Three-year NADINA data showed near-complete responders doing worse than partial responders. I think the explanation may be surgical — and nobody raised it.
Oct 25, 2026 · @Sajeve thomas
A result that should not happen
The three-year NADINA update presented at ESMO was, on its face, a triumph. Neoadjuvant ipilimumab plus nivolumab versus adjuvant nivolumab in macroscopic stage III melanoma: 3-year EFS 72.9% vs 50.0% (HR 0.42), 3-year DMFS 75.3% vs 57.4% (HR 0.46). Both p<0.0001. Every subgroup benefits.
Then look inside the neoadjuvant arm, at outcomes by depth of pathologic response:
| Pathologic response | 3-year RFS | 3-year DMFS |
|---|---|---|
| Complete response | 91.3% | 93.6% |
| Near-complete response | 62.3% | 69.3% |
| Partial response | 87.5% | 87.5% |
| Non-response | 43.0% | 39.4% |
Read that again. Patients with a deeper response did substantially worse than patients with a shallower one. Near-CR — by definition 1–10% viable tumor remaining — trailed partial responders by 25 percentage points in recurrence-free survival.
This is not supposed to happen. Depth of pathologic response is the most reliable prognostic variable we have in resectable melanoma, and it is supposed to be monotonic. In every prior neoadjuvant trial, near-CR patients did essentially as well as complete responders.
I asked about this in the hallways afterward. The honest summary of the responses I got was a pause, and then some version of huh — that might be it.
What NADINA did differently
There is one design feature that separates NADINA from every neoadjuvant melanoma trial that preceded it, and it is surgical.
NADINA mandated therapeutic lymph node dissection in every patient, in both arms.
In PRADO and OpACIN-neo, the approach was different. The largest involved node was marked before treatment, removed after neoadjuvant therapy, and if the patient had a major pathologic response, the rest of the basin was left alone. No completion dissection.
So compare the two trials on the one group in question:
| PRADO / OpACIN-neo | NADINA | |
|---|---|---|
| Near-CR: nodal surgery | Index node only, basin preserved | Full total lymph node dissection |
| Near-CR: adjuvant therapy | None | None |
| Near-CR: outcome | Comparable to complete responders | Markedly worse |
Same response category. Same decision to withhold adjuvant therapy. Different operation, different result.
The hypothesis: we removed the engine
Here is why I think this is more than a coincidence.
The entire rationale for neoadjuvant therapy is that you cannot prime an immune response against a tumor you have already thrown away (the baby). Treat first, while the antigen is still in the body, and you generate tumor-specific T-cell clones, expand them, and release them systemically. Remove the tumor first and give the same drugs afterward, and you are vaccinating against something that is no longer there. That is the finding NADINA was built on, and the three-year data confirm it emphatically.
Now apply the same logic one level deeper.
The tumor-draining lymph node is not a passive filter. It is increasingly understood as the site where tumor-specific stem-like T cells are maintained — the reservoir that replenishes the effector pool and sustains a checkpoint-driven response over time. It is where priming happens and where it keeps happening.
So consider the near-complete responder. Immunotherapy has worked. A robust local and systemic T-cell response has been generated. A small amount of viable tumor remains — and so, presumably, does an active immune population in that basin still engaged in clearing it.
And then we resect the entire basin.
In PRADO, those nodes stayed in. The response had somewhere to live. Patients did as well as complete responders.
In NADINA, they came out — and these patients received no adjuvant therapy either, because near-CR counts as major pathologic response. No reservoir, and no drug to compensate for its loss.
We did not throw out the baby with the bathwater this time. We gave the therapy first, exactly as we have learned to. But then we may have thrown out the nursery where this was not done on previous studies where the index node was removed and if near complete response, no further surgery or dissection.
Where I could be wrong
I want to be clear about the limits of this.
This is a cross-trial comparison. Different trials, different populations, different eras. Near-CR subgroups are small in both NADINA and PRADO. Nobody randomized anyone to basin preservation.
There is a competing explanation, and it is simpler. Within NADINA, near-CR and partial responders both received full dissection. What actually differs between them is adjuvant therapy: near-CR patients got none, partial responders got eleven cycles of nivolumab or 46 weeks of dabrafenib/trametinib. Patients with residual disease who received nothing did worse than patients with more residual disease who received something. That alone could account for it.
But notice that the simpler explanation does not account for PRADO, where near-CR patients also received no adjuvant therapy and did fine. The variable that changed between trials is the surgery.
The most likely answer may be an interaction: basin removal plus no adjuvant therapy is a double hit, and partial responders were rescued by the drug they received.
What I would consider Monday
If this hypothesis holds, it carries real consequences — and some of them are actionable now.
Enroll on MSLT-III. The trial is asking precisely this question: completion lymph node dissection versus index node resection alone. If you have a patient who qualifies, that is where they belong — and the NADINA signal is a reason to prioritize enrollment, not a reason to wait for someone else to answer it.
Off trial, for a near-complete responder, I would want a serious conversation about a PRADO-style approach: mark the index node, remove it, and reserve completion dissection for partial and non-responders. We already know from MSLT-II and DeCOG-SLT that completion dissection does not improve melanoma-specific survival. If it may also be removing the immune reservoir that a successful neoadjuvant response depends on, the calculation shifts from neutral to negative.
For near-CR patients who have already had a full dissection, I would think hard about whether “no adjuvant therapy” is still the right call. NADINA’s own data suggest that group is less protected than we assumed. Serial ctDNA monitoring and an honest conversation about continuing immunotherapy belong on the table.
And then the broader principle. Melanoma surgery has been de-escalating for three decades, and more surgery has rarely won — not in MSLT-II, not in DeCOG-SLT. If the systemic immune response is what actually determines outcome, then the operation’s job is to remove what the immune system could not, and nothing beyond that. That argues for reserving completion dissection for patients who lack a robust response, and leaving the basin alone in patients whose immune system is visibly doing the work.
Provocative? Certainly. But the evidence against routine TLND keeps accumulating, and this may be the strongest signal yet — arriving, as these things tend to, in a subgroup analysis nobody designed to answer the question.
This reflects notes taken during presentations at ESMO Congress 2026 in Madrid and my own interpretation of publicly presented data. It is educational and is not medical advice, and the central hypothesis here is exactly that — a hypothesis, not an established finding. Treatment decisions belong with your own oncology and surgical team.
Disclosure: Dr. Thomas is a principal investigator on cellular therapy and immunotherapy trials in melanoma. All data cited are drawn from public conference presentation and published reports.
Dr. Sajeve Thomas is a distinguished medical professional and a compassionate guide in the field of oncology. With over a decade of dedicated experience as a board-certified medical oncologist/internal medicine specialist, Dr. Thomas has become a trusted expert in the treatment of melanoma, sarcoma, and gastrointestinal conditions. He brings a wealth of expertise to the complex and challenging world of oncology.
Disclosures:
Dr. Thomas serves as a speaker for BMS, Merck, Ipsen, Natera, Immunocore, Pfizer, Sun Pharma, SpringWorks. He also receives industry grants in support of numerous clinical trials.
Patient cases described in this post are composites and have been altered — including but not limited to diagnosis specifics, demographics, timeline, and clinical details — to protect patient privacy and confidentiality. No case represents an actual, identifiable patient, and any resemblance to a specific individual is coincidental. Clinical scenarios involving other providers have similarly been altered and are presented for educational purposes only, not as a representation of any specific person’s practice. This post is for general educational purposes and does not constitute medical advice; it should not be used to guide individual treatment decisions. This article is for education and general information only. It is written about an anonymized case, shared with permission, and it is not personal medical advice. The individual described is not a patient of the author, is not treated in the United States or at the author’s institution, and no doctor–patient relationship is created by reading this. Statistics and treatment options are summarized from the current oncology literature and evolve quickly.
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