Several reasons support sequencing of EGFR TKI treatment

Maximilian Hochmair, MD, Respiratory Oncology Unit, Department of Respiratory and Critical Care Medicine, Otto Wagner Spital, Vienna, Austria

Maximilian Hochmair, MD, Respiratory Oncology Unit, Department of Respiratory and Critical Care Medicine, Otto Wagner Spital, Vienna, Austria

The first-line EGFR TKI choice in patients with EGFR-mutated NSCLC has been under debate ever since the results of the FLAURA were reported. From the current point of view, what are the limitations of this study?
The FLAURA trial has demonstrated a survival benefit of first-line osimertinib compared to gefitinib and erlotinib [1], but the fact that afatinib was not included in the control arm diminishes the insights that can be obtained based on this trial. Also, it cannot answer the question of sequencing, as T790M mutation testing was not mandatory in patients progressing on erlotinib or gefitinib, and osimertinib was not provided as a subsequent treatment. Only approximately 25 % of patients received osimertinib. We will therefore not be able to draw any conclusions here.
In Austria, afatinib is generally prescribed in the first-line setting in patients with EGFR-mutant NSCLC. A particular survival benefit has been demonstrated in patients with deletion 19 in the LUX Lung 3 and 6 studies [2]. We also know that afatinib doses can be reduced without loss of efficacy. On the other hand, if first-line osimertinib is used, resistance frequently poses a problem. Druggable targets are much rarer after failure of osimertinib than after failure of afatinib [3, 4]. In 60 %, no driver mutations are found at all. After the emergence of resistance to osimertinib, chemotherapy is the only option in most of the patients.

What would be the ideal sequence in a patient with EGFR-mutant NSCLC?
There are several reasons that support the sequence of afatinib followed by osimertinib. One is the prevalence of the resistance mutation T790M at the time of progression on first- or second-generation EGFR TKIs, which is as high as 60 % to 75 %. There is no question about the benefit of osimertinib in patients who have developed the T790M mutation. Another reason is the favourable long-term outcomes. At my centre, afatinib followed by osimertinib is routinely used, and we have seen many patients who derived great benefits. Patients generally tend to remain on afatinib and osimertinib treatment for extended periods of time.
Data presented at the ESMO Congress also emphasise the significance of afatinib as an effective first-line drug. A retrospective study showed that afatinib followed by osimertinib in any line provides significantly improved response rates and disease control rates compared to first-generation EGFR TKIs followed by osimertinib [5]. This is in keeping with a Japanese real-world analysis of 1,354 patients who were treated with either gefitinib, erlotinib, or afatinib [6]. The investigators noted a trend towards longer OS for afatinib compared to first-generation EGFR TKIs even after adjustment by propensity score.

What can be expected from the sequence in terms of treatment duration?
A retrospective analysis of the LUX-Lung 3, 6 and 7 studies showed that in patients who received osimertinib after afatinib, median time on osimertinib in any treatment line was 20.2 months [7]. According to a soon-to-be-published analysis conducted at our institution, 67 patients received afatinib and osimertinib for 12 months each, and half of them were still on osimertinib treatment at the time of the analysis. The global GioTag trial that was recently published assessed the time on treatment with first-line afatinib followed by osimertinib in a real-world setting [8]. Data were only collected in patients who had started osimertinib 10 months prior to data entry. Overall, 204 patients from ten countries received the sequence, and in 48 %, the treatment is still ongoing. The results were very encouraging. In the entire population, median time on treatment with the sequence was 27.6 months. Time to treatment failure was 11.9 months with first-line afatinib and 14.3 months with second-line osimertinib. This confirms our observations in smaller patient cohorts. At 24 and 30 months, 79 % and 69 % of patients, respectively, were alive. Time on treatment with the sequence was longer in patients with deletion 19 than in those with L858R mutation (30.3 vs. 19.1 months). Also, good baseline performance status, i.e., ECOG PS 0/1, was associated with longer treatment duration of 31.3 months compared to 22.2 months in patients with ECOG PS ≥  2. Cerebral control was achieved with frontline afatinib and with the introduction of osimertinib upon progression.

How do you rate the CNS activity of afatinib compared to the CNS effects of osimertinib?
Brain metastases can be treated very well with both afatinib and osimertinib. Actually the majority of data on the effects of EGFR TKIs in patients with CNS lesions have been obtained for these two drugs. Afatinib enters the cerebrospinal fluid and accumulates in relevant concentrations [9]. At our institution, we observed complete and long-lasting cerebral remissions with afatinib treatment in a number of patients [10]. Afatinib also appears to have protective effects against CNS metastases, as patients without brain lesions have been shown to develop mainly non-CNS progression on treatment [11].


  1. Soria JC et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378: 113-125
  2. Yang JC et al., Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16(2): 141-151
  3. Ramalingam SS et al., Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the double-blind, randomised phase III FLAURA study. ESMO 2018, abstract LBA50
  4. Papadimitrakopoulou V et al., Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. ESMO 2018, abstract LBA51
  5. Tamiya M et al., Which is better EGFR-TKI followed by osimertinib between afatinib and gefitinib/erlotinib? ESMO 2018, abstract 1459P
  6. Ito K et al., Comparative analysis of overall survival using propensity score between first- and second-generation EGFR TKI: real world data of 1,354 patients with EGFR mutant NSCLC. ESMO 2018, abstract 1455P
  7. 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, abstract 1349P
  8. Hochmair MJ et al., Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer: an observational study. Future Oncol 2018 Oct 19. doi: 10.2217/fon-2018-0711. [Epub ahead of print]
  9. Tamiya A et al., Cerebrospinal fluid penetration rate and efficacy of afatinib in patients with EGFR mutation-positive non-small cell lung cancer with leptomeningeal carcinomatosis: a multicenter prospective study. Anticancer Res 2017; 37(8): 4177-4182
  10. Hochmair M et al., Complete remissions in afatinib-treated non-small-cell lung cancer patients with symptomatic brain metastases. Anticancer Drugs 2016; 27(9): 914-915
  11. Girard N, Optimizing outcomes in EGFR mutation-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol 2018; 14(11): 1117-1132