Marisol Soengas
Head of the Melanoma Group at the Spanish National Cancer Research Centre (CNIO)
The scientific and medical community, along with a great many cancer patients, have been eagerly awaiting the results of a major international clinical trial involving Intismerán (the personalised mRNA vaccine designed to prevent relapses in melanoma and other tumours following surgery) since August. We have now learnt from data due to be presented at the European Society for Medical Oncology (ESMO) Congress that these expectations are supported by very promising findings. This is a phase 3 clinical trial involving 157 clinical centres across various countries and more than 1,300 patients – in itself a major challenge that deserves recognition. Interest was extremely high, as the developers (Moderna and Merck/MSD) announced that they had achieved two major milestones in modern oncology: moving towards a ‘tailor-made’ treatment for each patient, and enabling the patient’s own immune system to eliminate tumour cells that might have ‘escaped’ following the removal of the primary tumours. This was not a strategy to prevent melanomas, nor to treat advanced cases with metastases. The aim was to combine Intismerán with already approved immunotherapies (the antibody pembrolizumab) to reduce the occurrence of metastases and, in doing so, increase patients’ overall survival. The technology used for this personalisation is potentially so powerful that the interest was justified.
What does this phase 3 trial, known as INTerpath-001, appear to demonstrate? The most significant finding is that, after 24 months, 82.2 per cent of patients treated with the combination of Intismerán and pembrolizumab remained relapse-free, compared with 70.0 per cent on pembrolizumab alone, representing a 42 per cent reduction in the risk of relapse or death (hazard ratio 0.58). The risk of distant metastases or death was also reduced by 38 per cent (HR 0.62).
How has this been received? To find out the response from basic and clinical researchers, we will have to wait until tomorrow, Saturday, when Dr Georgina Long from the Melanoma Institute of Australia will present the specific data. The markets, however, have reacted with a fall in share prices. The effect on metastases was expected to be more significant because a previous phase 2 trial had indicated a 59 per cent reduction in the occurrence of distant metastases.
Another point requiring caution is the potential applicability of the technology. What Moderna and its collaborators have achieved is no small feat, but it is logistically complex. It is literally a bespoke vaccine. A tumour and blood sample are taken; these are sequenced to identify mutations that generate abnormal proteins, or neoantigens, which are absent from normal cells. Using algorithms (one of the major breakthroughs here), up to 34 neoantigens with the potential to be recognised by the immune system are selected, and a specific mRNA molecule encoding them is produced. Once administered, these neoantigens are produced and presented to the immune system, generating or amplifying T-lymphocytes capable of recognising tumour cells. Intismeran is combined with pembrolizumab, a PD-1 inhibitor. In this way, the vaccine enhances and directs the anti-tumour response, whilst pembrolizumab prevents the tumour from inactivating these T-lymphocytes.
It is, therefore, a particularly advanced form of personalised medicine. This is the major breakthrough, because conceptually it would make it possible to treat not only melanoma, but also other tumours in which the immune system can be reactivated. The challenge is to ensure that this personalisation can be scaled up to a large number of patients, and that the cost is affordable for healthcare systems.