What changes in practice have been brought about by the recent advances in the treatment of lung cancer?
In the context of progress obtained in the field of precision medicine in the last 10 years, the assessing of molecular differences between patients allows for a personalised approach, which means that the efficacy of the treatments is approximately three times that of treatments without any mutational selection. The anti-EGFR strategies have completely changed the face of treatment, because these mutations show the greatest incidence globally, and many trials have been conducted in this field. A patient with an EGFR-mutated tumour who receives anti-EGFR treatment can survive for more than 30 months. On the other hand, for a patient with adenocarcinoma without mutation, survival ranges between 8 and 10 months. Also, the quality of life is very high with treatment that consists of a pill that is taken daily at home. Here, we see large differences compared to chemotherapy, also with regard to toxicity.
Can you observe the same benefits in your own patients as shown in the trials?
Yes, and these benefits are even improved upon. Registration trials on EGFR inhibitors use the RECIST criteria, which are radiological criteria. In clinical practice, however, we use a broader evaluation, which is not confined to radiological criteria. We do not consider a progression of 2 millimetres, for instance, as an indication for discontinuation of treatment, and we continue to use local treatment. This way, the benefits achieved in the registration studies are almost doubled in practice.
Are new treatments being implemented in the real-world setting to a sufficient degree?
Precision medicine is based on genomic alterations. Up to now, molecular testing has been exclusively performed on tissue samples, but it is not possible to obtain tissue and receive this information in all cases. In nearly 40 % of patients, EGFR mutation or ALK rearrangement testing is impossible at the time of diagnosis of an adenocarcinoma of the lung. Not all hospitals are linked to distinguished molecular laboratories, and the time that elapses until the results come back varies between 6 or 8 working days in some academic centres, and 20 days in the south of Europe. The oncologist might decide to start chemotherapy treatment without waiting for the results, according to the degree of symptoms.
On a scientific level, are there currently any trends that are particularly promising?
One of the most interesting developments in the diagnostic field is liquid biopsy, which we have started to use at the European Institute of Oncology in Milan. Mutations can be diagnosed based on blood samples within 2 hours. To my mind, this is a revolution, because patients that have not yet benefited from modern treatments due to the issues involved in biopsy assessment can be prescribed targeted therapy thanks to liquid biopsy. It is estimated that more than one third of patients would be eligible for biologicals but are not being treated with the right drug. To date, there are two academic centres in Milan that perform this kind of test, but I am confident that this proportion will swiftly increase. Also, the costs of liquid biospy are moderate, which will contribute to this development.
With regard to treatment, immunotherapy is of course promising, but I think that some additional data is called for to select those patients who will particularly benefit from the treatment. It is not certain that immunotherapy works for all patients, which means that we have the same problem as with the targeted agents. The significance of the PD-L1 expression levels has been investigated, but trials have yielded conflicting results. Different assays for the measurement of PD-L1 levels are being used by different companies. This is a debated problem. Nivolumab was approved in the second-line setting in patients with squamous histology independent of biomarker expression. For patients with adenocarcinoma, on the other hand, the CheckMate 057 study showed that those expressing PD-L1 experienced higher efficacy of nivolumab than those without PD-L1 expression. We need more trials to clarify whether PD-L1 is the ideal biomarker. Also, the costs of immunotherapy must be taken into account. Selecting patients by means of biomarkers is of course cost-saving.
Which molecular targets are of particular interest?
At present, the story of molecular targeting is the story of EGFR mutation and ALK translocation. Second-generation ALK inhibitors such as ceritinib and alectinib offer better results compared to those achieved with the first-generation ALK inhibitor crizotinib. Recently, ceritinib was registered in the US by the FDA and in Europe by the EMA for the treatment of patients with ALK-positive advanced NSCLC after failure of crizotinib. The phase III ALEX trial is currently evaluating alectinib in the first-line setting of advanced ALK-positive NSCLC, in comparison to crizotinib.
For EGFR, second-generation and third-generation inhibitors are being tested. Rociletinib and AZD9291 have shown positive phase I and phase II results in patients expressing the T790M mutation resistance. With these agents, it is possible to obtain survival results similar to those observed in first line treatment. Therefore, a chemo-free schedule is being designed that includes second-line treatment with a biological after a first-line biological. This is of importance for the patients, as chemotherapy is not very popular with them.
Will chemotherapy disappear in the long run?
No. It will be possible to increase the percentage of patients treated without chemotherapy, but I do not think that chemotherapy will disappear from the schedules in the next 10 years. Research efforts will focus on combinations of chemotherapy with other options.
Interview: Filippo de Marinis, MD, PhD, Director of the Thoracic Oncology Division at the European Institute of Oncology (IEO), Milan, Italy