ORCID Profile
0000-0002-8251-0551
Current Organisation
The Chinese University of Hong Kong
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Publisher: Elsevier BV
Date: 05-2016
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.JTHO.2015.11.014
Abstract: Metastatic spread to the brain is common in patients with non-small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases prespecified subgroup analyses are assessed in this article. For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81). In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378 LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months HR, 0.50 p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports. These findings lend support to the clinical activity of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic brain metastases.
Publisher: Elsevier BV
Date: 04-2016
Publisher: Elsevier BV
Date: 10-2016
Publisher: Future Medicine Ltd
Date: 07-2019
Abstract: We investigate if PD-L1 expression and other clinical characteristics predict chemoimmunotherapy (CIT) benefits versus chemotherapy in advanced non-small-cell lung cancer. We performed a meta-analysis of randomized controlled trials of CIT versus chemotherapy identified through electronic searches. In seven randomized controlled trials (n = 4170), CIT prolonged progression-free survival over chemotherapy (hazard ratio [HR]: 0.62 95% CI: 0.58–0.67 p 0.00001). The treatment benefits differed between PD-L1-high (HR: 0.41 95% CI: 0.34–0.49) and PD-L1 low (HR: 0.63 95% CI: 0.55–0.72 interaction-p = 0.00002) and PD-L1-high and PD-L1-negative (HR: 0.72 95% CI: 0.65–0.80 interaction-p 0.00001). Similar benefits were observed regardless of gender, EGFR/ALK status and histological subtype. PD-L1 status is predictive of CIT benefit and may assist patient selection and design of future trials.
Publisher: Elsevier BV
Date: 02-2006
Publisher: Springer Science and Business Media LLC
Date: 14-09-2012
Publisher: Oxford University Press (OUP)
Date: 02-02-2017
DOI: 10.1093/JNCI/DJW279
Abstract: We performed an in idual patient data meta-analysis to examine the impact of first-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor (TKI) therapy on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Data from trials comparing EGFR-TKI against chemotherapy in exon 19 deletion (del19) or exon 21 L858R (L858R) EGFR mutations patients were used. We performed Cox regression to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Impact of postprogression therapies was examined in exploratory analyses. All statistical tests were two-sided. Six eligible trials (gefitinib = 3, erlotinib = 3) included 1231 patients 632 received EGFR-TKI and 599 received chemotherapy. At a median 35.0 months follow-up, there were 780 deaths and 1004 progressions. There was no difference in OS between EGFR-TKI and chemotherapy (HR = 1.01, 95% CI = 0.88 to 1.17, P = .84). There was also no difference in OS for Del19 (n = 682, HR = 0.96, 95% CI = 0.79 to 1.16, P = .68) and L858R (n = 540, HR = 1.06, 95% CI = 0.86 to 1.32, P = .59) subgroups ( P interaction = .47), or according to smoking status, sex, performance status, age, ethnicity, or histology. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P < .001) and in all subgroups. Following progression, 73.8% from the chemotherapy arm received EGFR-TKI, and 65.9% from the EGFR-TKI arm received chemotherapy. Nine percent from the EGFR-TKI arm received no further treatment vs 0.6% from the chemotherapy arm. Following disease progression, patients randomly assigned to EGFR-TKI had shorter OS than those randomly assigned to chemotherapy (12.8 months, 95% CI = 11.4 to 14.3, vs 19.8 months, 95% CI = 17.6 to 21.7). Despite statistically significant PFS benefit, there is no relative OS advantage with frontline gefitinib or erlotinib vs chemotherapy in EGFR -mutated NSCLC. This finding is likely due to the high rate of crossover at progression.
Publisher: Elsevier BV
Date: 06-0001
DOI: 10.1016/J.JTHO.2018.03.010
Abstract: Traditionally, marked tumor shrinkage has been assumed to portend better outcome. We investigated whether depth of tumor response was associated with improved survival outcomes in advanced EGFR-mutant NCLC. In idual patient data from randomized trials (EURTAC, IPASS, ENSURE, LUX-Lung 3, and LUX-Lung 6) were used. The association of depth of response with progression-free survival (PFS) and overall survival was examined using landmark analyses. Depth of response based on radiologic assessments at 6 weeks and 12 weeks was calculated as the relative changes in the sum of the longest diameters of the target lesions from baseline. Of 1081 evaluable patients at 6 weeks with no disease progression, 71.2% achieved Response Evaluation Criteria in Solid Tumors response. Using a landmark analysis, EGFR-TKI was more effective than chemotherapy (PFS hazard ratio = 0.36, p < .0001) and was associated with greater mean tumor shrinkage than chemotherapy (35.1% versus 18.5%, p < .0001). However, there was no significant difference in the relative PFS benefit between treatment groups across the entire spectrum of tumor shrinkage (p = .18 for test of interaction between treatment and continuously measured depth of response). Depth of response at 6 weeks was not associated with PFS when adjusted for treatment effect (hazard ratio = 0.96, p = .78). Similar results were obtained for 12-week landmark analysis and for OS outcome. The PFS advantage of EGFR-TKI over chemotherapy in advanced EGFR mutant NCLC is not explained by depth of response at 6 or 12 weeks. It should not be used as a surrogate of benefit in future trials or routine clinical decision making.
Publisher: Elsevier BV
Date: 09-2018
Abstract: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small s le sizes. Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054 PFS, P = 0.17). Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 07-2016
Publisher: Elsevier BV
Date: 08-2014
Abstract: To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.
Publisher: Elsevier BV
Date: 08-2014
Abstract: To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on first line/second and further lines of treatment in advanced disease.
Publisher: Future Medicine Ltd
Date: 04-2012
DOI: 10.2217/FON.12.25
Abstract: It is increasingly recognized that differences in overall survival and toxicity exist between Asian and caucasian patients with small-cell and non-small-cell lung cancer, with a longer survival, higher response rates and greater toxicity to chemotherapy and targeted therapy reported in Asian patients. Two global studies are used to illustrate how the proportions of Asian patients can influence survival outcome. Ethnicity is an important and complex characteristic that should considered in the design and conduct of a global clinical study, as the safety, tolerability and response may vary between Asian and caucasian patients. Whether ethnic differences in lung cancer survival are attributed to genetic differences among races or are simply a surrogate marker of differences in access to healthcare because of socioeconomic differences is unclear. Carefully designed prospective studies investigating ethnic-specific determinants of sensitivity and toxicity to systemic therapy are warranted.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2017
Abstract: The phase III OAM4971g study (METLung) examined the efficacy and safety of onartuzumab plus erlotinib in patients with locally advanced or metastatic non–small-cell lung cancer selected by MET immunohistochemistry whose disease had progressed after treatment with a platinum-based chemotherapy regimen. Patients were randomly assigned at a one-to-one ratio to receive onartuzumab (15 mg/kg intravenously on day 1 of each 21-day cycle) plus daily oral erlotinib 150 mg or intravenous placebo plus daily oral erlotinib 150 mg. The primary end point was overall survival (OS) in the intent-to-treat population. Secondary end points included median progression-free survival, overall response rate, biomarker analysis, and safety. A total of 499 patients were enrolled (onartuzumab, n = 250 placebo, n = 249). Median OS was 6.8 versus 9.1 months for onartuzumab versus placebo (stratified hazard ratio [HR], 1.27 95% CI, 0.98 to 1.65 P = .067), with a greater number of deaths in the onartuzumab arm (130 [52%] v 114 [46%]). Median progression-free survival was 2.7 versus 2.6 months (stratified HR, 0.99 95% CI, 0.81 to 1.20 P = .92), and overall response rate was 8.4% and 9.6% for onartuzumab versus placebo, respectively. Exploratory analyses using MET fluorescence in situ hybridization status and gene expression showed no benefit for onartuzumab patients with EGFR mutations showed a trend toward shorter OS with onartuzumab treatment (HR, 4.68 95% CI, 0.97 to 22.63). Grade 3 to 5 adverse events were reported by 56.0% and 51.2% of patients, with serious AEs in 33.9% and 30.7%, for experimental versus control arms, respectively. Onartuzumab plus erlotinib did not improve clinical outcomes, with shorter OS in the onartuzumab arm, compared with erlotinib in patients with MET-positive non–small-cell lung cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2009
DOI: 10.1158/0008-5472.CAN-08-3694
Abstract: Closely located at the tumor suppressor locus 16q22.1, CKLF-like MARVEL transmembrane domain-containing member 3 and 4 (CMTM3 and CMTM4) encode two CMTM family proteins, which link chemokines and the transmembrane-4 superfamily. In contrast to the broad expression of both CMTM3 and CMTM4 in normal human adult tissues, only CMTM3 is silenced or down-regulated in common carcinoma (gastric, breast, nasopharyngeal, esophageal, and colon) cell lines and primary tumors. CMTM3 methylation was not detected in normal epithelial cell lines and tissues, with weak methylation present in only 5 of 35 (14%) gastric cancer adjacent normal tissues. Furthermore, immunohistochemistry showed that CMTM3 protein was absent in 12 of 35 (34%) gastric and 1 of 2 colorectal tumors, which was well correlated with its methylation status. The silencing of CMTM3 is due to aberrant promoter CpG methylation that could be reversed by pharmacologic demethylation. Ectopic expression of CMTM3 strongly suppressed the colony formation of carcinoma cell lines. In addition, CMTM3 inhibited tumor cell growth and induced apoptosis with caspase-3 activation. Thus, CMTM3 exerts tumor-suppressive functions in tumor cells, with frequent epigenetic inactivation by promoter CpG methylation in common carcinomas. [Cancer Res 2009 (12):5194–201]
Publisher: Massachusetts Medical Society
Date: 16-02-2017
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2022
DOI: 10.1200/JCO.21.02278
Abstract: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non–small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day) no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention 17% with lorlatinib dose modification), and 38% were unresolved most required no intervention. Lorlatinib dose modification did not notably influence PFS. First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non–small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.
Publisher: Massachusetts Medical Society
Date: 20-06-2013
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2013
Abstract: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation–positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58 95% CI, 0.43 to 0.78 P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47 95% CI, 0.34 to 0.65 P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
Publisher: Elsevier BV
Date: 06-2011
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.LUNGCAN.2019.04.014
Abstract: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates. Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months median overall survival was not reached after a median follow-up of 4.7 years. Most patients treated with first-line afatinib received subsequent therapy. Although limited by s le size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.
Publisher: Massachusetts Medical Society
Date: 04-12-2014
Publisher: Elsevier BV
Date: 08-2015
Abstract: To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines of treatment in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on locally advanced disease.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 10-2016
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2015
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2014
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.CLLC.2012.05.009
Abstract: We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2005
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-09-2013
Abstract: Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin emetrexed. Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation–positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin emetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60 95% CI, 0.41 to 0.87 P = .007) and dyspnea (HR, 0.68 95% CI, 0.50 to 0.93 P = .015), but not pain (HR, 0.83 95% CI, 0.62 to 1.10 P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P = .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P .001) and dyspnea (P .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P .001), role (P = .004), and cognitive (P = .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P .01). In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-10-2009
Abstract: This study investigated whether sequential administration of erlotinib and chemotherapy improves clinical outcomes versus chemotherapy alone in unselected, chemotherapy-naïve patients with advanced non–small-cell lung cancer (NSCLC). Previously untreated patients (n = 154) with stage IIIB or IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned to receive erlotinib (150 mg/d) or placebo on days 15 to 28 of a 4-week cycle that included gemcitabine (1,250 mg/m 2 days 1 and 8) and either cisplatin (75 mg/m 2 day 1) or carboplatin (5 × area under the serum concentration-time curve, day 1). The primary end point was nonprogression rate (NPR) at 8 weeks. Secondary end points included tumor response rate, NPR at 16 weeks, duration of response, progression-free survival (PFS), overall survival (OS), and safety. The NPR at 8 weeks was 80.3% in the gemcitabine plus cisplatin or carboplatin (GC) -erlotinib arm (n = 76) and 76.9% in the GC-placebo arm (n = 78). At 16 weeks, the NPR was 64.5% for GC-erlotinib versus 53.8% for GC-placebo. The response rate was 35.5% for GC-erlotinib versus 24.4% for GC-placebo. PFS was significantly longer with GC-erlotinib than with GC-placebo (adjusted hazard ratio, 0.47 log-rank P = .0002 median, 29.4 v 23.4 weeks) this benefit was consistent across all clinical subgroups. There was no significant difference in OS. The addition of erlotinib to chemotherapy was well tolerated, with no increase in hematologic toxicity, and no treatment-related interstitial lung disease. Sequential administration of erlotinib following gemcitabine latinum chemotherapy led to a significant improvement in PFS. This treatment approach warrants further investigation in a phase III study.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Elsevier BV
Date: 02-2017
Publisher: Springer Science and Business Media LLC
Date: 16-01-2010
DOI: 10.1007/S00280-009-1228-X
Abstract: Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. Eligibility criteria included hormone refractory prostate cancer with a rising PSA at least 6 weeks after peripheral anti-androgen withdrawal, ECOG performance status (PS) 0-1, and no prior chemotherapy. Fenretinide was administered orally at 900 mg m(-2) twice daily for 7 of every 21 days. PSA was measured before each cycle. The primary endpoint was a > or =50% reduction in PSA maintained for at least 3 weeks secondary endpoints included duration of PSA response, time to treatment failure (TTF: treatment stopped for progression or toxicity) and adverse events (AE). Twenty seven pts were recruited from 7 centres over 27 months. Median age was 74 (range 49-86), median baseline PSA was 129 (range 19-1,000), and 70% had a PS of 0. The median number of cycles received was 2 (range 0-11) and 20 pts completed at least 1 cycle. One pt (4%) achieved a 50% reduction in PSA lasting 39 days and 15 pts (56%) had not progressed within 6 weeks of starting fenretinide. The median TTF was 54 days (IQR 19-73): 22 (81%) failed with tumour progression, 3 (11%) failed with toxicity and 2 (7%) never commenced the drug. Grade 3 rash occurred in 1 patient, all other AE were grade 1 or 2. The most common AE were nausea (40%), hot flushes (36%), constipation (32%) and nyctalopia (32%). High-dose fenretinide had limited anti-tumour activity in patients with advanced hormone refractory prostate cancer: further evaluation in this setting is not warranted.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.CLLC.2018.03.009
Abstract: Afatinib is approved in the US, Europe, and several other regions for first-line treatment for epidermal growth factor receptor mutation-positive (EGFRm Treatment-naive patients with advanced EGFRm Among the 134 of 345 (39%) and 86 of 364 (24%) patients aged 65 years and older in LL3 and LL6, median PFS was improved with afatinib versus chemotherapy (LL3: hazard ratio [HR], 0.64 [95% confidence interval (CI), 0.39-1.03] LL6: HR, 0.16 [95% CI, 0.07-0.39]). Afatinib significantly improved OS versus chemotherapy in elderly patients with Del19 Subgroup analyses of the LL3, LL6, and LL7 trials show that afatinib is an effective and tolerable treatment for patients with EGFRm
Publisher: Springer Science and Business Media LLC
Date: 22-12-2016
DOI: 10.1038/BJC.2016.420
Publisher: Elsevier BV
Date: 03-2016
Abstract: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor s les. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. One hundred twenty-one patients with any EGFR mutation were enrolled 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050 NCT01774721). ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 09-2014
Abstract: To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.
Publisher: Elsevier BV
Date: 11-2016
Abstract: Afatinib 40 mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10 mg decrements to a minimum of 20 mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Treatment-naïve patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229 LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30 mg versus those remaining at 40 mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30 mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40 mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25] LL6: 12.3 versus 11.0 months (HR 1.00)}. Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.
Publisher: Elsevier BV
Date: 02-2015
Publisher: Massachusetts Medical Society
Date: 19-11-2020
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 2017
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2018
Abstract: The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) –positive advanced nonsquamous non–small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin (area under the concentration–time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053 two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non–small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population.
Publisher: Korean Cancer Association
Date: 15-07-2018
DOI: 10.4143/CRT.2017.280
Publisher: Springer Science and Business Media LLC
Date: 19-02-2019
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2016
Abstract: Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non–small-cell lung cancer. Patients were randomly assigned to receive crizotinib (250 mg twice daily n = 172) or chemotherapy (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively intracranial time to tumor progression (IC-TTP per protocol) and intracranial disease control rate (IC-DCR post hoc) were measured. The intent-to-treat population was also assessed. Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60 P = .069), patients with tBM (HR, 0.45 P = .063), and patients without BM (HR, 0.69 P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively P .001) and 24 weeks (56% v 25%, respectively P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40 P .001 median, 9.0 v 4.0 months, respectively BM absent: HR, 0.51 P .001 median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45 P .001 median, 10.9 v 7.0 months, respectively). Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.JTHO.2016.10.007
Abstract: We performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC. Randomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation-defined subgroups. We used the fixed-effects inverse variance-weighted method to pool estimates of treatment efficacy. Statistical tests were two sided. In the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61-0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58-0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70-1.55, p < 0.81 treatment-mutation interaction p = 0.03). In EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.
Publisher: American Medical Association (AMA)
Date: 02-2018
Publisher: European Respiratory Society
Date: 09-2016
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 04-2016
Publisher: Wiley
Date: 09-2015
DOI: 10.1002/CNCR.29547
Abstract: Previous studies have shown that the levels of 15-lipoxygenase 1 (15-LOX-1) and 15-LOX-2 as well as their metabolites 13-S-hydroxyoctadecadienoic acid (13(S)-HODE) and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) are significantly reduced in smokers with non-small cell lung carcinoma (NSCLC). Furthermore, animal model experiments have indicated that the reduction of these molecules occurs before the establishment of cigarette smoking carcinogen-induced lung tumors, and this suggests roles in lung tumorigenesis. However, the functions of these molecules remain unknown in NSCLC. NSCLC cells were treated with exogenous 13(S)-HODE and 15(S)-HETE, and then the ways in which they affected cell function were examined. 15-LOX-1 and 15-LOX-2 were also overexpressed in tumor cells to restore these 2 enzymes to generate endogenous 13(S)-HODE and 15(S)-HETE before cell function was assessed. The application of exogenous 13(S)-HODE and 15(S)-HETE significantly enhanced the activity of peroxisome proliferator-activated receptor γ (PPARγ), inhibited cell proliferation, induced apoptosis, and activated caspases 9 and 3. The overexpression of 15-LOX-1 and 15-LOX-2 obviously promoted the endogenous levels of 13(S)-HODE and 15(S)-HETE, which were demonstrated to be more effective in the inhibition of NSCLC. This study has demonstrated that exogenous or endogenous 13(S)-HODE and 15(S)-HETE can functionally inhibit NSCLC, likely by activating PPARγ. The restoration of 15-LOX activity to increase the production of endogenous 15(S)-HETE and 13(S)-HODE may offer a novel research direction for molecular targeting treatment of smoking-related NSCLC. This strategy can potentially avoid side effects associated with the application of synthetic PPARγ ligands.
Publisher: Informa UK Limited
Date: 25-09-2019
Publisher: Elsevier BV
Date: 02-2017
Publisher: Elsevier BV
Date: 11-2014
Publisher: Elsevier BV
Date: 04-2021
No related grants have been discovered for Tony Mok.