They are called agnostic drugs, a term that derives from the ancient Greek without knowing, and they are like wild cards that work against a specific alteration, regardless of the single type of tumor, and represent a new way, already available for patients, to treat certain neoplasms. Now, for the first time in the world, in an all-Italian study she was subjected to an agnostic evaluation, so regardless of the organ affected, even the combination of two immuno-oncological molecules which act in a complementary way on the immune system, stimulating it on several fronts to react against cancer. The results show that the mix enhances disease control and improves survival over standard of care. The new survey, coordinated by the La Sapienza University of Rome and published in the Journal of Translational Medicine, a meta-analysis that considered the results achieved by seven different studies, conducted between 2010 and 2020, involving over 2,420 patients affected by melanoma, small cell and non-small cell lung cancer, bladder, gastric, sarcoma, mesothelioma .

The mix reimbursed in Europe, not yet in Italy

The combination of the two immunotherapy drugs nivolumab e ipilimumab demonstrated agnostic efficacy (across and beyond the type of cancer): it increased responses by 68% and reduced the risk of disease progression by 20% and death by 13% compared to monotherapy with nivolumab alone. Individual studies have also shown that, thanks to the union of the two molecules, it is possible to obtain long-term survival in various types of cancer that are particularly difficult to treat at an advanced stage, such as those of the lung (about 40,880 new cases estimated in Italy in 2020), of the kidney (13,520), melanoma (14,900) and pleural mesothelioma (1,900). The synergistic effect of the two molecules is not only additive, but allows a notable amplification of the responses, improving their speed, entity and duration – he explains Paolo Marchetti, director of Medical Oncology B of the Policlinico Umberto I in Rome, Professor of Oncology at the University La Sapienza and first signature of the meta-analysis -. Thus, more consistent and faster symptom control can be achieved. Nivolumab pi ipilimumab is the first example of a combination of molecules that act in a complementary way on the immune system and that allow to achieve important clinical results. To date nivolumab plus ipilimumab mix has been shown to be effective in different types of cancers and received European approval in the first-line treatment of advanced melanoma, also in the first-line of advanced intermediate-unfavorable risk renal cell carcinoma and, in combination with two courses of platinum-based chemotherapy, in the first-line therapy of non-small lung cancer metastatic cells without EGFR and ALK mutation. necessary – continues Marchetti – that the combination is also reimbursed in Italy, as in other European countries, to offer these patients above all an effective therapeutic alternative.


Lung cancer and mesothelioma

For patients affected by the most common form of lung cancer, non-small cell, the combination of nivolumab and ipilimumab combined with limited courses of chemotherapy, i.e. two instead of the classic 4-6, showed a distinct advantage in terms of survival. global compared to chemotherapy alone. This is demonstrated by the phase 3 CheckMate -9LA study on more than 700 patients, which led to the approval of this therapeutic regimen in Europe last November. Lung cancer is particularly difficult to treat, because about 70% of cases discovered at an advanced stage – recalls Carmine Pinto, director of the Medical Oncology Clinical Cancer Center IRCCS AUSL of Reggio Emilia -. Dual immuno-oncology therapy, consisting of nivolumab plus ipilimumab, in combination with two courses of first-line chemotherapy in metastatic cancer, reduced the risk of death by 31% compared to chemotherapy alone. IS one-year survival reached 63% compared with 47% with chemotherapy alone. The further advantage of this therapeutic scheme is represented by the use of limited courses of chemotherapy which is still scary, even if “sweeter” than in the past and we are able to better control the side effects. In the CheckMate-9LA study, only two courses of chemotherapy were administered, which is equivalent to 21 days of treatment, because the distance between courses was three weeks. Cos both the time and the toxicity of chemotherapy are reduced, with significant psychological benefits for the patient. Also in the mesothelioma, a rare tumor with a very strong link to occupational exposure to asbestos fibers, the combination of immuno-oncological molecules has shown important results. For the first time in 30 years – adds Pinto – research is leading to the overcoming of the standard front-line approach represented for decades by chemotherapy, which so far has offered little hope in increasing survival. In the Phase III CheckMate -743 study involving 605 patients, at a minimum follow-up of 22 months, treatment with nivolumab and ipilimumab reduced the risk of death by 26%, demonstrating a median overall survival of 18.1 months compared with at 14.1 months with chemotherapy.

Kidney cancer

Also an important percentage of the cases of kidney cancer discovery in an advanced or metastatic stage. Only 30% of patients recover thanks to the operation – he stresses Giuseppe Procopio, Head of Genitourinary Medical Oncology at the IRCCS National Cancer Institute Foundation in Milan -. 30% reach the diagnosis already at an advanced stage and, in a third of cases, the disease can recur in a metastatic form after surgery. Until a few years ago, just over 10% of patients with advanced kidney cancer were alive five years after diagnosis. Today, however, thanks to the mix of immuno-oncological molecules, more than half alive at 4 years. CheckMate -214 a phase 3, randomized study evaluating the combination of nivolumab and ipilimumab against the sunitinib standard of care in over 1,000 patients with advanced renal cell carcinoma, the most common form of kidney cancer. In all randomized patients, the four-year overall survival rates were 53.4% ​​with nivolumab and ipilimumab compared to 43.3% with sunitinib. Based on these findings, the combination was approved by the European regulatory agency in January 2019 in the first-line treatment of adult patients with intermediate / unfavorable risk advanced renal cell carcinoma.

Cutaneous melanoma

Studies on immunotherapy mixes started with melanoma, which pioneered this new strategy from the very beginning. In one year, new cases of this skin cancer in Italy increased by 20%, from 12,300 in 2019 to almost 14,900 in 2020 – he says. Paolo Ascierto, director of Melanoma Oncology, Oncological Immunotherapy and Innovative Therapies of the Pascale Cancer Institute of Naples -. No other malignancy has seen such a high increase in the past 12 months. If detected early and eliminated with a correct surgical removal during the initial phase, the melanoma is completely curable. Unfortunately, some of the diagnoses are already at an advanced stage or progressively evolve at this stage. In May 2016, Ema approved the combination of nivolumab plus ipilimumab for the first-line treatment of advanced (unresectable or metastatic) melanoma: a green light from the results of the international phase III study, CheckMate -067, which involved 945 patients: the combination showed a 5-year survival of 52%. A truly exceptional result, considering that, before the introduction of immuno-oncology, this percentage did not exceed 5%. At an international level – continues Ascierto – the mix is ​​considered the first treatment option for people with asymptomatic brain metastases, regardless of the mutational status of the BRAF gene. In Italy, at the moment, the combination not reimbursed by the National Health Service and only the Campania region has decided to guarantee reimbursement for all patients affected by melanoma with brain metastases.

April 6, 2021 (change April 6, 2021 | 12:17 pm)

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