Interview: “Survival is the result of multiple treatment lines”

Nicolas Girard, MD, PhD Institut Curie, Institut du Thorax Curie-Montsouris, Paris, France

To what extent will the data of the FLAURA trial that explored first-line use of osimertinib in patients with EGFR-mutated advanced NSCLC change clinical practice?

FLAURA is a positive trial, as its results favour osimertinib over gefitinib and erlotinib. Now we have to consider this among the multiple options that are available for the first-line treatment of EGFR-mutant lung cancer. Besides osimertinib, there are the first-generation TKIs erlotinib and gefitinib and the se­cond-generation TKI afatinib, but maybe sometime soon also dacomitinib, for which data were presented at the last ASCO Meeting [1].
Before starting treatment for a patient with EGFR-mutant lung cancer, it is neces­sary to consider the global sequence. We need to look at subsequent treatment options, including chemotherapy and other options, and to think about resis­tance mechanisms. It is important to understand what the best sequence for each patient is. Is it osimertinib upfront, or is it the sequence of first-generation or second-generation TKIs followed by osimertinib, based on the AURA3 data [2]?

How does sequencing of different EGFR-directed agents affect survival?

The ultimate objective of the anti-EGFR treatment sequence is improvement in survival. We clearly need to increase PFS, but I think that the median PFS results of first-line and second-line treatment do not necessarily add up to the actual OS of the patient. At this congress, Dr. Sequist et al. reported on subsequent treatments after afatinib in the LUX-Lung 3, 6 and 7 trials, showing that the OS of patients was far longer than the sum of median PFS results after several lines of treatment [3]. Clearly, there is an impact of the previous treatment on the effect of the subsequent therapy. This is mostly driven by tumour biology and by the emergence of the T790M resistance mutation, but possibly also by other resistance mechanisms to osimertinib that have not been identified yet.

What are the consequences for clinical practice?

We clearly need more data on sequencing of drugs in clinical trials. In addition, in order to guide our clinical decisions, we need to have a close clinical and radiological follow-up of patients, but also a molecular follow-up. One point is safety. We are aware that side effects might occur more frequently with second-generation TKIs, although after 10 years of experience with EGFR TKIs, we know how to prevent and manage these side effects. However, this is a factor to consider with respect to the global patient quality of life.

References

1. Mok T et al., Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase III trial. J Clin Oncol 2017; 35 (suppl; abstr LBA9007)
2. Mok TS et al., Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2017; 376: 629-64
3. Sequist LV et al., Subsequent therapies post-afatinib among patients with EGFR mutation-positive NSCLC in LUX-Lung (LL) 3, 6 and 7. ESMO 2017 Congress, abstract 1349P