The availability of several treatment options in epidermal growth factor receptor mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC), poses a challenge for clinicians as to what to consider when choosing the best treatment sequence?
First, a fast and comprehensive mutation screening is required to define subpopulations benefiting from target therapies, which should include, at present time, at least EGFR, ALK, ROS1 and BRAF genes.1
Choosing the first-line treatment should take into account several clinical and drug-related factors, such as pharmacological profile, efficacy, toxicity and progression mechanisms. Also, the first-line option will influence the treatment sequence.
There are currently several first-line treatment options available for EGFR M+ NSCLC patients, known as first (1G), second (2G) and third-generation (3G) EGFR tyrosine kinase inhibitors (TKIs) (Table 1).
EGFR TKIs profile.
| Mechanism of action | Advantages | Disadvantages | |
|---|---|---|---|
| 1G EGFR TKI | Blocks the activity of the tyrosine kinase receptor by reversibly binding the adenosine triphosphate site | Higher efficacy than chemotherapyBetter toxicity profile than platinum-based chemotherapy | Unknown benefit in uncommon mutationsLack of efficacy in presence of T790M mutationLimited data on CNS activity |
| Erlotinib | Allows dose adjustments | ||
| Gefitinib | Does not allow dose adjustments | ||
| 2G EGFR TKI | ErbB family irreversible inhibitors | Higher efficacy than chemotherapy and 1G EGFR TKI Allows dose adjustments | Lack of efficacy in presence of T790M mutation |
| Afatinib | Higher efficacy than 1G EGFR TKIProven efficacy even with dose reductionsApproved for uncommon mutationsLow hepatic toxicity/Less drug-to-drug interactionsActivity in CNS BM | Requires dose management due to the toxicity profile | |
| Dacomitinib | Unknown activity in the SNC and in uncommon mutations | ||
| 3G EGFR TKIOsimertinib | Developed to specifically and irreversibly target T790M mutationLower activity against wild-type EGFR | Efficacy in presence of T790M mutationCNS activityLess toxicity/Fewer severe AEs | Heterogeneous resistant mechanismsOS not yet known |
1/2/3G, first/second/third generation; BM, brain metastases; CNS, central nervous system; EGRF, epidermal growth factor receptor; OS, overall survival; RR, response rate; T790M, substitution of a threonine (T) with a methionine (M) at position 790 of exon 20; TKI, tyrosine kinase inhibitors; TTF, time to treatment failure.
Several phase III trials demonstrated superior efficacy of erlotinib (OPTIMAL, EURTAC, ENSURE), gefitinib (First-SIGNAL, IPASS, WJTOG3405, NEJ002) and afatinib (LUX-Lung 3, LUX-Lung 6) versus standard platinum-based chemotherapy.2 Toxicity profile and quality of life were also superior.3
Two head-to-head trials (LUX-Lung 7 and ARCHER 1050) compared the efficacy and safety of 1G and 2G TKIs. In the LUX-Lung 7, afatinib showed superior efficacy over gefitinib considering progression free survival (PFS), time-to-treatment failure (TTF) and the objective response rate (ORR). Also, a positive, but not statistically significant, trend was observed on overall survival (OS), favouring afatinib.4,5
The phase III ARCHER 1050 trial compared dacomitinib to gefitinib in the first-line setting, excluding patients with brain metastases (BM).6 Dacomitinib showed benefit on PFS and OS; however, no differences were found in ORR between groups.6,7
More recently, the FLAURA trial compared 3G osimertinib and 1G EGFR gefitinib and erlotinib.8 Osimertinib, in the first-line setting, showed better PFS, longer median duration of response and higher, although not statistically significant, ORR.8 At data cut-off, OS data was immature. Until now, there are no comparative data with 2G TKIs.8
Most of the evidence about EGFR rare mutations, which represent 10–15% of patients,9 comes from afatinib studies, where afatinib showed efficacy in patients with advanced-stage lung adenocarcinomas harbouring non-classical mutations, specifically on S768I, L861Q and G719X mutations.10
Another important clinical factor for first-line treatment decision is the central nervous system (CNS) activity and the presence of BM. Data on the direct intracranial activity of 1G TKIs is limited.9 Regarding 2G, afatinib demonstrated efficacy in patients with asymptomatic BM and delayed CNS progression9; no data is available on dacomitinib.9 Osimertinib demonstrated activity in patients with BM at standard therapeutic doses, and a reduction in CNS progression was also demonstrated.9
EGFR TKIs are associated with a class-related adverse event (AE) profile due to wild-type EGFR inhibition. Although afatinib is associated with a higher percentage of severe AEs, it is well demonstrated that the availability of several doses allows dose adjustments that do not compromise drug efficacy; therefore, the discontinuation rate due to AE was similar between afatinib and gefitinib on the LUX-Lung 7 study.2,4,5,8 Additionally, afatinib undergoes minimal hepatic metabolism and is not a substrate for liver primarily via cytochrome P450 (CYP)-dependent enzymes, having, therefore, a lower probability for drug interactions.9
Despite EGFR TKIs proven efficacy, inexorable disease progression still occurs. For patients with oligometastatic progression, the treatment strategy can be to keep the EGFR TKI, and local radiotherapy should be considered; for systemic progression, treatment should be changed.3
The most common mechanism of resistance related to 1G and 2G TKIs is the acquisition of the gatekeeper mutation in EGFR T790M, which occurs in 50–70% of cases.9
At the time of disease progression, EGFR T790M mutation can be detected through liquid biopsy or tissue rebiopsy.11 If the T790M is not present in the liquid biopsy, a tissue rebiopsy should be performed.11
Since rebiopsy may present some challenges (patients may refuse or not be eligible, progression may occur in an inaccessible location), the use of a highly sensitive liquid biopsy technique, which allows higher percentage of detection and a high agreement rate with the tissue biopsy, may maximise the detection of patients with T790M mutation and, therefore, the number of patients benefiting from osimertinib as a second-line treatment.12
Although a high sensitivity technique for the detection of the T790M mutation is not yet accessible in all hospitals, for hospitals with access to this technique, the choice of first-line therapeutic option may rely on therapeutic sequencing.
Resistance mechanisms to osimertinib present great variability and appear to be heterogeneous, with lack of specific therapeutic options after its use.2,9
Therapy sequencing is a critical point. If the first option is a 1G or 2G TKI, in patients with clinically relevant progression and confirmed T790M+, osimertinib is the second-line standard of care.11 Updated OS data from LUX-Lung 7 shows that sequential therapy with afatinib followed by a 3G EGFR TKI, namely osimertinib, was effective, with a 3-year OS rate up to 90%.5,13
For patients T790M-negative, after progression following 1G or 2G TKI, therapy sequencing is, for now, not applicable, and chemotherapy is the current standard treatment.2
If osimertinib is used in first-line treatment, we can guarantee access for patients that might not be able to use it in 2nd line after progression with a different mechanism than T790M, or patients without the opportunity of a 2nd line. We are still waiting for mature data on OS and PFS2 after first-line treatment with osimertinib.8
Unfortunately, to date, after progression, the standard of care for these patients is only platinum-based chemotherapy. There are many ongoing trials assessing agents that target specific mutations or combinations.2,9,11
With the recent approval from the European Medicines Agency of the combination chemotherapy+atezolizumab+bevacizumab, a new door has opened.
There is no single therapeutic solution for the first-line treatment of NSCLC patients with EGFR M+: depending on the patient's profile and on the access to the liquid biopsy technique that allows the detection of the T790M resistance mutation, the first-line therapeutic option will vary between sequencing approach or the use of a 3G EGFR TKI in 1st line. Optimised EGFR TKI sequencing might be the most critical determinant of OS in patients with activating EGFR mutations. Data on OS from clinical trials and real-life cohorts will help us to understand the best sequence for each individual patient.
Conflicts of interestFernanda Estevinho declares Having received speaking fees from AstraZeneca, Bristol-Myers Squibb, Pfizer, Pierre Fabre and Roche. Participating in advisory boards of Roche and Boehringer Ingelheim.
Margarida Felizardo declares Having received speaking fees from AstraZeneca, Merck Sharp & Dohme and Roche. Participating in advisory boards of Boehringer Ingelheim.
Gabriela Fernandes declares Having received speaking fees from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme and Novartis. Participating in advisory boards of Boehringer Ingelheim.
Ana Figueiredo declares Having received speaking fees from Boehringer Ingelheim, Bristol-Myers Squib, Merck Sharp & Dohme, Bristol, Novartis, Pfizer, Pierre Fabre and Roche. Participating in advisory boards of Boehringer Ingelheim and Merck Sharp & Dohme.
José Albino Lopes declares Participating in advisory boards of Boehringer Ingelheim.
Funding for this paper was provided by Boehringer Ingelheim. Funding was used to access all necessary scientific bibliography and cover meeting expenses. Boehringer Ingelheim had no role in the writing of the paper and in the decision to submit the paper for publication.
