Advanced melanoma: the new pill that ‘strips’ the tumour and slows its growth

A pill capable of ‘stripping’ the tumour to make it more visible to the immune system has proved to be a promising new weapon against advanced melanoma. The addition of the innovative tablet-form drug HBI-8000 to standard immunotherapy with nivolumab has, in fact, demonstrated significantly greater efficacy than monotherapy alone: it reduces the risk of the disease progressing by 27 per cent and extends the median progression-free survival to 11.7 months (compared with 7.4 months achieved with immunotherapy alone). Furthermore, the new combination also significantly increases the proportion of patients achieving tumour regression, reaching 41.4 per cent (compared with 32.3 per cent in the control arm). The benefits of the therapy are particularly remarkable for those who start treatment at a less aggressive stage of the disease, i.e. with normal blood levels of the LDH enzyme: in these patients, the median time to progression is significantly extended, reaching 20 months compared with 7.4 months for immunotherapy alone. These are the main findings of the international Phase 3 HBI-8000-303 trial, presented at the European Society for Medical Oncology (ESMO) congress in Madrid.

The trial, conducted on 404 patients with advanced melanoma who had never previously been treated with PD-(L)1, was developed by the biotech company HUYABIO International and counts Paolo Ascierto, full professor at the University of Naples Federico II and president of the Melanoma Foundation, among its principal authors.

 ‘With this combination, we are entering a new dimension of immunotherapy, in which we clearly overcome the tumour’s ability to hide,’ says Ascierto. The new molecule belongs to the class of HDAC inhibitors – drugs capable of blocking the ‘histone deacetylase’ enzymes that tumour cells use to compact their DNA and conceal antigens, the substances recognised by the immune system as targets for attack. By blocking these enzymes, we remodulate the expression of tumour antigens: essentially, we ‘strip’ the malignant cells of their physical defences, revealing their true identity and thus making them immediately visible and recognisable to the immune system. Once the tumour has been unmasked, immunotherapy with nivolumab can hunt down and destroy the tumour cells with significantly greater efficacy and a longer duration of action.”

In the Phase 3 trial, the 404 patients were randomised to receive either the combination of nivolumab and the oral tablet of HBI-8000 or nivolumab and a placebo. The data also demonstrate a marked improvement in clinical success, doubling the proportion of patients achieving complete remission of the disease, which rose to 14.3 per cent compared with the 7 per cent recorded with standard treatment. ‘As well as delivering a significant “leap forward” in progression-free survival, the combination has demonstrated a well-managed safety profile characterised by mild side effects, whilst offering the great convenience of oral administration of the new molecule,’ concludes Ascierto. The increase in progression-free survival from 7.4 to 11.7 months is of extraordinary clinical value for patients with advanced disease. Having an additional pill-based option that enhances immunotherapy without unduly compromising tolerability represents a further step forward that also benefits patients’ quality of life.”