ASCO 2025: Melanoma Oral Abstracts Emphasize Trial Limits
Welcome, everybody. My name is Teresa Amaral. Today, I'm here with you to follow up on the presentation on the best of ASCO 2025.
The second trial that was presented that I found very interesting to be chosen for the oral communications was an adjuvant trial of targeted therapy with encorafenib and binimetinib in stage II, the Columbus-AD trial. This trial was stopped early because of the low recruitment rate; it was initially planned to recruit a significant number of patients, at approximately 800.
The fact that the trial started quite late and in a phase where immunotherapy was already available for patients in the adjuvant setting, it was very difficult to recruit patients for this trial because the competitor arm was placebo.
Besides the fact that this was challenging, it also shows that — when you design a trial — you need to take into consideration the potential change in the landscape of the therapy with the time. Probably if this trial had started to recruit a little bit earlier, or started a little bit earlier, we could have the data on stage II for patients that have a BRAF mutation, which was the population that was included in this trial.
I think it's a pity that we don't have these data, because most likely in the future we will not have any head-to-head comparison between targeted therapy and immunotherapy in the adjuvant setting. We have a dedicated session on Medscape addressing this topic. If you'd like to see it, I invite you to look into that. Again, it shows the difficulties of recruiting patients for trials when the therapeutic landscape changes during the recruitment period.
The analysis that was presented is from a part of the population, around 90 patients, showing that targeted therapy might be better than placebo in this population at 12 months. Again, it's impossible to draw any kind of conclusions, because the trial was stopped quite early.
Another point that I would like to discuss with you, and I think it'll come up more as there are several other trials addressing this topic, is the duration of immunotherapy. We also have a dedicated session on Medscape looking into this topic.
I found it interesting that this work was chosen to be discussed here. This is the DANTE trial that looked into 1 year vs 2 years of immunotherapy in the metastatic setting in patients that received PD-1-based immunotherapy. Of course, it was very difficult to recruit patients to this trial because it ran during COVID. Also, some of the patients had some resistance to participating in the study due to some concerns about receiving a shorter time of immunotherapy as compared to the 2 years that we are giving now — which I must say, there is not really a strong scientific rationale to do that.
In some cases, the patients also mentioned that they were a little bit overwhelmed in terms of the information. We may need to change our approach to our patients when we want to address these very important questions, not only in terms of efficacy and safety, but also in terms of financial toxicity, which is one of the aspects that we discuss in this other Medscape session that I mentioned to you before.
Just for you to have an idea, this study had planned to recruit approximately 1200 patients and it recruited 166. This shows the difficulty of recruiting patients in this setting but also the very big need of looking into this particular question.
Moving into the advanced setting and sequencing therapy in patients that have a BRAF mutation. We also have a dedicated session for this topic on Medscape. This was the presentation of the final clinical results of the DREAMseq study which included patients with a BRAF mutation and investigated whether the patient should receive targeted therapy or immunotherapy first.
These final results are quite convincing, showing that patients that do receive immunotherapy first have a better outcome than patients that receive targeted therapy first. This is a sustained benefit after almost 5 years of follow-up. What is interesting also to show is that they looked into a specific endpoint that I think is very important in the stage IV setting, which is central nervous system metastasis-free survival.
Why is this important? The development of brain metastases is one of the reasons the patients die, and it's very important to look at whether the systemic therapies that we give upfront can delay the development of these central nervous system metastases.
Bear in mind that these patients who entered the study could not have brain metastases at entry. The results show that, indeed, patients who started with immunotherapy had a longer central nervous system metastasis-free survival than patients who started with targeted therapy.
Also, it is important to mention that patients who developed brain metastases while on the study were not able to do the crossover, which was one of the aspects that was being investigated in this study. Patients would start with immunotherapy and, if they progressed, they would go to targeted therapy, or the other way around. In the end, we still are looking forward to seeing the biomarker analysis and the analysis on all the samples that were collected during this study.
I think this is quite convincing in terms of the long-term benefit of starting with immunotherapy whenever possible. The question still remains as to who are the patients that have a BRAF mutation and might benefit from starting with a target therapy upfront. This is the question that's still not answered at this time point.
This leads us to the final discussion I would like to present, and this is very interesting work looking into patients who have brain metastases and a BRAF mutation. In this case, the patients were treated with their triple combination — so encorafenib, binimetinib, and nivolumab — or patients were treated with ipi/nivo.
Of course, we understand that patients who have symptomatic brain metastases have been systematically excluded from clinical trials. What is the best treatment option in these cases for these patients? It's still unclear.
Interestingly enough, in this study, the patients were able to be treated with steroids: up to 8 mg dexamethasone or equivalent a day. It was possible for them to have received previous local therapy for these brain metastases.
Basically, the study compared these two treatment options, the triple combination or the ipi/nivo combination. What was shown in this small number of patients — because again, it's difficult to recruit this population — is that the triple combination seems to do better in this specific population than the combination of ipi/nivo.
The intracranial progression-free survival was also better with the triple combination, but the overall survival was very similar in the two groups, showing that even if there is a benefit of the triple combination in the beginning, once the patients progress, it is still possible to rescue them somehow.
Again, this is a population of patients with a very poor prognosis. Therefore, it's difficult to have a significant number of patients included in the study and to move on with this kind of study, despite the fact that they are extremely necessary, because we do not really have many options for these patients.
In the end, what we need to continue to investigate is: How can we bring therapies to these patients who have symptoms, have progressed on their adjuvant therapy, and have brain metastases at the time that they possibly could enter a clinical study? How can we bring all of this together based on the previous therapies that the majority of patients who have symptomatic brain metastasis already received?
With this, I will end our second overview of ASCO 2025. I hope you enjoyed this not-so-short summary, but I think it's a very interesting overview of what was presented this year at ASCO.
I would like to invite you for the third part of this best of ASCO that we will dedicate to the neoadjuvant approaches, as there was a significant number of trials presented looking into this specific strategy in patients with melanoma and nonmelanoma skin cancers.
I hope I see you in the next session. Have a good day.
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Consistent intake of niacin is one strategy for reducing Lp(a), the UK researchers stated, but only 77 (0.02%) of the 460,544 participants in the analysis were taking the nutrient. Niacin has had its own star-crossed history as a risk-reduction strategy in ASCVD. Both the 2011 AIM-HIGH trial and the 2014 HPS2-THRIVE study found that people who took niacin supplements did not reduce their risk for ASCVD, although participants in AIM-HIGH on niacin had a 25% reduction in Lp(a) levels. These studies moved the consensus away from niacin therapy. Another recent revelation about Lp(a) is its apparent independence from LDL-C. Lowering LDL-C with statins does not affect cardiac risks associated with elevated Lp(a), said Sotirios Tsimikas, MD, who was the corresponding author for a 2024 meta-analysis on the question. Sotirios Tsimikas, MD 'Lp(a) is an independent risk factor at all levels of achieved LDL when you treat somebody with an LDL-lowering agent,' said Tsimikas, a cardiologist at the Sulpizio Cardiovascular Center and director of vascular medicine at the University of California San Diego (UCSD) Health. 'The implication is you have to treat it as your own independent risk factor and not assume that when you treat the LDL-C, even at very low levels, that you reduce Lp(a)-mediated risk.' In a study, patients with Lp(a) > 50 mg/dL but in the lowest quartile of LDL-C after treatment — in the 3.1-77 mg/dL range — had a 38% greater ASCVD risk than those with Lp(a) levels below the 50 mg/dL threshold. Tsimikas said this study built on research his group published in 2018. 'What this paper showed with more granularity was that the LDL level that was achieved in the statin trials did not reduce the Lp(a) risk,' he said. The State of Clinical Trials Block and his group have reported on clinical trials of six investigative therapies targeting Lp(a). Three subcutaneous therapies are in phase 3 trials: Pelacarsen, an antisense oligonucleotide that has demonstrated an 80% reduction in Lp(a); and two small interfering RNAs (siRNAs), olpasiran and lepodisiran, both of which have demonstrated up to a 98% reduction in Lp(a). Likewise, three agents are in phase 2 trials: Zeriasiran, a subcutaneous siRNA agent that has shown up to a 98% reduction in Lp(a); and two oral agents, muvalaplin, an Lp(a) inhibitor that has demonstrated up to an 85% reduction in levels of the molecule, and obicetrapib, a cholesterol ester transport protein inhibitor that has shown up to a 57% reduction in the substance and is used in conjunction with evolocumab. Deeper in the pipeline is at least one potential one-time gene therapy, CTX320, which is in preclinical stages. The pelacarsen trial is scheduled for completion early next year. The olpasiran trial is scheduled for completion at the end of 2026. 'We're right on the cusp of knowing if we lower Lp(a), do we get a benefit that's clinically meaningful?' Tsimikas said. Modify What You Can — Wait for the Calvary Despite the lack of commercially available therapies, providers can employ several interventions to manage ASCVD risks in patients with elevated levels of Lp(a). 'The theme here is to modify what you can modify until we have more directed therapy with good clinical trial outcomes,' Shah said. 'Drop LDL as low as you can. Consider starting aspirin therapy, especially if patients have multiple risk factors — and absolutely they should be on aspirin therapy if they've had a prior cardiovascular event. Then I look to modify other things. Are they hypertensive? Can I get them better? Are they obese? Can I reduce their weight? Do they have diabetes? What can we do to control this more?' First-degree relatives of people with high Lp(a) levels should get their Lp(a) levels tested, he added. Motivated patients could be encouraged to enroll in a clinical trial. 'As more people understand that there are changes you can make today, they may be more likely to test for Lp(a),' Shah said. Until clinical trial results are reported, clinicians are in a 'gray zone,' Tsimikas said. To get through that 'gray zone,' more education of providers and patients is needed, healthcare systems need to support more widespread Lp(a) testing, and insurance companies need to cover testing, he said. 'What I'm seeing is that a lot of physicians have become aware of Lp(a), and I'm seeing a lot of testing that normally I wouldn't,' Tsimikas said. 'I think the tide is already turning on this.' Block has no relevant relationships to disclose. Paruchuri reported having financial relationships with Allelica, Amgen, Apple, AstraZeneca, Boston Scientific, Genentech/Roche, Ionis, Novartis, and NewAmsterdam Pharma. Shah reported having received research grants from Amgen and Janssen and is a consultant/advisor for Esperion, Amgen, and Novartis. Tsimikas is a co-inventor and receives royalties from patents owned by UCSD. He is also a cofounder and holds equity in Oxitope and Kleanthi Diagnostics and has a dual appointment at UCSD and Ionis Pharmaceuticals.
