Shengxiang Ren

Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study

BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC. METHODS We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up. FINDINGS 83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]). INTERPRETATION Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC. FUNDING F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality.

Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG–0803)

BACKGROUND This phase II, open-label study evaluated the efficacy and safety of erlotinib as second-line therapy in non-small-cell lung cancer (NSCLC) patients with brain metastases (BM). PATIENTS AND METHODS Forty-eight patients aged 18-75 years with Eastern Cooperative Oncology Group performance status 0-2, confirmed adenocarcinoma or activating epidermal growth factor receptor (EGFR) mutation-positive NSCLC, and asymptomatic BM without extracranial progressive disease after first-line platinum-doublet chemotherapy were recruited. Treatment comprised erlotinib 150 mg/day. The primary end point was progression-free survival (PFS) determined by RECIST. RESULTS The median PFS was 10.1 months [95% confidence interval (CI) 7.1-12.3] for intracranial progression and 9.7 months (95% CI 2.5-17.8) for intracranial and systemic progression. Patients with EGFR mutation-positive disease had significantly longer median PFS versus EGFR wild-type disease [15.2 months (95% CI 8.3-22.2) versus 4.4 months (95% CI 0.0-11.6); P = 0.02]. The median overall survival was 18.9 months (95% CI 14.4-23.4); 6-month and 1-year survival rates were 85% and 73%, respectively. Overall response rate was 58.3%. Most common adverse events were rash (77.1%), paronychia (20.8%), hyperbilirubinemia (16.7%), and diarrhea (14.6%); these were predominantly of grade 1/2. CONCLUSIONS Single-agent erlotinib was active and well tolerated in NSCLC patients with BM. Further studies are warranted.

Final overall survival results from a randomised, Phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802)

BACKGROUND The OPTIMAL study was the first study to compare efficacy and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) erlotinib, versus standard chemotherapy in first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Findings from final overall survival (OS) analysis and assessment of post-study treatment impact are presented. PATIENTS AND METHODS Of 165 randomised patients, 82 received erlotinib and 72 gemcitabine plus carboplatin. Final OS analyses were conducted when 70% of deaths had occurred in the intent-to-treat population. Subgroup OS was analysed by Cox proportional hazards model and included randomisation stratification factors and post-study treatments. RESULTS Median OS was similar between the erlotinib (22.8 months) and chemotherapy (27.2 months) arms with no significant between-group differences in the overall population [hazard ratio (HR), 1.19; 95% confidence interval (CI) 0.83-1.71; P = 0.2663], the exon 19 deletion subpopulation (HR, 1.52; 95% CI 0.91-2.52; P = 0.1037) or the exon 21 L858 mutation subpopulation (HR, 0.92; 95% CI 0.55-1.54; P = 0.7392). More patients in the erlotinib arm versus the chemotherapy arm did not receive any post-study treatment (36.6% versus 22.2%). Patients who received sequential combination of EGFR-TKI and chemotherapy had significantly improved OS compared with those who received EGFR-TKI or chemotherapy only (29.7 versus 20.7 or 11.2 months, respectively; P < 0.0001). OS was significantly shorter in patients who did not receive post-study treatments compared with those who received subsequent treatments in both arms. CONCLUSION The significant OS benefit observed in patients treated with EGFR-TKI emphasises its contribution to improving survival of EGFR mutant NSCLC patients, suggesting that erlotinib should be considered standard first-line treatment of EGFR mutant patients and EGFR-TKI treatment following first-line therapy also brings significant benefits to those patients. CLINICALTRIALSGOV IDENTIFIER NCT00874419.

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials.

Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs), which have been approved for second‐line or third‐line indication in previously treated advanced Non‐small‐cell lung cancer (NSCLC) patients. The results of comparing the EGFR‐TKI with standard platinum‐based doublet chemotherapy as the first‐line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta‐analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR‐TKI as front‐line therapy had a significantly longer progression‐free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR) = 0.37; 95% confidence intervals (CI) = 0.27–0.52; p < 0.001]. The overall response rate (ORR) of EGFR‐TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR‐TKI [relative risk (RR) = 5.68; 95% CI = 3.17–10.18; p < 0.001]. The overall survival (OS) was numerically longer in the patients received EGFR‐TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR = 0.94; 95% CI = 0.77–1.15; p = 0.57). Comparing with first‐line chemotherapy, treatment of EGFR‐TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.

Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC)

BACKGROUND The OPTIMAL study found that erlotinib improved progression-free survival (PFS) versus standard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). This report describes the quality of life (QoL) and updated PFS analyses from this study. PATIENTS AND METHODS Chinese patients ≥ 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received erlotinib (150 mg/day; n = 82) or gemcitabine-carboplatin (n = 72). The primary efficacy end point was PFS; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS). RESULTS Patients receiving erlotinib experienced clinically relevant improvements in QoL compared with the chemotherapy group in total FACT-L, TOI and LCS (P < 0.0001 for all scales). Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 (non-significant). In the updated analysis, PFS was significantly longer for erlotinib than chemotherapy (median PFS 13.7 versus 4.6 months; HR = 0.164, 95% CI = 0.105-0.256; P < 0.0001), which was similar to the previously reported primary analysis. CONCLUSION Erlotinib improves QoL compared with standard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC.

MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer

BACKGROUND AND PURPOSE With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI. METHODS EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI. RESULT MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline (p<0.01). CONCLUSION miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3K/Akt pathway.

Predictive Effects of ERCC1 and XRCC3 SNP on Efficacy of Platinum-based Chemotherapy in Advanced NSCLC Patients

OBJECTIVE The purpose of the study was to investigate whether single-nucleotide polymorphisms of deoxyribonucleic acid repair gene excision repair cross-complementing group 1 at codon 118 and X-ray repair cross-complementing group 3 at codon 241 affected clinical outcomes in advanced non-small cell lung cancer patients receiving first-line platinum-based chemotherapy. METHODS A total of 130 patients treated with platinum-based doublets were examined for genotyping of excision repair cross-complementing group 1 118 and X-ray repair cross-complementing group 3 241 in peripheral blood lymphocytes with the method of the TaqMan assay plus the real-time polymerase chain reaction method. Multivariate logistic or Coxs regression analyses were used to adjust for possible confounding variables. RESULTS There were no differences in clinical characteristics among the different single-nucleotide polymorphisms. Overall response rate in the 130 patients was 20% with 85.4% of disease control rate. Followed up to 31 March 2008, there were 47 patients still alive. Overall survival was 15 months. No relationship was found between excision repair cross-complementing group 1 or X-ray repair cross-complementing group 3 single-nucleotide polymorphisms and tumor response to platinum-based chemotherapy. A significant correlation was found between excision repair cross-complementing group 1 118 C/T single-nucleotide polymorphisms and survival (P = 0.003). In the multivariate model, the survival was highly related with excision repair cross-complementing group 1 118 C/T or T/T genotypes and tumor response to chemotherapy. CONCLUSIONS Overall survival was significantly improved in the patients with excision repair cross-complementing group 1 118 T/T or C/T treated by platinum-based chemotherapy.

Role of circulating-tumor DNA analysis in non-small cell lung cancer.

The discovery of actionable driver mutations such as epidermal growth factor receptor (EGFR) and microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) and their highly responses to EGFR and ALK tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) allowed precise medicine into reality. However, a substantial part of patients still have no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations and epigenetic alteration and monitoring of tumor burden, acquired resistance, tumor heterogeneity and early diagnosis. Since precise therapy is a strategy that optimal therapy is decided based on simultaneous tumor genome information, ctDNA, as a liquid biopsy, may help to perform dynamic genetic surveillance. In this paper we will perspectively discuss the biology and identification of ctDNA in the blood of NSCLC patients and its clinical applications in patient management.

High Discrepancy of Driver Mutations in Patients with NSCLC and Synchronous Multiple Lung Ground-Glass Nodules

Background: The aim of this study was to investigate the discordance rates of eight known driver mutations among multiple matched intrapulmonary ground-glass nodules (GGNs) in non–small-cell lung cancer (NSCLC) patients. Methods: Tumors from 35 patients with multiple lesions resected, including confirmed NSCLC and at least one GGN, were analyzed for mutations in EGFR, KRAS, HER2, BRAF, and PIK3CA together with fusions in ALK, ROS1, and RET. Results: From 35 patients, a total of 72 lesions (60 were GGNs) were analyzed. These included nine adenocarcinoma in situ, nine minimal invasive adenocarcinoma, and 54 invasive adenocarcinoma. Among them, 33 tumor lesions (45.8 %) were found harboring EGFR mutations: 13 tumors with exon 19 deletion, 18 with L858R on exon 21, and two with both exon 19 del and L858R mutation. There were 5 tumors (6.9 %) harboring EML4-ALK fusion, four HER2 mutations (5.6%), three KRAS mutations (4.2%), one ROS1 fusion and one BRAF mutation. When we used the matched tumors to determine the intertumor discrepancy, only six out of 30 patients harbored identical mutations. The discordance rate of driver mutations was 80% (24 of 30) in those patients harboring at least one of the detected driver mutations. The median disease-free survival was 41.2 months (95% confidence interval: 35.8–52.6 months) and the median overall survival was “still not reached” in this cohort. Conclusions: We found a high discrepancy of driver mutations among NSCLC patients with GGNs and a favorable prognosis after multiple lesions resection, which support surgical resection in this situation as a reasonable approach.

Atypical Negative ALK Break-Apart FISH Harboring a Crizotinib-Responsive ALK Rearrangement in Non–Small-Cell Lung Cancer

Anaplastic lymphoma kinase rearranged (ALK+) non–small-cell lung cancer demonstrates remarkable sensitivity to crizotinib.1 Although other methods exist, the dominant method for determining ALK positivity uses the Abbott (Abbott Molecular, Des Plaines, IL) ALK break-apart fluorescent in situ hybridization (FISH) assay.2 The assay has clearly defined positivity criteria but borderline or atypical negative cases occur. Here we describe a case with an atypical negative FISH result that was later confirmed as ALK+ by both immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) and responded well to crizotinib.