressed the delicate scenario of melanoma during pregnancy (PEM, pregnancy-associated melanoma). Defined as melanoma diagnosed during pregnancy or up to one year postpartum, PEM raises diagnostic and therapeutic challenges.

Physiological pigmentary changes of pregnancy can complicate dermoscopic assessment, but ABCDE criteria remain valid. Surgery, including biopsy and wide local excision, is safe in all trimesters. Sentinel lymph node biopsy can be performed after the first trimester using radiocolloid, though blue dyes should be avoided due to risk of anaphylaxis and teratogenicity.

Epidemiologically, melanoma represents around 30% of all malignancies in pregnancy, with an estimated incidence of 1 in 2200 pregnancies. Prognostic data are conflicting: earlier studies suggested worse outcomes, but more recent meta-analyses do not confirm a significant adverse effect of pregnancy on melanoma survival.

Imaging options are limited: ultrasound and MRI without gadolinium are safe, whereas PET/CT should be avoided. Systemic therapies (ICIs, BRAF/MEK inhibitors) are contraindicated during pregnancy due to teratogenicity and are deferred until after delivery. Rare but clinically significant are cases of placental or neonatal metastases, warranting careful neonatal monitoring if maternal metastases are present.

A field in constant evolution

The session underscored how melanoma management continues to evolve on multiple fronts. Immunotherapy and targeted agents have rewritten survival curves but face the challenge of resistance. Neoadjuvant and adjuvant trials are reshaping the timing of systemic therapy, offering hope for more durable cures. Cellular therapies are entering clinical practice, promising personalised options for refractory disease. Pregnancy remains a special setting demanding multidisciplinary coordination and nuanced decision-making.

For dermatologists, the take-home message is clear: melanoma care in 2025 requires mastery not only of systemic drugs but also of timing, patient selection, and integration with surgery, imaging and supportive care.

Sources and further reading
  1. Haas N. Immunotherapy and targeted therapy. Melanoma session (Session ID D2T05.2A), EADV Congress 2025, Paris/Virtual, 18 Sept 2025, 10:15–10:35 CEST.
  2. Ribero S. Adjuvant and neoadjuvant therapies. Melanoma session (Session ID D2T05.2B), EADV Congress 2025, Paris/Virtual, 18 Sept 2025, 10:35–10:55 CEST.
  3. Flatz L. Cellular therapy. Melanoma session (Session ID D2T05.2C), EADV Congress 2025, Paris/Virtual, 18 Sept 2025, 10:55–11:15 CEST.
  4. Pásek M. Special focus: pregnancy. Melanoma session (Session ID D2T05.2D), EADV Congress 2025, Paris/Virtual, 18 Sept 2025, 11:15–11:35 CEST.
  5. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54. doi:10.1038/nature00766.
  6. Amaria RN, Postow MA, Burton EM, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. N Engl J Med. 2022;386(9):813-23. doi:10.1056/NEJMoa2114920.
  7. Rozeman EA, Hoefsmit EP, Reijers ILM, et al. Neoadjuvant ipilimumab plus nivolumab in resectable stage III melanoma. N Engl J Med. 2023;389(2):111-21. doi:10.1056/NEJMoa2301963.
  8. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage IIB or IIC melanoma. N Engl J Med. 2022;387(14):1223-34. doi:10.1056/NEJMoa2208685.
  9. Ascierto PA, Del Vecchio M, Mandalà M, et al. Adjuvant nivolumab versus placebo in resected stage IIB–C melanoma. N Engl J Med. 2023;389(25):2333-44. doi:10.1056/NEJMoa2310916.
  10. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377(19):1813-23. doi:10.1056/NEJMoa1708539.
  11. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med. 1988;319(25):1676-80. doi:10.1056/NEJM198812223192527.
  12. Stadtmauer EA, Fraietta JA, Davis MM, et al. Engineered T cell receptor therapy for melanoma. Nat Med. 2024;30(2):223-34. doi:10.1038/s41591-023-02676-7.