First-line treatment in NSCLC harboring EGFR common mutations: EGFR TKI in monotherapy or in combination with anti-VEGF?

KEYWORDS:

• NSCLC
• EGFR
• bevacizumab
• angiogenesis
• erlotinib
• tyrosine kinase inhibitor
• TKI

In the last years, the treatment paradigm of patients with epidermal growth factor receptor (EGFR)-positive non-small-cell lung cancer (NSCLC) changed dramatically. Before the advent of EGFR tyrosine kinase inhibitors (TKIs), first-line platinum-based chemotherapy was the cornerstone in the treatment of NSCLC, reaching a median survival of about 10–12 months [1,2].

The identification and the improvement in the knowledge of the EGFR family (including four members, known as HER1, HER2, HER3, and HER4) and its related TKIs allowed us to treat approximately 10–14% of patients affected by EGFR-positive NSCLC with a different perspective, in terms of efficacy, safety, and quality of life (QoL) [3,4].

From 2009 to 2016, several randomized clinical trials, evaluating different EGFR TKIs such as afatinib, erlotinib, and gefitinib confirmed their high efficacy in first-line setting for patients with NSCLC harboring EGFR mutations, in particular for exon 19 deletion and exon 21 L858R, in which the median survival is significantly more than the survival achieved with the only standard chemotherapy [5].

Despite these very interesting results, an efficacy plateau was reached in both progression-free survival (PFS) (10/12 months) and overall-survival (28/30 months), independently from reversible (erlotinib and gefitinib) or irreversible (afatinib) EGFR TKIs [4–6].

Different factors and reasons affected this issue of critical importance. Understanding the EGFR pathway should explain this efficacy plateau. Indeed, the activity of EGFR TKIs is crucial to induce signaling alteration in EGFR-mutant lung cancer cells. Preclinical data showed that EGFR TKIs (es. erlotinib) are able to induce the activation of signal transducer and activator of transcription 3 (STAT3) signaling of survival thought a mechanism of resistance of the MET-independent activation [7,8]. Consequently, the activation of STAT3 promotes the up regulation of anti-apoptotic gene, as Bcl-2, Bcl-XL, and c-Myc, which leads to persistent cell proliferation and several other genes involved in angiogenesis, such as hypoxia-inducible factor 1-alpha (HIF1A) [9].

In approximately 50–60% of EGFR-positive patients with NSCLC, the primary mechanism of acquired resistance to the EGFR TKIs used in first-line setting is the development of EGFR exon 20 T790M mutation.

This mutation leads to an enhanced affinity for ATP, thus reducing the ability of ATP-competitive reversible EGFR TKIs, including afatinib, erlotinib, and gefitinib, to bind to the tyrosine kinase domain of EGFR. Until now, no robust data are available to understand whether the combination treatment of EGFR TKI and bevacizumab can delay the development of T790M mutation. Although, there is no data available to understand whether antiangiogenic agent can delay the development of T790M or not, we hypothesize that the high efficacy of the combination treatment may delay resistance related to T790M mutation.

STAT3 plays a strategic role in tumor angiogenesis [10,11]. In particular, the angiogenesis plays an essential role in tumor growth, proliferation and metastasis process. In this view, hypoxia represents the stimulation factor, which drive to overproduction of pro-angiogenic factors that downstream transduction signal leading to endothelial proliferation, differentiation, permeability, migration, and the generation of new blood vessels. These molecular mechanisms STAT3-mediated are essential for the tumor angiogenesis, which is characterized by the formation of abnormal, tortuous, and poorly organized vessels with altered permeability [9].

Although the development of knowledge about angiogenesis is perpetually in progress, to date the issue to find robust and reliable biomarkers remain unsolved. Despite this lack, data about the use of antiangiogenic agents as bevacizumab, nintedanib, and ramucirumab showed an improved survival in patients with NSCLC when used in addition to chemotherapy (first- and second-line) or target agents (first-line) [12].

Considering patients with EGFR-positive NSCLC, the randomized Phase 2 trial (JO25567) comparing bevacizumab plus erlotinib versus erlotinib alone, showed interesting results for clinical practice. In this trial, 154 Asian patients with non-squamous NSCLC carrying common EGFR mutations (either exon 19 deletion or Leu858Arg mutation) were enrolled and assigned to the two arms of treatment, with the primary endpoint of PFS, as determined by an independent review committee. Exclusion criteria to receive bevacizumab included concomitant anticoagulant treatment, central tumor location, and the presence of cavitation [13].

The results showed a significant improvement in progression-free survival for patients receiving the combo-treatment (erlotinib plus bevacizumab): 9.7 vs. 16.0 months (HR 0.54 [95% CI 0 · 36–0 · 79]; p = 0 · 0015). The high efficacy of this combination was confirmed in all evaluated subgroups.

Combo-treatment was characterized by a high rate of side effects (AEs) related to bevacizumab, such as hypertension (all grade 76% vs. 13%) and proteinuria (52% vs. 4%); serious adverse events (SAEs) were similar in both groups: (24% patients in the erlotinib plus bevacizumab group and 25% of patients in the erlotinib-alone group). These side effects resulted well manageable with no effect on discontinuation rate, which was of 16% in the combo group and 18% in the erlotinib group [13].

In addition to these interesting results reported by Seto et al, the European BELIEF study evaluated the role of the combination of erlotinib and bevacizumab in patients harboring EGFR mutation, stratified according to the presence of T790M mutations, evaluated through the TaqMan assay peptide nucleic acid (PNA)-mediated PCR clamping. This method is able to improve the T790M detection rate from 1 to 8% of conventional DNA sequencing to 35–65%. The preliminary results showed that median-PFS was 16 months in T790M-positive arm (95% CI, 13.1-NE) and 10.5 months without T790M (95% CI, 9.2–16.2), confirming the high efficacy of this treatment and opening a new view on the role of EGFR T790M mutation, although the best method of analysis for these biomarkers has yet to be identified [14].

Waiting for the results of the BEVERLY trial, an ongoing randomized Phase III study evaluating the high efficacy of the combination of erlotinib plus bevacizumab versus erlotinib in 200 Caucasian patients [15], the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recently adopted a positive recommendation for the use of bevacizumab in addition to erlotinib for patients with non-squamous EGFR-positive NSCLC; starting the process that will bring the use of this very effective combination in daily clinical practice.

Although these results are exciting for clinical practice, some issues remain unsolved to select the best treatment for the first-line setting in this cluster of patients. As first, there is no data about the T790M mutation incidence evaluated with conventional DNA sequencing, in patients treated with the combo treatment [16,17]. In particular, it is unclear if the use of bevacizumab could reduce the rate of T790M, limiting the subsequent treatment with third-generation of EGFR TKIs, such as osimertinib or olmutinib.

A second issue of high value is the efficacy of third-generation EGFR TKIs to be used in first-line setting. For example, the FLAURA study, a randomized double-blind Phase III, comparing osimertinib versus gefitinib or erlotinib in about 650 treatment-naïve patients with advanced EGFR-positive NSCLC, is currently ongoing and should be empowered to resolve different issues in terms of efficacy of EGFR-TKIs [18].

Is it better to have an EGFR TKIs sequence (gefitinib/erlotinib/afatinib followed by osimertinib in T790M+ patients) or EGFR third-generation as front-line therapy?

Waiting for the results of these interesting trials, based on the multitude of data available about EGFR TKIs in patients with EGFR-positive NSCLC, we can consider the PFS as the most important landmark for patients with NSCLC harboring EGFR mutation receiving EGFR TKIsIn our opinion, although we should wait for the results of the BEVERLY trial, the potential role of the combo-treatment with erlotinib plus bevacizumab looks very promising for this group of patients with EGFR druggable common mutations, suggesting this combo-treatment as a new gold option in EGFR-positive first-line setting.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.