Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer

Abstract

Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.

Conflict of interest statement

Competing interests statement

The authors declare competing financial interests; see Web version for details.

Figures

Figure 1. Progress in the treatment of metastatic lung cancer

In 1976, a chemotherapy trial studied all patients with lung cancer, regardless of whether they had small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). In 2002, a landmark chemotherapy trial involving platinum doublets studied all patients with NSCLC, regardless of histological subtype (adenocarcinoma, squamous cell carcinoma and large-cell carcinoma). In 2006, bevacizumab (Avastin; Genentech/ Roche) was shown to confer an overall survival benefit when added to chemotherapy for patients with non-squamous NSCLC. The smoking history of patients was not recorded. In 2009, trials in epidermal growth factor receptor (EGFR)-mutant lung cancer with EGFR tyrosine kinase inhibitors (TKIs) demonstrated the longest survival rates currently seen for NSCLC,,. Notably, patients with EGFR-mutant lung tumours also have a better prognosis in the absence of therapy compared with those with EGFR-wild-type tumours.

Figure 2. Tissue accrual across multiple trials

Trials in colon cancer (left side of graph), in which KRAS mutations are observed in 33–40% of tumour samples, were highly efficient at collecting tissue samples (45–92% patients had suitable tissue available for molecular analyses and 16–40% of patients had KRAS mutations). Based on the poor responses observed in patients with KRAS-mutant tumours, the KRAS biomarker was easily found to be a negative predictor of anti-epidermal growth factor receptor (EGFR) therapy (for example, cetuximab and panitumumab (Vectibix; Amgen) efficacy,). By contrast, in lung cancer, the role of KRAS mutations (FLEX and BMSO99 trials) could not be accurately determined in trials with cetuximab. The prevalence of KRAS mutations is 15–25%, only 30–34% of patients had tissue available for analysis and only 5–6% of patients had KRAS mutations,. Similarly, study of the role of EGFR mutations has been hampered by low tissue accrual (right section of the graph). EGFR mutations are found in 10–28% of patients with non-small-cell lung cancer (NSCLC), but tissue accrual in the major trials involving EGFR tyrosine kinase inhibitors (IDEAL-1, IDEAL-2, INTACT-1, INTACT-2, TRIBUTE, TALENT, BR.21, ISEL and INTEREST) was < 24% (blue bars),,,–. Of the patients with available tumour samples, the percentage that harboured an EGFR mutation (purple bars) was <5%, making it difficult to draw conclusions. However, in IPASS and WJTOG3405, in which these percentages were much higher, EGFR mutations were readily found to be a positive predictor of benefit. BSC, best supportive care; Pan, panitumumab. *Represents clinically enriched trials.

Figure 3. Comparison of TKI-sensitive and TKI-resistant mutations in cancer-derived mutant TKs

Epidermal growth factor receptor (EGFR)-mutant lung cancer, breakpoint cluster region (BCR)–ABL-driven chronic myelogenous leukaemia (CML) and KIT-mutant gastrointestinal stromal tumour (GIST) have all been treated effectively with specific tyrosine kinase inhibitors (TKIs); that is, gefitinib or erlotinib for lung cancer, imatinib for CML and imatinib for GIST. Activating drug-sensitive mutations are shown on the top of EGFR. TKI-resistant mutations are depicted on the bottom of each kinase domain schematic. The most common activating mutations in EGFR are a point mutation in exon 21, which substitutes an arginine for a leucine (L858R), and a small deletion in exon 19 that removes four amino acids (LREA). Together, these genomic changes account for ~90% of TKI-sensitive mutations that are observed in EGFR-mutant tumours. Other major drug-sensitive mutations include G719X (encoded by exon 18) and L861Q (exon 21).

Figure 4. Multi-pathway inhibition as a strategy to treat EGFR-mutant NSCLC

Epidermal growth factor receptor (EGFR) mutants (starred) propagate signals through the PI3K–AKT and ERK pathways. Cross-activation of other membrane-bound receptor tyrosine kinases occurs under tyrosine kinase inhibitor (TKI)-sensitive states and following the development of acquired resistance (arrows). The boxes depict a sample of the targeted agents available for the treatment of the disease at various stages (see FIG. 6 for more details). IGF1R, insulin-like growth factor receptor 1; NSCLC, non-small-cell lung cancer; P, phosphorylation.

Figure 5. Comparison of second-site mutation frequency following development of acquired resistance to TKI therapy

All patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) will inevitably develop acquired resistance following treatment with the tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. In ~50% of cases, resistance is attributed to a second-site mutation in EGFR. The change of the gatekeeper threonine to a methionine (T790M) accounts for ~90% of secondary mutations observed in EGFR,,. By contrast, second-site resistance mutations found in ABL and KIT following treatment with imatinib in chronic myelogenous leukaemia (CML) and gastrointestinal stromal tumour (GIST), respectively, are found across the kinase domain (see graphs on right side of figure). Mutations affecting the analogous gatekeeper residue in ABL (T315), and KIT (T670), are observed in less than 20% of cases. Gatekeeper residues are shown in red in the crystal structures. For ABL and KIT, the most common secondary mutation is shown in green. EGFR is shown crystallized with gefitinib (yellow); ABL and KIT were both crystallized with imatinib (yellow). Crystal structures were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB Data Bank; see Further information; accession numbers 2ITY (EGFR), 2HYY (ABL) and 1T46 (KIT)). The structural graphics were produced using the University of California San Francisco (USCF) Chimera package (see Further information) from the Resource for Biocomputing, Visualization and Informatics at the USCF, USA.

Figure 6. Potential treatment strategies to cure EGFR-mutant lung cancer

The optimal treatment strategies for patients with epidermal growth factor receptor (EGFR)-mutant tumours that present with early-stage disease (pale blue, top), late-stage disease (blue, middle) and acquired resistance (purple, bottom) are an active area of investigation. Patients with resectable tumours may benefit from adjuvant chemotherapy, tyrosine kinase inhibitors (TKIs) or both in varying sequence of treatment. Patients with late-stage disease may benefit from combination therapy with a TKI, which may delay or prevent the emergence of acquired resistance. For example, agents targeting the apoptotic pathway combined with TKIs enhance cell death of EGFR-mutant cells in preclinical models,,,. Alternatively, the addition of chemotherapy before, after or concurrent with TKI treatment may induce a synergistic response. Finally, in the case of acquired resistance, continuation of the TKI in combination with various other agents may be the most beneficial strategy. However, the selection of additional therapies depends heavily on the molecular composition of the tumour and the mechanism of resistance. HDAC, histone deacetylase; IGF1R, insulin-like growth factor receptor 1; NSCLC, non-small-cell lung cancer.