VIII Franco Brazilian Congress of Oncology
Ipilimumab may improve outlook of metastatic melanoma in the elderly
Dr Antonio Grimaldi – National Cancer Institute of Napoli, Italy
For a lot of years melanoma has been a big problem for medical oncologists. As the Korn meta-analysis of 2008 showed, there was a median progression free survival of 1.7 months and a median overall survival of 6 months with only 25% of patients alive at one year. This has been for a lot of years and this clearly demonstrates that chemotherapy doesn’t work in the treatment of metastatic melanoma. But things changed with the development of the immune checkpoint blockade. It was recognised that CTLA4 is a receptor on the T-cell that goes to inhibit the immune response, the T-cell immune response. So if we can block the CTLA4 we can take out the brake to the immune system and it can work. And it works, as shown in a phase III trial MDX010-20, ipilimumab, the anti-CTLA4 monoclonal antibody, was able to improve for the first time the median overall survival of patients. If we analyse the Kaplan-Meier overall survival curve we see that we can divide it into two parts: the first part where there’s no separation in the curves when we compare ipilimumab with immune therapy or with the combination of ipilimumab plus immune therapy because in the first three months you have the building of the immune response. Then after this phase the separation of the curves with an advantage of about four months in median overall survival. But the real impact is after when you have the long-term survival with a plateau of patients with about 20-25% of patients that are alive at two years and this data are confirmed in data at three years, seven years and ten years too. So we can consider cured about 20% of patients affected by metastatic melanoma, so doubling the data that were identified by the meta-analysis of Korn of 2008. So not a lot of years ago, only six years ago.
These things have been demonstrated not only in a phase III trial but even in the Italian expanded access programme because ipilimumab was approved by the FDA and EMA in 2011 according with the results of the phase III trial we told you before, but in Italy only in 2013. In the meantime it was conducted in the Italian expanded access programme with ipilimumab at 3mg/kg and all the data were analysed. It was a great chance for patients with metastatic melanoma in Italy because if there was not this expanded access they would not achieve this treatment, they would not have this opportunity. And the data resulted absolutely comparable in terms of overall survival, disease count rate, basal response rate, to the ones that emerged from the phase III trial. Even in terms of safety there was no new toxicity compared with the ones observed in the phase III trial and the use of the treatments for toxicity could give a good outcome for patients that experienced adverse events.
From this big expanded access programme that enrolled 855 patients in 55 centres in Italy emerged a lot of information that is very important for the medical oncologists. For example, there’s an equal efficacy in patients mutated in BRAF and without this BRAF mutation. The same is for patients with mutational NRAS and without this mutation. Another important topic is that the side effects don’t mean to have the response because data from the Italian expanded access programme showed that they are the same data for patients that had adverse events and patients that did not have them. The same is for survival. Similar data were observed in some populations that were considered with high risk subpopulations like the ocular melanomas, there’s a good outcome for these patients too. There’s good activity in patients with mucosal melanoma and then interesting data from elderly patients. Elderly patients older than 70 years old have the same benefit, if not a better outcome, than patients that are younger than 70 years old.
So these are only the analysis of the Italian expanded access programme but have been performed in a lot of other ancillary studies just like the ones about the sequencing of treatment for patients with BRAF mutations. It has been demonstrated that we can’t treat patients with both vemurafenib or a BRAF inhibitor plus ipilimumab together due to the hepatotoxicity just like demonstrated in The New England Journal of Medicine by Antoni Ribas. We can sequence them but which is the best sequence? At our institution we have conducted a retrospective analysis on patients treated at our centre with ipilimumab before and then with BRAF inhibitors and patients that had the inverse sequence. So for all the patients, there were six, that were treated with ipilimumab first all of them when completing the treatment could be treated with a BRAF inhibitor and we know that the outcome is better when you treat with both of the treatments. The patients that were treated with a BRAF inhibitor before were 28 and all of them completed the BRAF inhibitor but 12 of them did not have the chance to come to the ipilimumab because they died before. Because after the progression from the BRAF inhibitor there’s a kind of selection of the patients: about 40-45% of patients die due to drug progression of disease in about 30 days so they have no time to make the four cycles for the induction of ipilimumab. This one, just like other ancillary studies as the one on the [?? 6:29] effect have emerged from the Italian expanded access programme.
