In recent years, immunotherapy has been the real novelty on the front of oncological therapies, demonstrating an important efficacy in some cancers, first of all melanoma, the most aggressive skin cancer. The idea is to remove the brakes on the immune system so that it can attack diseased cells, brakes that the body has to avoid excessive activity that could be harmful. Cancer cells, however, use this regulation to hide. Hence the need to unlock these security systems. “The first two brakes that we have come to know are PD-1 and CTLA-4, whose discovery was worth the Nobel Prize for medicine, today we know that there is also LAG-3 that can be unlocked”, explains Paolo Ascierto , Director of the Melanoma Oncology Unit, Oncological Immunotherapy and Innovative Therapies of the ‘Pascale’ of Naples. This is demonstrated by the data presented during the Congress of the American Society of Clinical Oncology concerning the combination of nivolumab, which unblocks PD-1, and relatlimab, an anti-LAG-3 antibody.
The results
The study involved over 700 previously untreated patients with metastatic or unresectable melanoma who received either the combination or monotherapy of nivolumab. The results show that the two molecules reduced the risk of disease progression by 25%. Notably, median progression-free survival reached 10.12 months with the combination compared with 4.63 months with nivolumab monotherapy. “The significant clinical benefit offered by the new relatlimab and nivolumab frontline combination, with good tolerability, is evident. Immune checkpoint inhibitors alone or in combination changed the history of the disease and improved survival rates. Nonetheless, there remains a percentage of patients who could benefit from the new combination therapy that influences complementary cellular pathways to enhance anti-tumor activity. Therefore, targeting the LAG-3 pathway in combination with PD-1 inhibition may prove to be a key strategy to enhance the immune response, ”comments Ascierto. “The challenge now is to understand which patients are candidates for this treatment and LAG-3 can be a valid biomarker for selecting the best therapy.”
The other combination
The demonstration of the significant impact that immunotherapy has had in melanoma comes from the results, also presented at Asco, of the international phase III study that evaluated the combination of the two immuno-oncological molecules, nivolumab and ipilimumab, at the forefront in advanced melanoma. “49% of patients treated with the combination are alive at 6 and a half years. Notably, median overall survival was 72.1 months with nivolumab plus ipilimumab – the longest to date reported in a phase III study in advanced melanoma – compared with 36.9 months with nivolumab and 19.9 with ipilimumab. The impact of the combination on overall survival is therefore decisive, especially considering that, before immunotherapy, the life expectancy of patients with metastatic melanoma was about 6 months and less than 10% were alive at five years, “he says. the oncologist.
In addition, 77% of patients who were alive at 5 years and who received the combination no longer needed to receive systemic treatment. The dual immunotherapy therefore maintains its long-term efficacy, even after the end of treatment.
The Italian contribution
The ‘Pascale’ of Naples has always been at the forefront in the study of immunotherapy in melanoma, with the “old” inhibitory check points as well as with the new one. The first studies on relatlimab were in fact started about four years right here, and that of Naples is the center where the largest number of patients was recruited. “We are constantly working on this front: to increase the number of patients who can benefit from immunotherapy and to extend the combinations of molecules to other pathologies as well. On the first front I think that in the future we will experiment the possibility of intervening with a triplet of inhibitory check points, on the second we are already participating in studies in which the new combination is tested for lung, kidney and head and neck cancer “, concludes Ascierto .
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