NSCLC remains the leading cause of cancer death in Western Countries. Lung adenocarcinoma has been extensively investigated and during the last 10 years several molecular events, including mutations, gene copy number alterations and translocations have been discovered, leading to a dramatic change in patient treatment. This is the case of EGFR mutant NSCLC in which drugs targeting the EGFR, such as gefitinib, erlotinib or afatinib, have demonstrated superiority versus standard chemotherapy. Osimertinib, (AZD9291, Tagrisso, AstraZeneca) is a third-generation EGFRTKI which irreversibly and specifically targets both sensitizing and the resistant T790M-mutated EGFRs. It has shown greater efficacy against EGFR T790M mutation than the standard platinum plus pemetrexed therapy and was thus recently fully approved by the FDA for metastatic EGFR T790M-positive NSCLC1. More recently, the large phase III FLAURA study, comparing osimertinib versus the first-generation EGFR-TKIs gefitinib or erlotinib, demonstrated the superiority of osimertinib in terms of progression-free survival (PFS; median PFS 18.9 months versus 10.2 months; HR: 0.46; p\<0.0001)2. Based on this result, in October 2017, the FDA has granted Breakthrough Therapy Designation (BTD) for osimertinib for the first-line treatment of patients with metastatic EGFR mutation-positive NSCLC. In addition, the FLAURA trial clearly established the superiority of osimertinib even in special populations, including individuals with brain metastases. Due to these results, international consensus confirms osimertinib to be the standard of care as first-line therapy for NSCLC patients with EGFR M+ and as second-line therapy in patients with clinically relevant progression and confirmed T790M+. Dacomitinib (PF-00299804, Pfizer) is a second-generation, irreversible EGFRTKI, that has shown efficacy in NSCLC patients with EGFR mutations. Preclinical data showed that the drug is more potent than first-generation EGFR-TKIs, thus leading to comparative studies. The phase III ARCHER 1050 trial compared first-line dacomitinib versus gefitinib in patients with EGFR Del19 or L858R mutation-positive NSCLC. The trial met its primary endpoint, demonstrating a PFS improvement in favor of dacomitinib, (median PFS 14.7 months versus 9.2 months; HR: 0.59; p\<0.0001) and, most importantly, it significantly prolonged OS (median OS 34.1 months versus 26.8 months; HR: 0.76; p=0.048). The most frequent adverse events (AEs) with dacomitinib were diarrhea, skin rash and stomatitis, requiring dose reduction in more than 60% of patients3. Importantly, patients with brain metastases were excluded precluding any conclusion on dacomitinib efficacy in this clinically relevant subgroup. Even with such limitations, indirect comparison with FLAURA showed that PFS was similar to that obtained with osimertinib, particularly in the Asian population, raising the question on the optimal sequencing of drugs. Data from different phase III studies suggested that median PFS with first- or second-generation EGFR-TKIs followed by osimertinib could be superior to the current standard of care, which is osimertinib followed by platinum-based chemotherapy. An important consideration is that only a fraction of patients receiving first- or second-generation EGFR-TKIs are eligible for osimertinib, because EGFR-T790M mutation occurs in up to 50% of cases. Therefore, at present, platinum-based chemotherapy is the only available option for EGFR-T790M negative patients. This algorithm is supported by the lack of efficacy of immunotherapy in presence of EGFR mutations, even if no study so far has been specifically conducted in patients progressing to first-line EGFRTKIs.

Optimised EGFR TKI sequencing might be the most critical determinant of OS in patients with activating EGFR mutations. Data on OS will help to understand the best sequence for each individual patient. Based on these premises, there is a strong rationale for conducting a trial exploring the best EGFR-TKI sequencing (i.e., that to achieve optimal clinical outcomes) in advanced or metastatic NSCLC individuals with EGFR mutations.