Notes from Madrid — the data as presented, and my take on each
Four studies and one excellent symposium defined day one of the melanoma program. For each I have laid out what was presented, then what I think it means. The individualized mRNA vaccine results everyone is waiting for are being presented today, and I will cover those in a separate post once I have seen the data firsthand.
1. HBI-8000-303 — an oral pill added to immunotherapy
Tucidinostat plus nivolumab versus nivolumab plus placebo, 404 patients across 15 countries, as first treatment for advanced melanoma. The drug is already approved for lymphoma in China and Japan, and works by making cancer cells more visible to the immune system.
| HBI-8000 + nivolumab | Nivolumab alone | |
|---|---|---|
| Median PFS | 11.7 mo | 7.4 mo (HR 0.73, p=0.014) |
| Response rate | 41% | 32% |
| Grade 3–4 adverse events | 54.8% | 17.9% |
| Stopped for toxicity | 14% | 5% |
Overall survival is immature, 38% of patients needed a dose reduction, and no FDA submission has been filed.
My take. Credit first where it is due. Dr. Nikhil Khushalani of Moffitt presented this data, and he presented it well — clear, balanced, and straightforward about the limitations as well as the signal. He is about an hour up the road from me in Tampa, we share a number of patients, and he has long been someone I highly respect in this field.
On the data itself: interesting rather than practice-changing, for one main reason. The comparison was against nivolumab by itself, while nivolumab plus relatlimab already reaches roughly 10 months with about a third of the serious toxicity. That, not single-agent nivolumab, is the real bar.
The part I found most interesting, and where I agree with Dr. Khushalani, was in the subgroups. Patients with normal or low LDH showed notably better progression-free survival and disease control with the combination, while PD-L1 and BRAF status predicted nothing at all. If that holds up in an updated analysis, it may tell us which patients are actually worth selecting for this approach. The combination also worked poorly in patients already progressing on anti-PD-1 — which is where the drug’s mechanism suggested it should have helped most.
2. STARBOARD — targeted therapy added to immunotherapy
Encorafenib plus binimetinib plus pembrolizumab versus pembrolizumab plus placebo, in previously untreated BRAF V600-mutant advanced melanoma. Roughly 70% of patients responded, and about 54% were free of progression at two years.
The design is what makes it notable. Earlier trials — IMspire150, KEYNOTE-022, COMBI-i — all asked whether adding immunotherapy improved targeted therapy, with modest or negative results. STARBOARD reversed the question, which is the relevant one now that DREAMseq has established immunotherapy-first as the better sequence. Pfizer has described the trial as non-registrational, meaning it is not being submitted for approval.
My take. I like the design. Every earlier triplet trial asked whether adding immunotherapy improved targeted therapy; this one finally asked the question in the other direction, which is the one that matters now.
The caveat is the comparator. A BRAF-mutant patient starting immunotherapy in my practice is usually getting a doublet, not single-agent pembrolizumab, so these results are hard to map onto what most of us actually do.
Where I see this fitting is close to what I already do. For BRAF-mutant patients with brain metastases or symptomatic disease, I frequently use triplet therapy now. For most others, the preferred strategy remains induction BRAF/MEK followed by ipilimumab/nivolumab — the sandwich approach. But some patients simply cannot come off the pills: stop them and the disease moves quickly. For a patient with aggressive, fast-moving biology who is not a good candidate for ipilimumab/nivolumab, continuing BRAF/MEK and adding a PD-1 inhibitor is already my approach, and STARBOARD gives that practice some evidence behind it.
3. IOV-COM-202 — moving TIL cell therapy to the front line
TIL therapy takes the immune cells that have already found their way into a patient’s tumor, grows them into the billions in a laboratory, and gives them back. It is approved as lifileucel (Amtagvi) for melanoma that has progressed after immunotherapy. The question has been whether waiting that long is the right approach.
This was the final analysis of Cohort 1A: lifileucel plus pembrolizumab in 24 patients who had not yet received immunotherapy.
| Outcome | Result |
|---|---|
| Objective response rate | 62% |
| Complete response rate | 29% |
| Disease control rate | 83% |
| Median overall survival | Not reached at more than 4 years |
Most responses appeared by about six weeks and deepened over time. In responders, the same immune cell clones found in the laboratory product were identified in the tumor — direct evidence the infused cells were doing the work, not the pembrolizumab alone. Patients who later needed other treatments were still able to receive them.
For comparison, in patients who have already progressed on anti-PD-1, lifileucel produces roughly a 31% response rate with about 9% complete responses.
My take. I was one of the original principal investigators on this study and presented earlier results at ASCO 2024, so I am not a neutral observer — but the complete response rate is the number that matters. Using TIL earlier roughly doubled the response rate and tripled the complete response rate compared with the post-PD-1 setting, and median survival has not been reached after four years. A one-time infusion achieving that, with later treatment options preserved, is a different proposition from years of continuous therapy. The phase 3 TILVANCE-301 trial is now testing this in roughly 670 patients, and we expect to open it at AdventHealth in the coming months.
4. MIZAR-003 — the first randomized trial of TIL therapy anywhere
The hardest part of TIL therapy is not the cells. Patients receive strong chemotherapy to clear space in the immune system, then high-dose interleukin-2 to help the new cells survive — which requires close inpatient monitoring and is why the treatment exists at only a limited number of centers.
This Chinese trial tested GC101 (nolgileucel) on a deliberately stripped-down regimen: no interleukin-2 at all, low-dose lymphodepletion, fludarabine replaced by hydroxychloroquine as an immune-modulating agent, and a short low-dose course of PD-1 blockade. Ninety-eight patients whose melanoma had progressed on anti-PD-1 were randomized to TIL therapy or chemotherapy.
| GC101 TIL | Chemotherapy | |
|---|---|---|
| Response rate | 42% | — |
| Disease control rate | 72% | — |
| Median PFS | 4 mo | 1 mo |
Roughly 70% of patients had acral or mucosal melanoma — subtypes arising on the palms, soles, nail beds and internal surfaces that respond poorly to nearly everything. Side effects were substantially lower in both frequency and severity than with conventional TIL therapy. Overall survival is not mature.
My take. What makes this interesting is how much they took away and still saw activity. No interleukin-2, reduced lymphodepletion, fludarabine swapped out for hydroxychloroquine — and a 42% response rate, in a population that was roughly 70% acral and mucosal melanoma, which are the subtypes that respond poorly to nearly everything we have.
The significance is access as much as potency. This is the first randomized controlled trial of TIL therapy in late-line melanoma anywhere in the world, and it suggests the treatment may be deliverable without an ICU-capable setting — which would widen who can offer it considerably. The open question is durability: the intensive parts of conventional TIL therapy exist because they help the transferred cells survive long-term, and four months of progression-free survival does not yet tell us whether this lighter version preserves the long remissions that make TIL therapy worth doing. Survival data will settle that.
5. Metastatic uveal melanoma — a symposium worth the afternoon
Uveal melanoma is a rare cancer that starts in the eye, spreads preferentially to the liver, carries very few mutations, and responds poorly to standard checkpoint immunotherapy. Before 2022 there was no systemic therapy shown to improve survival. The afternoon symposium laid out how much that has changed.
| Approach | Key data | Status |
|---|---|---|
| Tebentafusp, for HLA-A*02:01-positive patients | Median OS 21.7 vs 16.0 mo | Approved |
| Darovasertib + crizotinib (PKC plus MET inhibition) | Median PFS 6.9 vs 3.1 mo; response 37% vs 6%, in HLA-A*02:01-negative patients | FDA submission underway |
| Hepatic perfusion + ipilimumab/nivolumab (CHOPIN) | 1-year PFS 55% vs 16%; 82% grade 3–4 toxicity | Randomized phase 2 |
| Melphalan hepatic perfusion alone (FOCUS) | Median OS 20.5 mo; 26.7 mo with low liver burden | Approved |
| PRAME-directed TCR cell therapy (anzu-cel) | Response 67%, including after tebentafusp failure | Trials ongoing |
| RP2 oncolytic virus + nivolumab | Phase 1 response 33%, median duration 22.1 mo | Randomized phase 2/3 enrolling |
Three threads are worth pulling out. Checkpoint inhibitors alone remain weak in this disease — the 6% response rate in the darovasertib trial’s control arm is the cleanest confirmation we have. Combining liver-directed therapy with systemic immunotherapy appears to be more than the sum of its parts, likely because treating the liver releases tumor antigen inside an organ that otherwise suppresses immune responses. And liver tumor burden is the most consistent predictor of benefit across every one of these datasets.
My take. No single groundbreaking dataset here — this was a symposium rather than a late-breaking session — but it was one of the most useful hours of the day. We see a fair amount of metastatic uveal melanoma in Florida practice, and the landscape has changed faster than most providers realize.
Two practical points. HLA-A*02:01 typing now belongs at the first visit, because it determines which pathway a patient is on. And these cases need a genuine multidisciplinary discussion rather than a single rule — medical oncology, interventional radiology and surgery together — because the liver-directed and systemic options now both compete and combine. For a disease that had essentially nothing a few years ago, having six credible approaches to sequence is a remarkable place to be.
Where this leaves us
Two themes ran through the day. The first is that melanoma treatment keeps moving earlier — cell therapy into the front line, combinations into first-line use — because the immune system works best when the disease is smallest and the patient is strongest. The second is that we still cannot predict who benefits. PD-L1 and BRAF status did not predict response to the HDAC combination, and across every dataset presented the only consistent signals were low LDH and low tumor burden, which are markers of favorable biology more than of any particular drug.
What nobody solved is melanoma that has already progressed on anti-PD-1 therapy. The HDAC combination worked poorly there, and cell therapy works but with shorter responses than when it is used earlier. That remains the hardest conversation in my clinic, and nothing presented on day one changed it.
Still, a strong first day in Madrid — four randomized trials, a genuinely useful symposium, and a field that keeps finding ways to move treatment earlier. More to come, including the highly anticipated individualized mRNA vaccine results being at the Presidential session.
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.
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