Objective. To establish first-line therapy for advanced non-small-cell lung cancer (NSCLC), especially taking into account that patient’s light smoking history testing for EGFR mutation is a fundamental step.
In patients whom biopsy is not possible, genotyping of cell-free DNA circulating in plasma is now an available alternative, and one called “liquid biopsy” has received US Food and Drug Administration (FDA) approval. The EGFR mutation is the most targetable genotype in NSCLC.
A French study about molecular profiling of patients with advanced non-small-cell lung cancer concluded: “Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit”(1).
Another study about the multiplex test encourages the widely use of genotyping determination to decide the first-line therapy in NSCLC. Another important conclusion of this study was that individuals with drivers receiving a matched targeted agent lived longer(2).
D’Angelo S. et al. had studied a large number of EGFR mutations found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. The authors show that if only women who were never smokers were tested, 57% of all EGFR mutations would be missed. They recommend that testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number of people with the potential for substantial benefit(3).
An important finding was the observation that dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. In a study led by Tony Mok, in patients with EGFR mut(+) cfDNA at baseline, median PFS was 7.2 versus 12 months for cycle 3 EGFR mut(+) cfDNA versus cycle 3 EGFR mut(-) patients, respectively (HR 0.32; 95% CI, 0.21-0.48; P<0.0001)(4).
In the management of non-squamous NSCLC with EGFR mutations, the liquid biopsy was an important progress. Plasma dd PCR can detect EGFR and KRAS mutations rapidly with the high specificity enhancing the selection of therapy and avoiding repeated biopsies. This assay may also detect EGFR T790M missed by tissue genotyping in resistant disease(5).
At the moment, FDA approved three oral EGFR TKIs for first-line treatment of EGFR-mutant NSCLC. For researchers is not clear which of these three drugs is the optimal first-line therapy, and it is likely that they are all comparable. Each of these three drugs has its particularities. Gefitinib is administered at a flat dose (250 mg daily) with no dose reductions. Erlotinib has the greatest flexibility in dosing comparing to gefitinib and afatinib. The approved dose is 150 mg daily, but retrospective series have described a high response rate with 100 mg daily and anecdotal activity at 25 mg daily(7).
Afatinib inhibits both EGFR and human epidermal growth factor receptor 2 (HER2) in a covalent way. This TKI inhibitor has a slightly different toxicity profile than other EGFR TKIs, with more diarrhea and mucositis and paronychia. A head-to-head trial (LUX-Lung 7) compared afatinib with gefitinib. The conclusion was that afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. However, despite a better progression free survival (PFS) with afatinib (hazard ratio [HR] 0.73), no difference in overall survival was noticed(8).
Clinical research demonstrated that erlotinib in monotherapy was active and well tolerated in NSCLC patients with brain metastases(9). This finding is important because, generally, old patients do not tolerate very well radiotherapy. A trial in China (CTONG 1201) randomized patients with advanced EGFR-mutant lung cancer and at least 3 brain metastases to icotinib (an EGFR TKI used in China) versus whole brain radiation followed by chemotherapy(13). The EGFR inhibitor was superior in terms of PFS, as well as CNS response rate. Thus, in patients with asymptomatic brain metastases and an EGFR mutation, brain radiation can be deferred in favor of systemic therapy with an EGFR TKI.
A treatment schedule represented by the association between erlotinib and bevacizumab was approved by ESMO as an option for advanced non-squamous carcinoma of the lung after a positive study. One of the arguments in favor of this decision was a phase II study which was published in Lancet Oncol in 2014. This study compared the efficacy and safety of the combination of erlotinib and bevacizumab with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC(10).
Another phase II study compared bevacizumab, pemetrexed and cisplatin, or bevacizumab and erlotinib for patients with advanced non-small-cell lung cancer stratified by Epidermal Growth Factor Receptor mutation. The authors concluded that both combination therapies were promising for further studies and both schedules of treatment had similar results(11).
The osteoblastic bone flare or response is the paradoxical phenomenon of increase in the quantity and/or density of bone lesions in the presence of well-documented disease response to treatment in other tumor sites. It results from the rapid repair and increased osteoblastic activity in bone metastases responding to therapy and therefore represents the treatment efficacy. The awareness of this phenomenon with epidermal growth factor receptor tyrosine kinase inhibitors is important for physicians treating patients with NSCLC, so that it is not misinterpreted as progressive disease resulting in premature cessation of effective therapy(12).
A problem that arises in the treatment with TKIs is represented by acquired resistance to epidermal growth factor receptor kinase inhibitors. Strategies for managing acquired resistance in patients with advanced non-small-cell lung cancer are complex and must be adapted to the individual characteristics of each patient(13).
A step forward was the discovery that patients with T790M-positive and advanced NSCLC had disease progression after first-line EGFR-TKI therapy and the cause is represented by the presence of T790M gene. A phase III study led by Tony Mok tested T790M osimertinib. This drug had significantly greater efficacy than platinum therapy plus pemetrexed (another option to overcome the acquired resistance to TKIs) in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom the disease had progressed during first-line EGFR-TKI therapy(14).
Regarding treatment with osimertinib, the value of association between plasma genotyping and outcomes of treatment with osimertinib was highlighted by the results of a retrospective study. In this retrospective analysis, patients positive for T790M in plasma had outcomes with osimertinib that were equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine the presence or absence of T790M(15).
Another issue regarding the treatment with TKIs is the therapeutic conduct after disease progression. We present the conclusion of a study in this direction. Anecdotal experience suggests that erlotinib may provide continuous disease control after patients develop objective progression of disease (PD), although this has not been systematically investigated when the study started. The conclusion of this retrospective study was that a change in systemic therapy commonly can be delayed in patients with EGFR-mutant lung cancer who objectively progress on first-line erlotinib, particularly in those with a longer time to progression, a slow rate of progression, and a lack of new extrathoracic metastases(16).
In the treatment with TKIs appears a situation when reconsidering the criteria for progression was necessary to be introduced. This situation occurred when progressive disease did not mean treatment failure. The problem is that RECIST used to define the disease progression in clinical trial don’t cover the evaluation of results by progression-free survival. Now that progression-free survival has become an increasingly important trial endpoint, the criteria that define progression deserve critical evaluation to determine whether alternate definitions of progression might facilitate the development of stronger surrogate endpoints and more meaningful trial results(17).
If we go back to the treatment with osimertinib, we must also address the acquired resistance to this drug. A study of Thress K.S. et al. found a gene mutation responsible for acquired resistance. The researchers performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; the expression of this mutant EGFR construct in a cell line rendered it resistant to osimertinib(19).
In 2016, Gainor J.F. and col. analyzed the immunotherapy using PD-1/PD-L1 inhibitors for patients with advanced NSCLC and EGFR mutations or ALK rearrangements after progression under therapy with TKIs or ALK inhibitors. The conclusion was that NSCLCs harboring EGFR mutations or ALK rearrangements were associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8(+) TILs within the tumor microenvironment may underlie these clinical observations(20). A meta-analysis of three trials comparing second-line docetaxel with an immune checkpoint inhibitor found no overall survival benefit “in a total of 186 patients with EGFR-mutant lung cancer (HR 1.05; 95% confidence interval [CI]; 0.70-1.55). Moreover, the phase 1 TATTON trial that studied osimertinib in combination with a PD-L1 inhibitor, durvalumab, found an increased incidence of interstitial lung disease”, potentially suggesting risk for patients when osimertinib and immune checkpoint inhibitors are given in proximity(21). For this reason, PD-1 and PD-L1 inhibitors are not indicated in patients with EGFR-mutant NSCLC and should be reserved until patients have failed at least one or two lines of chemotherapy.