Randomized Adjuvant Chemotherapy of EGFR-Mutated Non-Small Cell Lung Cancer Patients with or without Icotinib Consolidation Therapy.
ABSTRACT: Epidermal growth factor receptor (EGFR) mutations occur in up to 50% of Asian patients with non-small cell lung cancer (NSCLC). Treatment of advanced NSCLC patients with EGFR-tyrosine kinase inhibitor (EGFR-TKI) confers a significant survival benefit. This study assessed the efficacy and safety of chemotherapy with or without icotinib in patients undergoing resection of stage IB to ?A EGFR-mutated NSCLC.Patients with surgically resected stage IB (with high risk factors) to ?A EGFR-mutated NSCLC were randomly assigned (1:1) to one of two treatment plans. One group received four cycles of platinum-based doublet chemotherapy every three weeks, and the other group received platinum-based chemotherapy supplemented with consolidation therapy of orally administered icotinib (125 mg thrice daily) two weeks after chemotherapy. The icotinib treatment continued for four to eight months, or until the occurrence of disease relapse, metastasis or unacceptable icotinib or chemotherapy toxicity. The primary endpoint was disease-free survival (DFS).41 patients were enrolled between Feb 9, 2011 and Dec 17, 2012. 21 patients were assigned to the combined chemotherapy plus icotinib treatment group, while 20 patients received chemotherapy only. DFS at 12 months was 100% for icotinib-treated patients and 88.9% for chemotherapy-only patients (p = 0. 122). At 18 months DFS for icotinib-treated vs. chemotherapy-only patients was 95.2% vs. 83.3% (p = 0. 225), respectively, and at 24 months DFS was 90.5% vs. 66.7% (p = 0. 066). The adverse chemotherapy effects predominantly presented as gastrointestinal reactions and marrow suppression, and there was no significant difference between the two treatment groups. Patients in the chemotherapy plus icotinib treatment group showed favorable tolerance to oral icotinib.The results suggest that chemotherapy plus orally icotinib displayed better DFS compared with chemotherapy only, yet the difference in DFS was not significant. We would think the preliminary result here was promising, and further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.ClinicalTrials.gov NCT02430974.
Project description:Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.
Project description:Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20-16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97-12.45 months; hazard ratio, 0.68; 95% CI, 0.51-0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1-2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01745302.
Project description:Icotinib hydrochloride is a novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with preclinical and clinical activity in non-small cell lung cancer (NSCLC). This retrospective analysis was performed to assess the efficacy of icotinib on patients with non-small-cell lung cancer (NSCLC).82 consecutive patients treated with icotinib as first (n = 24) or second/third line (n = 58) treatment at three hospitals in Nanjing were enrolled into our retrospective research. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the tumor responses and the progression-free survival (PFS) and overall survival (OS) was evaluated by the Kaplan-Meier method.Median PFS was 4.0 months (95% CI 2.311-5.689). Median OS was 11.0 months (95% CI 8.537-13.463) in this cohort. Median PFS for first and second/third line were 7.0 months (95% CI 2.151-11.8) and 3.0 months (95% CI 1.042-4.958), respectively. Median OS for first and second/third line were 13.0 months (95% CI 10.305-15.695) and 10.0 months (95% CI 7.295-12.70), respectively. In patients with EGFR mutation (n = 19), icotinib significantly reduced the risk of progression (HR 0.36, 95% CI 0.18-0.70, p = 0.003) and death (HR 0.10, 95% CI 0.02-0.42, p = 0.002) compared with those EGFR status unknown (n = 63). The most common adverse events were acne-like rash (39.0%) and diarrhea (20.7%).Icotinib is active in the treatment of patients with NSCLC both in first or second/third line, especially in those patients harbouring EGFR mutations, with an acceptable adverse event profile.
Project description:Tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) are becoming the standard treatment option for patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR mutation, but the economic impact of this practice is unclear, especially in a health resource-limited setting. A decision-analytic model was developed to simulate 21-day patient transitions in a 10-year time horizon. The health and economic outcomes of four first-line strategies (pemetrexed plus cisplatin [PC] alone, PC followed by maintenance with pemetrexed, or initial treatment with gefitinib or icotinib) among patients harboring EGFR mutations were estimated and assessed via indirect comparisons. Costs in the Chinese setting were estimated. The primary outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. The icotinib strategy resulted in greater health benefits than the other three strategies in NSCLC patients harboring EGFR mutations. Relative to PC alone, PC followed by pemetrexed maintenance, gefitinib and icotinib resulted in ICERs of $104,657, $28,485 and $19,809 per quality-adjusted life-year gained, respectively. The cost of pemetrexed, the EGFR mutation prevalence and the utility of progression-free survival were factors that had a considerable impact on the model outcomes. When the icotinib Patient Assistance Program was available, the economic outcome of icotinib was more favorable. These results indicate that gene-guided therapy with icotinib might be a more cost-effective treatment option than traditional chemotherapy.
Project description:The study was performed to investigate the antitumor efficacy of histone deacetylase inhibitor (HDACi) chidamide alone or with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) icotinib in non-small cell lung cancer (NSCLC). The cell viability, cell cycle, apoptosis, protein expression, and the molecular mechanisms were explored among ten NSCLC cell lines with chidamide and icotinib alone or in combination, and further validated in xenograft models of nude mice. Chidamide significantly reduced the viability of A549, HCC827, HCC827IR (icotinib resistant) cells, increased the sensitivity of icotinib synergistically in EGFR-TKI resistant cell line, especially in H1975 cells. Chidamide alone or combined with icotinib induced cell cycle arrest by inhibiting the activation of RAS/MAPK, PI3K/AKT and/or JAK/STAT pathways, and caused apoptosis by activating caspase 3 and PARP. Chidamide alone or with icotinib suppressed β-catenin expression in HCC827, HCC827IR, and H1975 cells. The sensitivity of H1975 cells to icotinib was increased by chidamide through restoring E-cadherin expression. Furthermore, chidamide alone or in combination with icotinib inhibited HCC827IR and H1975 xenograft growth in athymic nude mice, respectively, with no appreciable side effects. Chidamide or combinating with icotinib exhibits antitumor activity in NSCLC cells, and has potential clinical implication for the treatment of NSCLC.
Project description:Previous studies have suggested that a variety of tumor driver genetic alterations affected the treatment efficacy of chemotherapy and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). The present study aimed to investigate the association between the tumor genetic alteration landscape and the treatment outcome of first-line chemotherapy and EGFR-TKIs in advanced NSCLC. A total of 94 patients with advanced NSCLC were recruited. All patients received first-line chemotherapy and/or EGFR-TKIs (either first- or second-generation EGFR-TKI, or third-generation EGFR-TKI) alone or sequentially. Prior to chemotherapy and/or EGFR-TKI treatment, plasma, effusion and/or tumor tissues from the included patients were subjected to next-generation sequencing, targeting 59 genes. The results indicated that the positive genetic alteration status prior to first-line chemotherapy was associated with prolonged progression-free survival (PFS) time compared with the negative status [9.1 vs. 4.0 months; hazard ratio (HR)=6.68; 95% CI, 2.25-19.82; P=0.001). Furthermore, patients with EGFR activating mutation harboring concomitant alterations exhibited a shorter PFS (11.1 vs. 7.4 months; HR=2.14; 95% CI, 1.03-4.44; P=0.04) and overall survival (OS) time [not reached (NR) vs. 32.8 months; HR=4.30; 95% CI, 1.41-13.16; P=0.01] than those without concomitant alterations, with first- and second-generation EGFR-TKI treatment. Similarly, patients with T79M mutation harboring concomitant alterations exhibited a shorter PFS (15.6 vs. 3.6 months; HR=9.48; 95% CI, 2.29-39.28; P=0.002) and OS time (NR vs. 32.8 months; HR=4.85; 95% CI, 1.16-20.29; P=0.03) with osimertinib treatment. Taken together, the results demonstrated that positive genetic alteration status predicted greater efficacy of first-line chemotherapy, while concomitant genetic alterations were associated with poor treatment outcome for first- or second-generation EGFR-TKI and third-generation EGFR-TKI treatment.
Project description:BACKGROUND:The optimal neoadjuvant regimen for locally advanced resectable non-small cell lung cancer (NSCLC) remains controversial. EGFR inhibitors have significantly improved survival in patients with EGFR-mutant advanced NSCLC. However, their efficacy in neoadjuvant settings, particularly for treating locally advanced NSCLC, remains unclear. We compared the clinical benefits of chemotherapy and erlotinib as neoadjuvant therapy for stage IIIA NSCLC. METHOD:Thirty-one treatment-naïve Chinese patients with stage IIIA NSCLC were enrolled. Patients without EGFR mutation received cisplatin-based doublet chemotherapy (n?=?16; N-chemo group) while EGFR-mutant patients received erlotinib (n?=?15; N-TKI group) as neoadjuvant therapy. RESULTS:After completing neoadjuvant treatment, 12 and 8 patients from the N-TKI and N-chemo groups underwent surgery, respectively. Our data revealed that patients who received erlotinib had a marginally better clinical objective response rate (67% vs. 19%), pathological response rate (67% vs. 38%), and overall survival (51.0 months vs. 20.9 months) compared with those who received chemotherapy. Furthermore, patients in the N-TKI group had a significantly greater reduction in tumor diameter, serum carcinoembryonic level, and maximum allelic fraction. CONCLUSION:Our findings demonstrate that erlotinib is an effective neoadjuvant regimen in patients with EGFR-mutant locally advanced NSCLC, paving the way for its extended use in neoadjuvant settings.[ClinicalTrials.gov identifier: NCT01217619].
Project description:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are approved for second-line treatment of EGFR wild-type (EGFR-wt) nonsmall cell lung cancer (NSCLC). However, results from randomised trials performed to compare EGFR-TKIs with chemotherapy in this population did not show any survival benefit. In the era of immunotherapy, many drugs are approved for second-line treatment of EGFR-wt NSCLC and there is a need to reassess the role of EGFR-TKIs in this setting.The Biomarkers France study is a large nationwide cohort of NSCLC patients tested for EGFR mutations. We used this database to collect clinical, biological, treatment and outcome data on EGFR-wt patients who received second-line treatment with either EGFR-TKIs or chemotherapy.Among 1278 patients, 868 received chemotherapy and 410 received an EGFR-TKI. Median overall survival and progression-free survival were longer with chemotherapy than with an EGFR-TKI. Overall survival was 8.38 versus 4.99?months, respectively (hazard ratio 0.70, 95% CI 0.59-0.83; p<0.0001) and progression-free survival was 4.30 versus 2.83?months, respectively (hazard ratio 0.66, 95% CI 0.57-0.77; p<0.0001).This study is helpful to guide a multiline treatment strategy for EGFR-wt NSCLC patients. Immunotherapy is approved for second-line treatment. For third-line treatment, chemotherapy results in longer overall survival and progression-free survival, and should be preferred to EGFR-TKIs.
Project description:The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis and the meta-analysis of individual participant data reported by non-small cell lung cancer (NSCLC) Meta-analysis Collaborative Group in neo-adjuvant setting validated respectively that adjuvant and neoadjuvant chemotherapy would significantly improve overall survival (OS) and recurrence-free survival for resectable NSCLC. However, chemotherapy has reached a therapeutic plateau. It has been confirmed that epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeting therapy provides a dramatic response to patients with advanced EGFR-mutation positive NSCLC. Researchers have paid more attention to exploring applications of TKIs to early resectable NSCLCs. Several studies on adjuvant TKI treatment concluded its safety and feasibility. But there existed certain limitations of these studies as inference factors to interpret data accurately: the BR19 study recruited patients among which almost 52% had stage IB and only 15 (3.0%, 15/503) had been confirmed with EGFR-mutant type; retrospective studies performed at Memorial Sloan Kettering Cancer Center (MSKCC) selected EGFR mutant-type NSCLC patients but couldn't avoid inherent defects inside retrospective researches; the RADIANT study revised endpoints from targeting at EGFR immunohistochemistry (IHC)+ and/or fluorescence in situ hybridization (FISH)+ mutation to only EGFR IHC+ mutation, leading to selective bias; despite that the SELECT study validated efficacy of adjuvant TKI and second round of TKI after resistance occurred, a single-arm clinical trial is not that persuasive in the absence of comparison with chemotherapy. Taking all these limitations into account, CTONG1104 in China and IMPACT in Japan have been conducted and recruiting patients to offer higher level of evidences to explore efficacy of preoperative TKI therapy for early resectable EGFR mutation positive NSCLC patients (confirmed by pathological results of tumor tissue or lymph node biopsy). On the other hand, case reports and several phase II clinical trials with small sample size tried to elbow their way on respect of preoperative TKI treatment and advised that TKI tended to improve response rate. However, no data on survival rate was present. The first phase II study of biomarker-guided neoadjuvant therapy for stage IIIA-N2 NSCLC patients stratified by EGFR mutation status, sponsored by CSLC0702, showed erlotinib tended to improve response rate, but failed to show benefits of disease-free survival (DFS) or OS. Subsequently, CTONG1103 was designed to investigate efficacy of erlotinib vs. combination of gemcitabine/cisplatin (GC) as neoadjuvant treatment in stage IIIA-N2 NSCLC with sensitizing EGFR mutation in exon 19 or 21. All these ongoing trials should be worthy of our expect to provide convincing evidences for customized therapy for patients with resectable NSCLC.
Project description:OBJECTIVE:To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). DESIGN:Systematic review and network meta-analysis. DATA SOURCES:PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:Published and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher. RESULTS:18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation. CONCLUSIONS:These results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42018111954.