Osimertinib in the Treatment of Non-small Cell Lung Cancer: Design, Development and Place in Therapy

TARGETING EGFR IN NSCLC

The epidermal growth factor receptor (ErbB1 or human epidermal growth factor receptor 1 [HER1]) is a transmembrane receptor with tyrosine kinase activity involved in the regulation of cell proliferation, survival, differentiation and other crucial processes through activation of multiple downstream signaling cascades, including PI3K/AKT, RAS/RAF/mitogen-activated protein kinase (MAPK) and STAT pathways.^25,26 EGFR pathway is often deregulated in a variety of tumor types, including NSCLC, through different molecular mechanisms involving gene encoding for EGFR, such as mutations or amplifications, altered expression of the EGFR protein, or its cognate ligands, EGF, or transforming growth factor-α, establishing autocrine loops that hyperactivate the receptor. Indeed, in squamous cell lung cancer, which is a particularly aggressive disease, EGFR gene amplification occurs in 7%–10% of cases and EGFR protein overexpression is most common in squamous- compared with the nonsquamous NSCLC.^27,28 Somatic activating mutations of EGFR are instead predominant in adenocarcinoma.²⁹ Activating EGFR mutations were first identified in NSCLC in 2004 and characterized as oncogenic mutations conferring high sensitivity to targeted inhibition by EGFR TKIs.^30–32 EGFR gene mutations cluster in the region encoding for adenosine triphosphate (ATP)-binding pocket of the kinase domain (exons 18–21) and induce constitutive activation of the receptor and downstream pro-survival pathways and, consequently, confer oncogenic properties to cells which become dependent on EGFR for their survival.³³ The most common, “classic” mutations are the in-frame exon 19 deletion and the exon 21 point mutation, resulting in a substitution of arginine for leucine at position 858 (L858%), accounting for about 90% of all mutations. Other relatively rare, sensitizing EGFR mutations have been described, such as G719X and L861Q mutations. The prevalence of EGFR mutations is higher in never-smokers, females and patients of East Asian ethnicity. Through a systematic review and meta-analysis, including 456 studies, Zhang et al have found that the overall pooled prevalence for EGFR mutations in patients with NSCLC is 32.3%, ranging from 38.4% in China to 14.1% in Europe.³⁴ The first-generation, reversible EGFR TKIs, gefitinib and erlotinib, are orally bioavailable synthetic anilinoquinazolines designed to compete for ATP binding to the catalytic site of the receptor, switch off prosurvival signals, and cause tumor cell death, whereas the second-generation inhibitors, including afatinib and dacomitinib, are irreversible inhibitors with greater affinity for the EGFR kinase domain and can also inhibit and block signaling from other members of the ErbB family, thus providing enhanced EGFR blockade. The Iressa Pan-Asia Study, including advanced NSCLC patients with clinical characteristics predictive of response to TKIs (East Asian patients, adenocarcinoma, never- or mild-smokers), was the first study demonstrating the superiority of gefitinib compared with chemotherapy in patients with EGFR mutations, thus leading to its approval in this setting.⁵ Indeed, within this subgroup of patients, gefitinib was associated with a significantly longer PFS and ORR compared with chemotherapy. Subsequent multiple, randomized Phase III trials, exclusively enrolling patients with EGFR-mutated NSCLC, explored the use of gefitinib, erlotinib or afatinib as first-line treatment in comparison with standard platinum-based chemotherapy. In all studies, EGFR TKIs improved ORRs, PFS and QoL over chemotherapy.^6–12,35 However, none of the above studies have shown any benefit in OS for any of the EGFR TKI over platinum-based chemotherapy, likely due to treatment crossover effects at progression. Only a pooled OS analysis of patients included in 2 Phase III trials, LUX-Lung 3 and LUX-Lung 6, showed a significant OS benefit in patients with exon 19 deletions treated with afatinib, compared with chemotherapy. The same OS difference was not seen in patients with L858R mutations.³⁶ These positive results have led to the approval of gefitinib, erlotinib and afatinib, as upfront therapies of advanced NSCLC patients with EGFR mutations. These drugs have dramatically improved the therapeutic management of NSCLC patients and have also impacted on the diagnostic process, since tumor molecular profiling has been rapidly incorporated over the past few years into clinical routine practice to guide treatment selection.^14,37

MECHANISMS OF RESISTANCE TO FIRST-LINE EGFR TKI THERAPY

Unfortunately, despite marked and often durable responses to EGFR TKIs, the vast majority of patients will develop progressive disease, generally within 1 year of treatment, due to development of acquired resistance that ultimately limits the long-term efficacy of these agents. A variety of mechanisms responsible for acquired resistance have been identified and can be broadly categorized into the following types: secondary mutations within the EGFR kinase domain, activation of alternative signaling pathways, namely bypass tracks, and phenotypic changes (including small-cell lung cancer transformation and epithelial to mesenchymal transition).³⁸ The most common and best characterized mechanism of acquired resistance is represented by a C to T change at nucleotide 2369 in exon 20, which results in the substitution of the non-polar hydrophobic and larger amino acid methionine for the hydrophilic threonine residue within the ATP-binding cleft of the kinase domain.^39–42 Other mechanisms include the activation of parallel signaling pathways, the so-called bypass tracks, leading to EGFR-independent growth, including amplification, overexpression and autocrine loops involving MET, HER2, AXL, insulin-like growth factor (IGF-1R), fibroblast growth factor receptor, and ephrin type-A receptor 2 or molecular alterations of key downstream molecules of the PI3K/AKT/mammalian target of rapamycin (mTOR) or the RAS/RAF/MAPK pathways.^38,42–44 A crucial role in acquired resistance has also been demonstrated for other key mediators downstream of EGFR, including nuclear factor-κB, the proapoptotic protein BIM (BCL2-like 11) and STAT3.^45–47

In addition, epithelial–mesenchymal transition and small-cell lung cancer transformation have been also correlated with resistance to EGFR TKIs.^38,43

Until recently, no standard treatment options after failure of EGFR TKI therapy were available. Because of possible coexistence of different subclonal populations of tumor cells in EGFR TKI-resistant cancers, some evidence suggests that for those patients experiencing central nervous system (CNS) progressive disease or oligo-progressive disease, local therapy (e.g., surgery, radiotherapy, or both) to the site of progression to target the TKI-resistant subclones might be appropriate, with continuation of treatment with the same initial TKI.^38,48–50

Systemic treatment is generally represented by platinum-based doublet or single-agent chemotherapies, with modest benefit in terms of PFS. A Phase III randomized trial failed to demonstrate the superiority of gefitinib plus cisplatin and pemetrexed compared with chemotherapy and placebo after progression on first-line gefitinib.⁵¹ In addition, the combination of gefitinib and chemotherapy had a detrimental effect on OS, mainly driven by T790M-positive mutation status detected by circulating tumor DNA (ctDNA) genotyping.⁵² Alternative treatment strategies, including investigational drugs or novel combinations, have been explored in clinical trials, but none of these has been approved as standard treatment in this setting.³⁸