Introduction to Neoadjuvant Therapy for Melanoma
Neoadjuvant therapy is changing how we treat melanoma, offering big benefits over traditional adjuvant treatments alone. At the MOASC/ANCO Immuno-Oncology Symposium on September 6, 2025, Dr. Katy K. Tsai, MD, shared key insights. She serves as Associate Professor of Clinical Medicine and Medical Director of the Melanoma & Skin Cancer Program at the University of California, San Francisco. According to her, giving immunotherapy before surgery—while the tumor remains—helps the immune system recognize more tumor-specific antigens. This leads to a stronger, more varied response, which is a major advantage.
Why Neoadjuvant Therapy Works
The main benefit of this approach is its ability to boost immune activation. As Dr. Tsai noted, having the tumor present during treatment releases more antigens, strengthening the body’s defense. For example, the OpACIN trial (Phase 1) showed this effect clearly. It found a 4x increase in neoantigen-specific T-cell clones in the neoadjuvant group compared to the adjuvant group (median clones: ~30-50 vs. ~10-20). Additionally, pooled data from later trials, led by the International Neoadjuvant Melanoma Consortium (INMC), supports shorter neoadjuvant periods (e.g., 6-12 weeks) paired with adjuvant therapy. This often reduces total treatment time compared to adjuvant-only plans. For instance:
- Blank (OpACIN-neo, IT): 6 weeks neoadjuvant, no adjuvant
- Huang (IT): 3 weeks neoadjuvant, 51 weeks adjuvant
- Amaria (IT): 12 weeks neoadjuvant, 26 weeks adjuvant
These findings show how neoadjuvant therapy can improve results while possibly cutting exposure time.
How Pathologic Response Predicts Success
A key point from Dr. Tsai’s talk is the link between pathologic response and recurrence-free survival (RFS). Major pathologic response (MPR), defined as less than 10% viable tumor, strongly predicts better long-term outcomes. Pooled data from 184 patients revealed:
- pCR (0% viable): 100% RFS at 33 months
- near-pCR (>0 to ≤10% viable): 93% RFS
- pPR (>10 to ≤50% viable): 89% RFS
- pNR (>50% viable): 50% RFS (log-rank P<0.001)
Moreover, patients achieving MPR, especially complete response, often stay disease-free for years, nearing 100% in some studies. This makes MPR a vital marker for success.
Major Trials: SWOG 1801 and NADINA
Dr. Tsai discussed key trials that prove neoadjuvant therapy’s edge.
- SWOG 1801 (Phase 2): This compared neoadjuvant-adjuvant pembrolizumab (3 cycles before surgery + 15 after) to adjuvant-only (18 cycles after surgery). The 2-year event-free survival (EFS) was 72% for neoadjuvant vs. 49% for adjuvant (P=0.004).
- NADINA (Phase 3): This pitted neoadjuvant nivolumab + ipilimumab (2 courses) against adjuvant nivolumab. The 1-year EFS was 83.7% vs. 57.2% (HR 0.32, P<0.001). For those achieving MPR, no adjuvant was needed; partial responders got extra therapy.
These results highlight how neoadjuvant methods lower recurrence risk more effectively.
Open Questions in Neoadjuvant Therapy for Melanoma
Dr. Tsai also tackled ongoing challenges:
What’s the Best Drug Regimen?
FDA-approved options include:
| Regimen | N | Stage | Duration | MPR | 1-yr EFS | 2-yr EFS | Toxicity ≥G3 |
|---|---|---|---|---|---|---|---|
| PEMBRO¹ (Huang) | 27 | IIIB-D, IVA | 3 wk | 30% | 63% | 60% | 22% |
| PEMBRO² (S1801) | 89 | IIIB-D, IVA | 9 wk | 51% | 72% | 72% | 14% |
| IPI/NIVO³ (NADINA) | 212 | IIIB-D | 6 wk | 59% | 84% | — | 30% |
| NIVO/RELA⁴ | 30 | IIIB-D, IVA | 8 wk | 63% | 90% | 81% | 0% neo; 26% adj |
| IPI3/NIVO1⁵ (C-IT) | 22 | IIIB/C, IV | 3 wk | 59% | — | — | 9% |
Newer drugs, like PEMBRO/TLR4* (79% MPR, 89% 1-yr EFS), show promise with lower toxicity.
Can We Reduce Surgery and Adjuvant Therapy?
Yes, in some cases. The PRADO trial found MPR patients (no therapeutic lymph node dissection, TLND) had a 93% 24-mo RFS. Three-year follow-up from OpACIN-neo/PRADO confirms TLND can be skipped in MPR (96% vs. 93% RFS with/without TLND). Adjuvant therapy boosts pNR survival (77% vs. 35%). However, partial response (pPR) cases vary, needing more research. The upcoming MSLT-III trial will compare index lymph node (ILN) vs. TLND after neoadjuvant treatment.
What About Pathology Standards?
Standardize reporting using % remaining viable tumor (RVT) as a continuous measure. High agreement between local and central reviews ensures scalability. Properly annotating specimens is essential for accuracy.
Is It Suitable for Early Stages (IIB/C)?
The EA6194 trial tested pembrolizumab in Stage IIB/C, showing no surgical delays, 14% ≥Gr3 immune-related adverse events (irAEs), and a reduced sentinel lymph node (SLN) positivity rate in IIC (23.5% vs. historical 40%, P=0.0499). Still, longer follow-up and better selection tools are needed.
Summary and Next Steps
Neoadjuvant therapy for melanoma offers better outcomes with possible reductions in surgery and adjuvant use. However, the best regimens and early-stage use need more study. Dr. Tsai stressed the value of current options while calling for data from trials like MSLT-III.
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