For a long time chemotherapy, platinum-based doublet, has remained the standard of treatment for advanced non-small cell lung cancer, even for frailer elderly patients. For more than ten years several driver mutations have been identified in non-small cell lung cancer, especially in adenocarcinoma. Part of them are real major driver mutations, for example EGFR, ALK translocation, ROS1 translocation and BRAF mutations for example. EGFR mutation which has been the first to be identified in 2004 is the most well-known. We have now three drugs that have obtained their regulatory approval in first line treatment in EGFR mutated patients. We have a greater efficiency with this treatment and the profile of tolerance is good, even for elderly patients. We have some phase II trials that have demonstrated that the outcomes in terms of efficiency are quite equivalent to what have been identified in younger patients with a good toxicity profile. Unfortunately we have an inevitable progression in the EGFR TKIs in these patients and we have now identified several resistance mechanisms and the most frequent is a T790M mutation which occurs in nearly 60% of the patients. This is a key challenge for the clinicians to identify this T790M mutation because now we have a new drug, a third generation EGFR TKI , that has demonstrated that it’s able to overcome this resistance mechanism. We have a phase I and then after more recently a phase II trial that has demonstrated that in this specific population of T790M positive patients we have under imatinib an overall response rate of 70% with a great median PFS of 9.9 months. This is quite equivalent to what we had in first line, in fact, in these pre-treated patients. We can now identify this mechanism of resistance, the T790M mutation, by plasma genotyping with a great sensibility of 70%. Of course if the plasma genotyping is negative the clinician must try to obtain a biopsy in order to realise the analysis of the T790M genotyping.
After the EGFR we have also the ALK translocation and the ROS1 translocation which occur in nearly 4% for ALK translocation and 2% for the ROS1 population, that occur predominantly in young patients. These two drivers confer a great sensitivity to crizotinib in first line treatment and for ALK translocation who progress after first line by crizotinib we have new drugs, for example ceritinib which is efficient and new drugs like brigatinib, lorlatinib and, in the near future, alectinib are available.
Another predominant driver is the BRAF mutation. BRAF mutations occur in between 2-4% of the non-small cell lung cancers and the median age of this population of patients is near 65 years old. That means that we can have elderly patients with this BRAF mutation. We have now a phase II trial that enrolled patients with a V600E BRAF mutation and especially one phase II that evaluated the association of dabrafenib, an anti-BRAF, plus trametinib, an anti-MEK compound, with a great efficiency. The overall response rate is 63% and the median PFS 9.7 months. Of course we can have some toxicities but they seem to be manageable. We have no specific data in the elderly population with BRAF mutations.
I will finish with an emergent driver which is less known which is a MET exon 14 skipping mutation. That occurs in 2-3% of patients and what we can note is that the median age of the patients with this alteration is 73 years old. That means that we have real elderly patients with this mutation. This mutation confers a sensibility to crizotinib so of course we need prospective data to confirm the efficiency but that can be easily researched, that can be identified, that can be easily identified by next generation sequencing techniques that, for example, we have available in our centre. So this is an emergent driver that we’ll have to keep in mind for the future.
Would PD1 work in the same geriatric setting?
In phase II trials there are a few that are confirming the elderly patients but we have case reports that show that we can have really encouraging results with these compounds. Trials specifically dedicated to this population of elderly patients will be soon available. The remaining question is, of course, whenever we talk about targeted therapies or immunotherapies is how we can fund all these drugs in the future because all of them are very expensive.