Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report.
ABSTRACT: Brain metastasis (BM) has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR) of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE). This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M.
Project description:The response to icotinib in advanced non-small cell lung cancers (NSCLC) with EGFR uncommon mutation (EGFRum) is unclear. Here we reported the efficacy and potential resistance mechanism of icotinib in Chinese EGFRum NSCLC patients. Between July 2013 and November 2016, 3117 NSCLC patients were screened for EGFRum in a multi-center study in China. Circulating tumor DNA (ctDNA) was detected and analyzed using next-generation sequencing (NGS) after progression from icotinib. The efficacy, safety and the potential resistance mechanism of icotinib were explored. After a median follow-up of 6.2 months, 69 patients (70.41%) developed disease progression, the objective rate (ORR) and disease control rate (DCR) were 13.27% and 29.59% respectively, and the median progression-free survival (PFS) was 5.5 months (95% CI: 1.2-13.0 months). Both complex-pattern with EGFR classical mutations (EGFRcm) and single-pattern have better PFS than complex-pattern without EGFRcm (median PFS was 7.2 (95% CI: 4.65-9.75), 5.2 (95% CI: 3.24-7.16) and 3.2 (95% CI: 2.97-3.44) months, respectively, P < .05); patients harboring S768I mutation had the worst PFS than others (2.0 months, P < .05). Diarrhea was the most frequent side effect (42.9%). Forty-eight (69.6%) patients developed drug resistance after 3.0 months and 81.2% of them acquired T790M mutation. Better response was observed in complex-pattern with the EGFRcm group. S768I mutation carriers may not benefit from icotinib. Acquired T790M mutation was common in icotinib-resistant EGFRum NSCLC patients.
Project description:EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.
Project description: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:UNLABELLED:First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE:We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.
Project description:BACKGROUND:The prognosis of non-small-cell lung cancer (NSCLC) with brain metastases is very poor. Currently, therapeutic methods for this patient population include whole-brain radiation therapy (WBRT), surgery, radiosurgery and systemic treatment. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could be effective on cerebral metastases of mutated NSCLC. However, which EGFR-TKIs is more appropriate is still unknown. METHODS:We conducted a retrospective analysis of advanced NSCLC patients with brain metastases for EGFR targeted therapy from November 2013 to April 2018 at Dongguan People's Hospital, Southern Medical University, China. A total of 43 patients were recruit in this study. Among them, 21 cases received icotinib (125?mg, thrice a day) and 22 cases received gefitinib (250?mg, once a day) until disease progression or unacceptable toxicity. The primary end point of this study was intracranial PFS (iPFS). The relationships between therapeutic arms and patients characteristics were performed using Pearson's chi-square test or Fisher's exact test. The differences in PFS among the two arms were analyzed using Kaplan-Meier curves and log rank tests. RESULTS:There was no significant difference of intracranial ORR (66.6% versus 59.1%, P?=?0.62) and DCR (85.7% versus 81.8%, P?=?0.73) between the two arms. The median intracranial PFS (iPFS) for icotinib and gefitinib arms were 8.4?months (95% CI, 5.4 to 11.3?months) and 10.6?months (95% CI, 6.3 to 14.8?months), respectively (P?=?0.17). Adverse events of the two study arms were generally mild. None of the patients experienced dose reduction of EGFR-TKIs. CONCLUSIONS:Our study showed that icotinib and gefitinib had similar efficacy for brain metastasis of EGFR mutated NSCLC. Large randomized studies are suggested to further illuminate the effect of these two EGFR-TKIs on cerebral lesions of NSCLC.
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:AZD9291 (osimertinib) is approved for standard care in patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) after prior EGFR TKI progression. Furthermore, AZD9291 is now being evaluated as a first-line treatment for NSCLC patients with activation EGFR mutations. Based on previous experiments, resistance to AZD9291 as a first-line treatment may also emerge. Thus, identification and understanding of resistance mechanisms to AZD9291 as a first-line treatment can help direct development of future therapies. AZD9291-resistant cells (PC9/AZDR) were established using EGFR inhibitor-naïve PC9 cells. Resistance mechanisms were analyzed using next-generation sequencing (NGS) and a proteome profiler array. Resistance to AZD9291 developed through aberrant activation of ERK signaling by an EGFR-independent mechanism. The combination of a MEK inhibitor with AZD9291 restored the sensitivity of PC9/AZDR cells in vitro and in vivo. PC9/AZDR cells also showed increased MET expression and an HRAS G13R mutation. In addition, maspin expression was higher after AZD9291 treatment in PC9/AZDR cells. Sustained ERK activation confers resistance to AZD9291 as a first-line therapy. Thus, co-targeting EGFR and MEK may be an effective strategy to overcome resistance to AZD9291.
Project description:The T790M mutation is recognized as a typical mechanism of acquired resistance to first generation of epithermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib in non-small cell lung cancer (NSCLC) patients who are commonly treated by third generation of EGFR-TKI AZD9291 (osimertinib). However, the therapeutic strategy for overcoming acquired resistance to EGFR-TKIs in NSCLC patients without T790M remains to be definitively determined. In the present study, gefitinib-resistant H1650 (H1650GR) or AZD9291-resistant H1975 (H1975AR) was generated by exposing NSCLC cell line H1650 or H1975 to progressively increased concentrations of gefitinib or AZD9291 over 11 months. The cytotoxic effects of gefitinib or AZD9291 in vitro were evaluated via the half maximal inhibitory concentrations (IC50s) determined by the MTT assay. IC50 of gefitinib in H1650GR (50.0?±?3.0 µM) significantly increased compared with H1650 (31.0?±?1.0 µM) (p?<?0.05). Similarly, the IC50 of AZD9291 in H1975AR (10.3?±?0.9 µM) significantly increased compared with H1975 (5.5?±?0.6 µM) (p?<?0.05). However, IC50 of AZD9291 on H1650GR (8.5?±?0.5 µM) did not increase compared with H1650 (9.7?±?0.7 µM). On the other hand, IC50 of AZD9291 on gefitinib-resistant A549 (A549GR established in our previous study) (12.7?±?0.8 µM) was significantly increased compared with A549 (7.0?±?1.0 µM) (p?<?0.05). AZD9291 induced caspase 3/7 activation in A549, H1650, and H1650GR, but not in A549GR. Western blot analyses showed that p-Akt played a key role in determining the sensitivities of A549, A549GR, H1650, and H1650GR to gefitinib or AZD9291. Additionally, increased expression of Twist1 was observed in all cells with acquired EGFR-TKI resistance and knockdown of Twist1 by shRNA was found to significantly enhance the sensitivity of A549GR to gefitinib or AZD9291 via reversing epithelial-mesenchymal transition and downregulating p-Akt, but not of H1975AR to AZD9291. The enhanced cytotoxic effect of AZD9291 on A549GR by Twist1 knockdown in vitro was further validated by in vivo studies which showed that Twist1 knockdown could lead to significantly delayed tumor growth of A549GR xenograft with increased sensitivity to AZD9291 treatment in nude mice without any observed side toxic effects. In summary, our study demonstrated that the mechanisms of acquired resistance in different NSCLC cell lines treated by even the same EGFR-TKI might be quite different, which provide a rationale for adopting different therapeutic strategies for those NSCLC patients with acquired EGFR-TKI resistance based on different status of heterogeneous mutations.
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: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.