Epidermal Growth Factor Receptor Mutation-positive Non-small Cell Lung Cancer Research Articles

Highlights of This Issue

The ability to predict the efficacy of molecularly targeted therapies for non-small cell lung cancer (NSCLC) for an individual patient remains problematic. Nagji and colleagues used the refined coexpression extrapolation (COXEN) algorithm to identify tumor biomarkers that predict drug sensitivity and therapeutic efficacy in NSCLC to Vorinostat (histone deacetylase inhibitor) and Velcade (proteasome inhibitor). Importantly, they provide an in silico method to generate biomarkers that predict tumor sensitivity to novel molecularly targeted therapies. Use of this refined COXEN methodology has significant implications for the a priori examination of targeted therapies to more effectively streamline subsequent clinical trial design and cost.Since αvβ3 integrin plays a key role in angiogenesis and metastasis of human tumors, ligands against this integrin are potentially useful in targeted therapy and cancer imaging. Xiao and colleagues report that a novel RGD peptide ligand, LXW7 with a built-in handle, was identified using OBOC combinatorial chemistry. LXW7 demonstrated high targeting efficacy and specificity for the αvβ3 integrin expressed in tumor cells. Moreover, LXW7 permits easier functionalization for payload conjugation without attenuating the binding affinity of the peptide compared with RGD cyclopentapeptide ligands. LXW7, therefore, has great potential as a highly efficient peptide ligand for targeted imaging and drug delivery.Non-small cell lung cancer (NSCLC) with an activating mutation of the epidermal growth factor receptor (EGFR) ultimately develops resistance to EGFR tyrosine kinase inhibitors (TKI). Okamoto and colleagues show that EGFR mutation–positive NSCLC (HCC827) cells engineered to stably overexpress HGF (HCC827-HGF) exhibit gefitinib resistance. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib suppressed their growth in HCC827-HGF cells both in vitro and in vivo. Our findings suggest that the addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation.Aurora A kinase (AAK), a protein kinase critical for tumor proliferation and survival, is a novel target for cancer treatment. MLN8054, an oral small-molecule AAK inhibitor, produces broad preclinical antitumor activity. In this Phase I study, Macarulla and colleagues evaluated safety, pharmacokinetics, and pharmacodynamics in serial tumor and skin biopsies. Total daily doses of 70 or 80 mg led to marked changes in mitotic cell chromosome alignment and spindle bipolarity in some patients. These results provide evidence for the dominant mechanism to inhibit AAK and support ongoing efforts to target this enzyme in the clinical treatment setting.

The quantitatively analysis of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) and its correlation with response rate of EGFR tyrosine kinase inhibitors (TKI)

Abstract Background and Purpose: Lung cancer is the most frequent malignant tumor in China. Epidermal growth factor receptor (EGFR) had been validated as one of the most important therapeutic targets of non-small cell lung cancer (NSCLC), and tyrosine kinase inhibitors (TKI) have improved the overall outlook and quality of life for most of EGFR mutation positive NSCLC patients; however, the fact that 30% of EGFR mutation positive patients still do not response to TKIs. The current diagnostic test qualitatively measures the overall EGFR mutation status of the cancer tissue, ignored the impacts of nonmutated, TKI-unresponsive cancer cells. 274 NSCLC patients were recruited for the study to carry out the mutation analysis and its correlation with the response rate to EGFR TKIs with a novel quantitative methodology. Experimental Procedures: 1) Selection of paraffin sections of each recruited patients by pathologist to ensure the tumor cells exceeds 70% of total tissue; 2) Extraction of genomic DNA from paraffin sections; 3) Construction of plasmids of both mutated transcripts and wild-type transcripts for each mutation to be analyzed; 4) Real-time PCR amplification of extracted genomic DNA samples with both mutated probes and wild-type probes, and measurement of mutated copy numbers and wild-type copy numbers of each sample with standard curves made by mutated plasmids and wild-type plasmids respectively; 5) Confirmation of the mutation status of each sample with sequencing; 6) Calculation of the percentage of mutated EGFR copy numbers among the total EGFR copy numbers to derive quantitatively mutation data of each patient sample; 7) Observation of EGFR mutations and its demographic features with quantitative data; 8) Evaluation of the outcomes of the therapy with EGFR TKIs (including gefitinib and erlotinib) and analysis of the correlation of increased EGFR mutated transcripts with response rate to EGFR TKIs Summary of New Data: 1) 94 recruited samples was detected with EGFR mutation among total samples, the mutation ratio various from 5% to 90%; 2) The most frequently detected EGFR mutations among the 94 samples are deletions of Exon 19 (56 cases) and L858R (23 cases); 3) The mutation positive NSCLC patients are divided into 4 groups: a) low mutation rate + gefitinib; b) high mutation rate + gefitinib; c) low mutation ratio + erlotinib; d) high mutation rate + erlotinib. There are significant differences between group a and group b, group c and group d. 4) There is no significant difference between various EGFR mutation types against response rate to TKIs. Conclusions: 1) The EGFR mutation ratios in NSCLC patients are various; 2) The EGFR mutation ratio is significant correlated with the response rate to TKIs. This talk is also presented as Poster B36.

The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations

Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.

ITARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors

7504 Background: Somatic EGFR mutations correlate with increased response and survival in NSCLC patients (pts) treated with gefitinib. We conducted the 1st prospective US trial of 1st-line gefitinib in pts with advanced NSCLC harboring EGFR mutations. Methods: Chemotherapy-naïve pts with stage IIIB with effusion or IV NSCLC, measurable disease, and = 1 characteristic associated with mutations (female (F), adenocarcinoma (AC), never-smoking (NS), East Asian (EA)) underwent direct DNA sequencing of tumor tissue EGFR exons 18–24. Mutation-positive pts received gefitinib (250 mg/d) until progression or unacceptable toxicity. The primary outcome was response rate (RR) by RECIST criteria. Results: We sequenced 98 pts and detected EGFR mutations in 34 (35%); 3 were not assessable. Observed mutations were 18 (53%) exon 19 deletions (del), 9 (26%) L858R, 3 (9%) exon 20 insertions (ins), 2 T790M/L858R, 1 G719A, and 1 L861Q. Characteristics of the 98 screened pts were 69 F, 89 AC, 37 NS, and 5 EA; those of the 34 mutation pts were 20 (59%) F, 31 (91%) AC, 19 (56%) NS and 2 (6%) EA. The best predictor of EGFR mutation was NS. Of the 34 mutation pts, 31 (91%) received gefinitib. Reasons for non-treatment were pt preference (1 exon 19 del) and mutation associated with gefitinib-resistance (1 T790M/L858R, 1 exon 20 ins). Adverse events were mainly grade 1–2 rash and diarrhea; 1 case of grade 4 interstitial lung disease occurred after 2 weeks of therapy. The RR was 58% (95% confidence interval 39–75) and was 78% in L858R pts and 65% in del 19 pts. There were no responses among the G719A, L861Q, T790M/L858R and exon 20 ins pts treated. 12 pts have progressed, 18 remain on therapy. The median progression-free survival (PFS) is currently 11.8 mo and does not differ by mutation type, though follow-up is short (median 6.8 mo, range 1–24). 27 pts are still alive. Of the 31 pts treated, 22 (71%) had high EGFR gene copy number (amplification (3) or high polysomy (19)); RR and PFS did not vary by copy number. Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible in a multi-institutional study, well tolerated, and yields a substantial RR and PFS. This strategy should be compared to standard chemotherapy in a genotype-directed randomized trial. No significant financial relationships to disclose.