Another mRNA vaccine? What a melanoma trial tells us about benefit and safety

A personalised mRNA treatment for melanoma, designed from the mutations in each patient's own tumour, has reduced the risk of the cancer returning in a phase 3 trial of 1,137 high-risk patients. At two years, 82.2% of those given intismeran with pembrolizumab remained recurrence-free, against 70.0% on pembrolizumab alone. Survival data are still immature and long-term safety unknown. For South Africa, the harder question is access: the treatment depends on timely diagnosis, surgery, pathology and tumour sequencing. Funding it while delays persist in existing cancer care could leave much of its promise out of reach for local patients..By Prof Colleen Aldous.Imagine having a melanoma removed, sending it off to a lab that reads the mutations in that particular tumour, and getting a treatment that teaches your immune system to recognise what remains. That is the idea behind intismeran autogene, an individualised mRNA treatment developed by Moderna and Merck. A randomised trial now suggests that adding it to established immunotherapy after surgery may reduce the chance of the cancer returning.This should pique our interest. It deserves the sort of scrutiny that many of us now bring to any product described as an mRNA vaccine. Concerns about adverse effects after COVID-19 vaccination should be addressed with evidence, and the risks of this cancer treatment should be assessed in patients who would receive it.The phase 3 INTerpath-001 trial enrolled 1,137 people with high-risk melanoma that had been completely removed by surgery. They were assigned to receive pembrolizumab, an immune checkpoint drug, with either individualised intismeran or a placebo injection. At two years, an estimated 82.2% of the combination group remained free of recurrence, compared with 70.0% of the pembrolizumab-only group. The difference is 12.2 percentage points, or roughly one additional person remaining free of recurrence or death for every eight treated over that period. That “one in eight” is an approximate interpretation of the two-year estimates, not a proven number of cures. The reported hazard ratio of 0.58 describes a 42% relative reduction in the rate of recurrence or death during follow-up; it does not mean that 42% more patients were curedBut, for a patient at high risk after melanoma surgery, these results could be meaningful. Its value still depends on adverse effects, cost, and whether the benefit lasts. The trial has not yet established a survival benefit, because overall survival data remain immature.The combination also improved the measure of time free from distant spread or death. Follow-up at the main analysis had a median of 24.6 months. Overall survival results are still immature. We therefore know more about recurrence than about whether this treatment helps people live longer. Intismeran remains investigational, with regulatory review still to come.How a personal treatment is madeMelanoma cells accumulate mutations. Some produce altered proteins, called neoantigens, that can distinguish cancer cells from normal tissue. A tumour sample is sequenced, candidate targets are selected, and an mRNA product is designed to carry instructions for those targets. For melanoma treatment, researchers analyse each patient’s tumour and normal DNA, select the neoantigens as potential targets, and produce an mRNA product for that patient. After injection, cells produce and display the selected targets to the immune system, aiming to stimulate recognition of cancer cells. This is a therapeutic intervention for a person who already has cancer. It is given after surgery to reduce the risk of recurrence. It uses the mRNA platform, but its target, patient population, dosing, and companion medicine differ from those of preventive Covid-19 mRNA vaccines. Safety experience with one product does not establish the safety of another. Nor does sharing a platform prove that adverse effects observed with one formulation will occur at the same frequency with another.The safety question cannot be waved awayIt's important to distinguish this mRNA vaccine approach from that used to treat SARS-CoV-2 virus (COVID-19). .Read more:.Genetics and personalised medicine: How functional genomics guides cancer treatment.The two approaches use mRNA to give cells instructions, but they select their targets differently. COVID-19 mRNA vaccines instruct cells to make a form of the SARS-CoV-2 spike protein. The immune system responds by producing antibodies and activating other immune cells, preparing it to recognise the virus. The spike protein was selected to prompt protection against SARS-CoV-2; however, subsequent safety surveillance established that mRNA COVID-19 vaccines can cause myocarditis. Researchers have detected circulating spike protein in some affected patients. This experience makes careful study of the targets, distribution and longer-term safety of new mRNA treatments essential. The CDC recognises a causal association between mRNA Covid-19 vaccines and myocarditis or pericarditis. Many patients improved by the time of hospital discharge, but this is not the same as complete recovery. An Australian follow-up study found that some people with confirmed or probable post-vaccination myocarditis still reported symptoms 12 to 18 months later. The US Food and Drug Administration has required updated warnings and longer-term cardiac studies. These findings concern a recognised adverse effect in a subset of vaccine recipients. Other reports of persistent symptoms also merit careful investigation, with their causes assessed individually.For the melanoma trial itself, the companies reported treatment-related adverse events in 95.8% of patients receiving intismeran plus pembrolizumab and 90.0% of patients receiving pembrolizumab plus placebo. Adding intismeran brought substantially more fever and injection-site pain, and more patients stopped a study drug because of treatment-related effects; the reported rates of grade 3–5 treatment-related events (the more serious adverse events) were similar at this stage of follow-up. Long-term safety still needs observation. These figures describe events during the trial and cannot yet exclude uncommon or late effects. They also require careful interpretation because pembrolizumab itself can cause serious immune complications, including inflammation of the lungs, bowel and endocrine glands. Longer follow-up and transparent reporting of the nature, duration and attribution of adverse events are essential.The comparison is between two groups of patients who already had melanoma and were considered at high risk of recurrence. Their choice involves a different balance of potential benefit and harm than that faced by a healthy person considering a preventive vaccine. Patients should have both the absolute recurrence figures and a clear account of side effects, including what remains unknown.Who will be able to receive it?Making a distinct product for every patient requires a tissue sample, reliable sequencing, target selection, manufacturing capacity and a delivery schedule that works while the patient is recovering from surgery. Each step adds time and cost. The Phase 3 result establishes a clinical signal in the studied population. We still do not know costs, how many patients can be served or whether production can reach people outside wealthy specialist centres.South Africa has a particular reason to watch that question. An advanced treatment is useful only to patients whose melanoma is diagnosed, removed and assessed in time, and whose clinicians can arrange the subsequent therapy. Funding a personalised product while delays persist in pathology, surgery or access to existing cancer medicines would leave substantial benefit unrealised. Decisions about adoption will need evidence of clinical benefit, mature safety and survival data, the full cost of delivery, and the opportunity cost within our cancer services..Read more:.Aspen crashes 34% on surprise MRNA dispute, faces R770mn hit.Australian investigators at the Melanoma Institute Australia helped lead this international trial. Their result is an important advance in testing a treatment designed from an individual tumour. The next test is the important one: whether longer follow-up confirms durable benefit, whether uncommon harms are detected, and whether the manufacturing model can bring this treatment within reach of patients who need it..Sign up for your early morning brew of the BizNews Insider to keep you up to speed with the content that matters. The newsletter will land in your inbox every morning on weekdays. Register here.Support South Africa's bastion of independent journalism, offering balanced insights on investments, business, and the political economy, by joining BizNews Premium. Register here.If you prefer WhatsApp for updates, sign up to the BizNews channel here.

Another mRNA vaccine? What a melanoma trial tells us about benefit and safety

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