Hit the tumor and not the organ. This is what can be done by following the so-called agnostic approach which launches its attack regardless of the affected organ. Now from Italy comes the first agnostic evaluation in the world of two immuno-oncological molecules, nivolumab plus ipilimumab, which act in a complementary way on the immune system. This is a meta-analysis, coordinated by the La Sapienza University of Rome and published in the “Journal of Translational Medicine”. The results were presented today in a virtual media tutorial sponsored by Bristol Myers Squibb.
The agnostic evaluation
The meta-analysis examined 7 studies, conducted between 2010 and 2020, on more than 2,420 patients affected by melanoma, small cell and non-small cell lung cancer, bladder, gastric, sarcoma, mesothelioma. The combination of nivolumab and ipilimumab demonstrated agnostic efficacy, i.e. across and beyond cancer type. Specifically, it increased responses by 68% and reduced the risk of disease progression by 20% and death by 13% compared with nivolumab alone. Individual studies have also shown that, thanks to the combination of nivolumab and ipilimumab, it is possible to achieve long-term survival in various types of cancer that are particularly difficult to treat at an advanced stage, such as those of the lung (approximately 40,880 new cases estimated in Italy in 2020 ), kidney (13,520), melanoma (14,900) and mesothelioma (1,900).
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Towards precision immuno-oncology
“The synergistic effect of the two molecules is not merely additive, but allows a significant amplification of the responses, improving their speed, magnitude and duration – he explains Paolo Marchetti, Director of Medical Oncology B of the Policlinico Umberto I in Rome, full professor of Oncology at La Sapienza University and first signature of the meta-analysis. Thus, more consistent and faster symptom control can be achieved. Nivolumab plus ipilimumab is the first example of a combination of molecules that complement the immune system and enable important clinical results to be achieved. This approach based on response and resistance mechanisms represents a first step towards precision immuno-oncology, moving beyond the model of medicine based on patient stratification based on predictive factors of response. The latter model is aimed at reducing the number of patients to be treated to obtain a clinically relevant advantage, while the agnostic model allows for the expansion of the number of patients who can benefit from a specific therapeutic modality “.
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Efficacy in different types of cancer
To date, the nivolumab-ipilimumab combination has shown and is demonstrating efficacy in several types of cancers and has received European approval in the first-line treatment of advanced melanoma, in the first-line treatment of intermediate / unfavorable risk advanced renal cell carcinoma. and, in combination with two courses of platinum-based chemotherapy, in the first-line treatment of metastatic non-small cell lung cancer (NSCLC) without EGFR and ALK mutation. “It is necessary – continues Marchetti – for the combination to be reimbursed also in Italy, as in other European countries, in order to offer these patients above all an effective therapeutic alternative”.
The efficacy on lung cancer
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 clear 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 are discovered at an advanced stage,” he says Carmine Pinto, Director of 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. And the one-year survival reached 63% compared to 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, although today it is softer and with fewer side effects. “In the CheckMate -9LA study – continues Pinto – only two cycles of chemotherapy were administered, which is equivalent to 21 days of treatment, because the distance between the cycles is three weeks. Thus both the time and the toxicity of chemotherapy are reduced, with considerable psychological advantages for the patient “.
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Efficacy for kidney cancer
A significant percentage of kidney cancer cases are also discovered in an advanced or metastatic stage. “Only 30% of patients recover thanks to the operation – he underlines Giuseppe Procopio, Head of Genitourinary Medical Oncology of the Ircss National Cancer Institute Foundation of Milan. 30% arrive at the diagnosis already at an advanced stage and, in a third, the disease can recur in a metastatic form after surgery. Up until 5 years ago, just over 10% of patients with advanced kidney cancer were alive within five years of diagnosis. Today, however, thanks to the combination of immuno-oncological molecules, more than half are alive at 4 years old ”. CheckMate -214 is a phase 3, randomized study that evaluated the combination of nivolumab and ipilimumab against the standard of care sunitinib in more than 1,000 patients with advanced renal cell carcinoma, the most frequent form at the forefront. of kidney cancer. “In all randomized patients – adds Procopio – the overall four-year 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.
The efficacy in melanoma
Combination studies started with melanoma. 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. “No other neoplasia – he declares Paolo Ascierto, director of the Melanoma Oncology, Oncological Immunotherapy and Innovative Therapies Unit of the ‘Pascale’ Institute in Naples – has seen such a high increase in the last 12 months. If detected early and eliminated with proper surgical excision during the initial phase, melanoma is completely curable. Unfortunately, some of the diagnoses already occur 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. This approval came from the results of the international phase III study, CheckMate -067, which involved 945 patients: “The combination – adds Ascierto – 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% “.
The question of the reimbursement of the combination
Internationally, the combination of nivolumab plus ipilimumab is believed to be the first treatment option for people with asymptomatic brain metastases, regardless of BRAF mutational status. “At the moment, in Italy – Ascierto points out – the combination is not reimbursed by the National Health Service and only the Campania Region, with a choice of civilization, has decided to guarantee reimbursement for all patients affected by melanoma with brain metastases”.
The findings in mesothelioma
Even in 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 – says Pinto – research is leading to the overcoming of the standard first-line approach represented for decades by chemotherapy, which has so far 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 “.
The urgency triggered by Covid
In short, the international phase 3 studies that analyzed nivolumab plus ipilimumab in non-small cell lung cancer, renal cell carcinoma, melanoma and mesothelioma have shown the consistent improvement in survival compared to standard of care. Particularly valuable results in this phase of health emergency. “The pandemic – concludes Marchetti – underlined the urgency of making innovative therapies immediately available. Cancer can’t wait either. We are already seeing cancer diagnoses at a more advanced stage than in the pre-Covid period, as a consequence of the interruption of screenings and failure to adhere to therapies. A change of pace is also needed in Italy in the approval procedures for new treatments capable of changing long-term survival expectations “.
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