“41” is a number that can give a lot of hope. We are talking about the percentage of patients with melanoma and brain metastases that exceed 5 years from diagnosis, thanks to treatment with double immunotherapy: a figure that is difficult to imagine only 10 years ago, if we consider that the median survival is about 6 months. And it is the result of one of the six clinical studies on cancer promoted by the NIBIT Foundation and carried out by the Immuno-Oncology Center (CIO) of the Sienese University Hospital in this year of pandemic, despite all the difficulties.
Three trials: on melanoma, mesothelioma and epigenetic drugs
In particular, this on melanoma with brain metastases treated with the double immunotherapy drugs nivolumab and ipilimumab (study NIBIT-M2) is among the three most important trials. “For the first time in the world we have broken the ‘dogma’ that immunotherapy does not work in these cases,” says Anna Maria Di Giacomo, Coordinator of the IOC Phase I and II Clinical Trials Program “. The second trial concerned pleural mesothelioma (NIBIT-MESO-1 study), where the value of re-treatment with immunotherapy after progression was demonstrated. Finally, a new way is being sought to overcome resistance to immunotherapy (which occurs in about half of the patients) in both lung cancer and melanoma, using the so-called epigenetic drugs (NIBIT-ML1 study). But let’s go in order.
Two immunotherapies against melanoma brain metastases
Melanoma is a skin cancer that affects almost 15,000 people every year in Italy, and is very aggressive in an advanced stage. About half of patients with metastatic melanoma also develop brain metastases. The phase 3 NIBIT-M2 study involved 9 centers coordinated by the IOC of Siena, for a total of 80 patients never treated before, who were divided into three groups. The first was given a chemotherapy drug, fotemustine, the second the combination ipilimumab plus fotemustine and the third the combination nivolumab plus ipilimumab (without chemotherapy). NIBIT-M2 represents the ideal continuation of the NIBIT-M1 study, published in 2013 in Lancet Oncology, which included only the first two arms. “For the first time in the world, data on long-term immunotherapy treatment are available in this third population”, says Di Giacomo: “41% of patients treated with the combination of nivolumab and ipilimumab are alive at 5 years compared to 10.9 % with fotemustina “. Survival is therefore almost quadrupled.
Brain metastases are an absolutely unfavorable prognostic factor: “The median survival of these patients is about 6 months”, underlines Michele Maio, President of the NIBIT Foundation and Director of the Chair of Oncology of the University of Siena and of the IOC: “Thanks to results of the NIBIT-M2 study, we can state that patients with brain metastases respond to the combination of first-line immunotherapy molecules in a similar way to people affected by metastatic melanoma but without brain metastases ”.
New hopes also for mesothelioma
Another breach opened on the front of pleural mesothelioma, one of the most aggressive cancers associated with asbestos fibers, which affects 1900 people every year in our country. Here the goal is to identify with ever greater precision the patients who can respond to immunotherapy. The NIBIT-MESO-1 study involved 40 patients: “To provide the best therapy to each patient and, at the same time, make the best use of available resources, a solid biomarker and Tumor Mutational Burden (TMB ), which measures the number of molecular mutations in the tumor, goes precisely in this direction ”, explains Maio. To evaluate the mutational load it is necessary to analyze a large amount of genes: “The test is performed on tumor tissue, thanks to modern genome analysis techniques that make use of next generation gene sequencing. And it must be done at the time of diagnosis: so the clinician has a complete molecular photograph for each patient and can identify which ones will respond best to immunotherapy ”.
There has been no advancement in mesothelioma therapy for thirty years. “In 2009, our Siena group developed the first research in the world of immunotherapy with antibodies directed against different immunological checkpoints precisely in mesothelioma”, says Luana Calabrò, IOC Head of Thoracic Neoplasms: “The NIBIT-MESO-1 study , published in April 2021 in Lancet Respiratory Medicine, first of all showed that a significant percentage of patients, about 50%, retreated with a combination of immuno-oncological molecules respond again to immunotherapy treatment. The median overall survival was 25.6 months compared to 11 months in those not retreated ”. Until now, there was a lack of data on the efficacy of retreatment with immunotherapy in mesothelioma.
In the NIBIT-MESO-1 study, the mutational burden of the tumor was also retrospectively analyzed: “We observed better results both in terms of response and survival in patients treated with immunotherapy who had a TMB above the median. In particular, survival reached 30.9 months in patients with higher TMB compared to 14.9 months in patients with a lower TMB value ”, adds Calabrò. The tumor mutational burden can therefore help predict the likelihood that a patient with mesothelioma will benefit from immunotherapy treatment.
The epigenetic way against resistances
The third study that testifies to the commitment of the NIBIT Foundation in research is NIBIT-ML1, promoted also thanks to the contribution of Bristol Myers Squibb and Astex Pharmaceuticals, which started in October 2020, during the second wave of the pandemic. A total of about 20 Italian centers will be involved and 160 patients are expected to be enrolled, 80 with advanced melanoma and 80 with lung cancer, who have not responded to a previous immunotherapy treatment. The aim of the research is to understand the mechanisms of resistance to immuno-oncology to overcome them. “We know that about 50% of patients with melanoma respond to long-term immunotherapy”, explains Maio: “In lung cancer the percentage is about 35%. To increase these numbers, one of the strategies to be followed is to make cancer cells more ‘visible’ to the immune system, for example by using hypomethylating drugs. We want to analyze the efficacy of the combination of nivolumab and ipilimumab with a hypomethylating molecule in patients who have failed a previous therapy with antibodies directed against PD-1 / PD-L1 already available in daily practice ”.
The scientific basis of this study was developed within the AIRC 5 per thousand project, which includes 5 important Italian institutions and is coordinated by the Siena Center. “Thanks to the commitment of the Sienese hospital-university company – concludes Maio – in May 2020 we also inaugurated the new Phase I Clinical Trials Center, which will allow us to welcome and follow in an increasingly effective way the cancer patients who come from all over Italy”.
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