The Italian drug agency Aifa has approved the reimbursement of the nivolumab-ipilimumab combination in melanoma and in kidney and lung cancers. In particular, the green light from the regulatory body for the immunotherapy mix concerns the first-line treatment of advanced melanoma, intermediate / unfavorable risk advanced renal cell carcinoma and, in association with two courses of platinum-based chemotherapy, of metastatic non-small cell lung cancer without mutation of the Egfr and Alk genes. The AIFA also authorized second-line nivolumab monotherapy in esophageal cancer. Experts agree: “We are facing substantial changes in daily clinical practice“, presented today during a virtual press conference promoted by Bristol Myers Squibb (Bms).
“The combination of nivolumab and ipilimumab allows for a complete and synergistic mechanism of action, because it is directed towards two different proteins that inhibit the activation of the immune system (Pd-1 and Ctla-4) – explains Paolo Marchetti, full professor of oncology at the La Sapienza University of Rome and president of the Foundation for Personalized Medicine – Thanks to the dual immunotherapy, the possibility of chronicizing many forms of metastatic cancer becomes concrete “, underlines the specialist.
“The benefits offered by the combination of the two molecules – need – immunocologics consist of faster and more lasting responses and long-term survival, as also highlighted in the meta-analysis, coordinated by Sapienza and published in the ‘Journal of Translational Medicine’, which considered 7 studies conducted between 2010 and 2020 on more than 2,420 patients affected by melanoma, small cell lung cancer and not a small cell, bladder, gastric, sarcoma, mesothelioma. The combination of nivolumab and ipilimumab demonstrated agnostic efficacy, ie across and beyond the type of cancer, increasing responses by 68%. “
In 2020, almost 14,900 new diagnoses of melanoma were estimated in Italy. “This skin cancer represented the ideal model to verify the efficacy of immunoncology – he highlights Paolo Ascierto, director of the Unit of melanoma oncology, oncological immunotherapy and innovative therapies of the ‘Pascale’ of Naples – Until a few years ago there were no really effective therapies: before the arrival of immunotherapy the life expectancy of patients with metastatic disease was approximately 6 months and less than 10% were alive at five years. Italy has made a decisive contribution to the research that has made it possible to make immunoncological therapies available to people affected by neoplasms at a very advanced stage. The Pascale of Naples, with over 4 thousand patients treated with immunotherapy since 2010, ranks among the first centers in the world for the number of treatments. And Campania, on the proposal of Pascale, is the only Region in Italy that, since 2019, guarantees the reimbursement of the combination of nivolumab and ipilimumab for all patients affected by melanoma with brain metastases “.
For Ascierto “Aifa’s decision represents a conquest of civilization and a step forward in treatment. In the international phase 3 study CheckMate -067 – he recalls – 49% of patients treated with the combination of nivolumab and ipilimumab on the first line were alive at 6 and a half years. Notably, the median overall survival was 72.1 months, the longest to date reported in a phase 3 study in advanced melanoma. Furthermore, dual immunotherapy is effective in the long term, given that 77% of patients alive at 5 years and who received the combination no longer needed to receive systemic treatment “.
With the nivolumab-ipilimumab mix the prospects for treatment also change in kidney cancer, which in Italy has 13,500 cases estimated in 2020 and over 144,000 people living after diagnosis. “The most frequent form is the clear cell one – he says Giuseppe Procopio, head of genitourinary medical oncology of the Irccs Foundation National Cancer Institute of Milan – More than 50% of patients with early stage disease recover. However, 30% reach the diagnosis already in an advanced stage and, in a third, the disease can recur in a metastatic form after surgery. Historically, the 5-year survival in advanced or metastatic disease did not exceed 13%. Today instead, thanks to the combination of nivolumab and ipilimumab at the forefront, 48% are alive at 5 years, as evidenced by the Phase 3 CheckMate -214 study.
“The data from the compassionate use program on the combination confirm the excellent results of the pivotal study in daily clinical practice – the expert points out – 324 patients with kidney cancer from 86 Italian centers, not ‘selected’ usually in the studies, were involved randomized, for example elderly people with comorbidities and people in very advanced stages, therefore more difficult to treat, or with particular histological variants of kidney cancer. The real world program has shown, in a heterogeneous and unselected population, that the efficacy and the tolerability profile of the combination remain unchanged and in line with what emerged in the pivotal phase 3 study “.
Also turned against lung cancer. In our country there are almost 41 thousand new cases estimated in 2020, with a 70% diagnosis occurring when the cancer is now at an advanced stage and there are few possibilities for a cure. The 5-year survival in metastatic non-small cell lung cancer is in fact around 15%. “Hence the importance of Aifa’s decision which makes available a new very effective weapon for clinicians and patients in our country – assures Cesare Gridelli, director of the onco-hematology department of the Moscati di Avellino hospital – In the most common form of lung cancer, non-small cell lung cancer, dual immunotherapy with nivolumab plus ipilimumab, combined with limited courses of chemotherapy, i.e. two instead of the ‘classic’ four, reduces the risk of death by 28% and by 33. % risk of disease progression. In addition, as evidenced in the Phase 3 CheckMate -9La study, 38% of patients receiving this regimen are alive at 2 years compared to 26% of those treated with chemotherapy alone. ”
“The dual immunoncological therapy in association with two courses of chemotherapy at the forefront of metastatic cancer – remarks Cesare Gridelli – improves both overall and progression-free survival.Another advantage of this approach is the use of limited courses of chemotherapy, which allows to reduce side effects. Chemotherapy still scares patients, even if today we are able to better control the side effects. With this scheme, the patient ends chemotherapy in less than a month and continues treatment with immunotherapy “.
“We strongly believed in the value of our therapies and the long-awaited reimbursement of the combination of nivolumab and ipilimumab has arrived – he declares Cosimo Paga, Executive Country Medical Director, Bms Italia – This increases the number of patients who can benefit from immunotherapy, increasing the number of patients who respond to monotherapy.. Based on the different mechanism of action of the two molecules that act on different moments of the induction of the immune response, we have studied their combination to increase the power and therefore the effectiveness of the therapy. We are developing other immunoncological molecules, which interact on different targets of the immune system, such as relatlimab, a monoclonal antibody that interacts with the Lag-3 receptor, inhibiting its function and thus reactivating the immune system. Our goal is to extend the efficacy of immunoncology to improve patient survival. ”
Another neoplasm too often identified in an advanced stage is the tumor of the esophagus: 2,400 new cases estimated in Italy in 2020, constantly increasing. “About half are diagnosed at an advanced stage, with a strong impact on the patient’s daily life, especially on his ability to eat and drink – he reports. Stefano Cascinu, director of the Cancer Center Irccs San Raffaele hospital in Milan and professor of medical oncology at the Vita-Salute San Raffaele university – Today chemotherapy is the standard treatment for these patients, but the prognosis remains poor because survival does not exceed 10 months. Hence the importance of identifying new effective and tolerable options. Aifa has established the reimbursement of nivolumab for the treatment of unresectable, relapsed or second-line metastatic advanced esophageal squamous cell carcinoma, ie after previous chemotherapy “
Nivolumab was the first immunotherapy approved in Europe, in November 2020, in gastroesophageal cancer based on the results of the Phase 3 Attraction-3 study, which demonstrated a statistically significant and clinically relevant improvement in overall survival in patients who received nivolumab compared to to chemotherapy. “Nivolumab has reduced the risk of death by 23% compared to chemotherapy alone – details Cascinu – Furthermore, immunotherapy has shown an improvement in the quality of life, a very important aspect in patients who are often frail and affected by other pathologies. The challenge is to bring the advantages of immunotherapy also in adjuvant, ie in the early phase immediately after surgery. The use of nivolumab in the early stages of the tumor, in fact, has the potential to avoid relapses. As demonstrated by the phase 3 CheckMate study – 577, adjuvant treatment with nivolumab doubled disease-free survival (22.4 months) compared to placebo (11 months), reducing the risk of relapse or death by 31%. “