Skin cancers

mRNA vaccine shows efficacy in reducing melanoma recurrence

Preliminary results with a novel mRNA-based therapeutic vaccine for melanoma have been given a cautious welcome by Australian clinicians who described the clinical trial findings as “an excellent step in the right direction.”

The results are from the KEYNOTE-942 Phase 2b trial involving 157 patients with resected stage III/IV melanoma who received a personalised mRNA cancer vaccine known as mRNA-4157/V940 in combination with the anti-PD-1 therapy pembrolizumab (Keytruda).

In a media release (link here) from sponsors Moderna and Merck, the vaccine was reported to have shown a statistically significant and clinically meaningful improvement in the primary endpoint of recurrence-free survival (RFS) versus pembrolizumab alone.

Adjuvant treatment with the mRNA vaccine in combination with pembrolizumab reduced the risk of recurrence or death by 44% (HR=0.56 [95% CI, 0.31-1.08]; one-sided p-value=0.0266) compared with pembrolizumab alone.

According to Moderna, the vaccine consists of a single synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient’s tumour.

“Upon administration into the body, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity,” it said.

Dr John Frew, a dermatologist at Liverpool Hospital and Conjoint Senior Lecturer at UNSW Medicine & Health said the vaccine was highly personalised and there would be no one-size-fits-all vaccine due to the unique mutation differences between individual melanoma patients.

“It is an excellent step in the right direction using new personalised medicine technology, which has come to us as a silver lining out of the COVID-19 pandemic and experience with mRNA vaccines,” Dr Frew said.

“It certainly opens up new doors to novel therapeutics and novel adjuvant therapies – but it is as yet unclear whether this is a true ‘penicillin moment’.”

Medical oncologist Professor Georgina Long of the Melanoma Institute Australia, who was involved in the Australian arm of the clinical trial, described the early results as potentially “the second penicillin moment in cancer treatment”.

‘This is the first trial to demonstrate that we can use both the mRNA technology and a personalised approach to cancer to improve outcomes for patients with cancer,” she said.

‘We found when we added a personalised vaccine – so an mRNA very similar to the COVID vaccine technology but based around the patient’s personal melanoma – the chance of recurrence was reduced by 44%. We now need to confirm results in a larger trial which we are hoping to start early next year.’

Moderna and Merck say they are planning to discuss the results with regulatory authorities and initiate a Phase 3 study in melanoma patients in 2023.

Commenting on the findings, Professor Anthony Joshua, a medical oncologist and Head of Clinical Science at the Garvan Institute of Medical Research, said melanoma was suited to a therapeutic vaccine approach because it was a highly mutated cancer, but he advised caution based on previous disappointments with this approach.

“Melanoma vaccines have been worked on for decades, albeit with little efficacy. However, this is one of the first that has shown promising enough results to proceed to a larger definitive study,” he said.

“It’s certainly exciting… But these are early results and the trial is quite small, and this concept needs to be tested further. It will also be important to see how and if the vaccine did indeed generate an immune response against the tumour and how long it lasts,” Prof. Joshua added.

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