Publications by authors named "Chee Keong Toh"

63 Publications

A phase II study of nimotuzumab (TheraCim-hR3) concurrent with cisplatin/radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.

Head Neck 2021 Feb 5. Epub 2021 Feb 5.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Background: The efficacy of a combination of nimotuzumab, a humanized monoclonal antibody to the epidermal growth factor receptor, with chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated in a phase II study.

Methods: Patients with stage III/IV HNSCC received 3-weekly cisplatin 100 mg/m for three cycles and weekly nimotuzumab 200 mg for 8 weeks concurrently with radiotherapy. Primary endpoint was best overall response (BOR) and secondary endpoint was progression-free survival (PFS).

Results: Thirty-seven patients were included; the majority were Chinese (76%), male (89%), and had stage IVA/IVB HNSCC (92%). BOR of complete and partial response was seen in 22/37 (59%) and 10/37 (27%) patients, respectively. Median PFS was 17.5 months (95% CI: 11.1-54.5) and 3-year PFS was 40.4% (95% CI: 24.3-55.9). The frequency and type of adverse events observed were similar to standard chemoradiation.

Conclusion: The combination of nimotuzumab with cisplatin and radiotherapy was safe and achieved high response rates in HNSCC.
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http://dx.doi.org/10.1002/hed.26635DOI Listing
February 2021

Immune checkpoint inhibitor-associated myositis and myasthenia gravis overlap: Understanding the diversity in a case series.

Asia Pac J Clin Oncol 2020 Sep 27. Epub 2020 Sep 27.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Immune checkpoint inhibitors (ICI) have improved survival across tumor types however they cause immune-related toxicities through removal of the inhibition of auto-reactive T cells. In this case review, we present 4 patients with metastatic cancer who developed de-novo neuromuscular side effects of myositis with overlapping seropositive myasthenia gravis after ICI treatment. Declaration: This study was performed in accordance to the ethical standards set by the SingHealth Institutional Review Board, with consent taken from living patients and waiver of consent from deceased patients (CIRB Ref 2019/2485). Supporting data were collected from our institution's digital medical records system.
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http://dx.doi.org/10.1111/ajco.13442DOI Listing
September 2020

Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore.

J Med Econ 2020 Nov 21;23(11):1330-1339. Epub 2020 Sep 21.

Agency for Care Effectiveness, Ministry of Health, Singapore, Singapore.

Objective: Non-small cell lung cancer (NSCLC) accounts for 80-90% of all lung cancer cases and is usually associated with a poor prognosis. However, targeted therapy with first and second generation tyrosine kinase inhibitors (TKIs) has so far improved progression-free survival of epidermal growth factor receptor (EGFR) mutant NSCLC patients. Osimertinib, a third generation EGFR TKI has recently shown improved overall survival of 6.8 months in previously untreated EGFR mutant NSCLC patients. We assessed the cost-effectiveness of osimertinib versus standard EGFR TKIs (gefitinib or erlotinib) as first-line treatment for advanced or metastatic EGFR mutant NSCLC patients in Singapore.

Methods: A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from the Singapore healthcare payer perspective. Survival curves based on the overall trial population from the FLAURA trial were extrapolated beyond trial period over a 10-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from public healthcare institutions in Singapore. Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results.

Results: Compared with first or second generation TKI, osimertinib had a base-case incremental cost-effectiveness ratio (ICER) of SG$418,839 (US$304,277) per quality-adjusted life year gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon and variations in progression-free utility values. Scenario analyses showed that a 50% reduction in the cost of osimertinib was still associated with a high ICER that was unlikely to be deemed cost effective.

Conclusions: Osimertinib is not cost effective as a first-line treatment compared to standard EGFR TKIs in advanced EGFR mutant NSCLC patients in Singapore. The findings from our evaluation, alongside other considerations including the lack of survival benefit in the Asian subgroup of the FLAURA trial, will be useful to inform policy makers on funding decisions for NSCLC treatments in Singapore.
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http://dx.doi.org/10.1080/13696998.2020.1819822DOI Listing
November 2020

High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.

Int J Radiat Oncol Biol Phys 2020 Sep 13;108(1):70-80. Epub 2020 Jun 13.

Division of Radiation Oncology, National Cancer Centre Singapore, Singapore; Oncology Academic Programme, Duke-NUS Medical School, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore. Electronic address:

Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated.

Methods And Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses.

Results: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype.

Conclusions: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.007DOI Listing
September 2020

Cost-effectiveness analysis of pembrolizumab monotherapy versus chemotherapy for previously untreated advanced non-small cell lung cancer.

J Med Econ 2020 Sep 22;23(9):952-960. Epub 2020 Jun 22.

Agency for Care Effectiveness, Ministry of Health, Singapore, Singapore.

To assess the cost-effectiveness of pembrolizumab monotherapy compared with standard chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) in previously untreated adults who have a high programmed death ligand 1 (PD-L1) tumor proportion score of 50% or greater in Singapore. A partitioned-survival analysis model was developed from a healthcare system's perspective that extrapolated clinical and economic outcomes of first-line pembrolizumab (maximum treatment duration of 2 years) versus platinum doublet chemotherapy over a 10-year time horizon for patients with advanced NSCLC. The model consisted of three health states: alive with no progression, alive with progression, and dead. Key clinical inputs were based on Kaplan-Meier survival curves from the interim (median follow-up = 11.2 months) and updated analysis (median follow-up = 25.2 months) of the KEYNOTE-024 randomized controlled trial. Local cost data were applied. Utilities were derived from published international estimates. Both one-way and multivariate probabilistic sensitivity analyses (PSA) were conducted to identify key drivers of the results. Using the results from the updated analysis of KEYNOTE-024, patients treated with pembrolizumab experienced more quality adjusted life-years (QALYs), but incurred higher costs compared to chemotherapy over a 10-year time horizon (pembrolizumab: 1.9983 QALYs, SGD215,761; chemotherapy: 1.1317 QALYs, SGD70,444). The base-case incremental cost-effectiveness ratio (ICER) was SGD167,692 per QALY gained. One-way sensitivity analysis showed the ICER was most sensitive to the cost of pembrolizumab, followed by the time horizon. Multivariate PSA indicated that pembrolizumab had 0% probability of being cost-effective at a hypothetical willingness-to-pay threshold of SGD100,000 per QALY gained. While pembrolizumab is superior to standard chemotherapy in improving overall survival and progression-free survival, results suggest that it is unlikely to be cost-effective at its current price in Singapore. Factors including clinical effectiveness, safety, and budget impact should also be considered when making national funding decisions.
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http://dx.doi.org/10.1080/13696998.2020.1775620DOI Listing
September 2020

HPLC-MS/MS coupled with equilibrium dialysis method for quantification of free drug concentration of pazopanib in plasma.

Heliyon 2020 Apr 27;6(4):e03813. Epub 2020 Apr 27.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Background: The selective occurrence of hepatotoxicity observed with use of pazopanib may be attributed to its high level of plasma protein binding and low hepatic extraction ratio. The primary objective was to investigate changes in free drug concentration amongst patients with varying albumin concentrations.

Methods: A HPLC-MS/MS method using C18 column (4.6 × 150 mm, 5 μm) with ESI source in positive mode had been developed and validated for the quantitative determination of free pazaopanib concentration in human plasma. Prior to sample preparation, patient samples were subjected to 6-hour equilibrium dialysis with molecular weight cut-off set at 8000 Da.

Results: The calibration curves were linear over the range of 5-1000 ng/mL, with a lower limit of quantification of 5 ng/mL. The intra-day and inter-day precisions and accuracies were all within ± 15 %, at 3 different quality controls. Higher median fraction unbound of pazopanib were observed in patients (n = 17) with lower than normal albumin concentrations.

Conclusion: With the developed assay, monitoring of plasma free concentrations may be evaluated as an indicator of pazopanib exposure in patients.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191207PMC
April 2020

Genomic landscape of lung adenocarcinoma in East Asians.

Nat Genet 2020 02 3;52(2):177-186. Epub 2020 Feb 3.

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.
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http://dx.doi.org/10.1038/s41588-019-0569-6DOI Listing
February 2020

PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas.

J Clin Pathol 2020 Aug 24;73(8):463-469. Epub 2020 Jan 24.

Anatomical Pathology, Singapore General Hospital, Singapore

Background/aims: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.

Methods: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.

Results: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ=5.25; p=0.022), compared with clinicopathological features alone.

Conclusions: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.
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http://dx.doi.org/10.1136/jclinpath-2019-206092DOI Listing
August 2020

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

Lung Cancer 2020 01 26;139:207-215. Epub 2019 Nov 26.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore. Electronic address:

Objectives: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients.

Materials And Methods: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted.

Results: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time.

Conclusions: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.022DOI Listing
January 2020

Real-world outcome with abiraterone acetate plus prednisone in Asian men with metastatic castrate-resistant prostate cancer: The Singapore experience.

Asia Pac J Clin Oncol 2020 Feb 11;16(1):75-79. Epub 2019 Nov 11.

National Cancer Centre Singapore, Singapore.

Introduction: Several small studies have reviewed the efficacy of abiraterone acetate plus prednisolone (AAP) in clinical practice outside a trial setting. We report the largest cohort study of clinical outcomes in metastatic castrate-resistant prostate cancer (mCRPC) patients treated with AAP in a multicenter multiracial clinical setting.

Methods: A retrospective analysis on mCRPC patients treated at four tertiary hospitals in Singapore from 2012 to 2017 was conducted. Disease characteristics, treatment outcomes, and adverse events were retrieved from electronic medical records. Primary clinical end-point was overall survival (OS). A subset analysis of patients with various variables and OS curves were generated using the Kaplan-Meier method and compared using the log-rank test.

Results: Out of 200 patients with mCRPC treated with AAP, 163 (81.5%) patients were chemo-naïve (CN) and 37 (18.5%) patients were postchemotherapy (PC), with the median age of 68 (34-87) and 65 (52-80) years, respectively. Median OS was 20.0 (95% CI, 18.3-22.9) and 10.5 months (95% CI, 1.1-40.5) for CN and PC cohorts, respectively. A subset analysis of 108 patients showed a significantly longer OS in patients who had prior ADT for more than 12 months in CN patients (P < 0.001). Incidences of G3/G4 events were around 6.6%; most common side effect being hypertension with an incidence of 2.4%.

Conclusions: Treatment of CN and PC patients with AAP was associated with a comparable OS and progression-free survival to the reported series. Patients who were responsive to prior ADT of 12 months or more were associated with an improved OS.
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http://dx.doi.org/10.1111/ajco.13241DOI Listing
February 2020

Gallium-labelled PSMA-PET/CT as a diagnostic and clinical decision-making tool in Asian prostate cancer patients following prostatectomy.

Cancer Biol Med 2019 Feb;16(1):157-166

Division of Radiation Oncology, National Cancer Centre Singapore, Singapore 169610.

Objective: Prostate cancers (PCa) in Asian individuals are molecularly distinct from those found in their Caucasian counterparts. There is no risk stratification tool for Asian men with rapid biochemical recurrence (BCR) following radical prostatectomy (RadP). This study aims to assess the detection rate of Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA-PET/CT) for diagnosis of clinical recurrence and as a treatment decision making tool in Asian patients with BCR post-RadP.

Methods: Ga PSMA-PET and CT body with/without bone scan [conventional workup (CWU)] were performed in 55 Asian patients with BCR within 36 months post-RadP. Two blinded reviewers assessed the images. Detection rates of Ga PSMA-PET/CT were evaluated, and impact on management was reviewed by comparison with CWU.

Results: Median time to BCR post-RadP was 8.1 months. Detection rate for Ga PSMA-PET/CT was 80% (44/55). A positive scan was significantly associated with increasing prostate-specific antigen (PSA) level [odds ratio (OR) = 1.13 (95% CI 1.05-1.30), = 0.017], but not with higher Gleason grade or shorter PSA doubling time. Compared to CWU, Ga PSMA-PET/CT detected an additional 106 lesions in 33/44 patients with a positive scan, resulting in a change in management in 25/44 (56.8%) patients: 10 to hormonal therapy (HT) and whole pelvis radiotherapy (RT) in addition to bed RT, and 15 to palliative HT alone.

Conclusions: In the present report, we demonstrated the diagnostic and treatment decision utility of Ga PSMA-PET/CT in Asian men with rapid BCR. Detection of small volume nodal and systemic recurrences at low PSA levels (< 1.0 ng/mL) highlights the role of the tool in assigning patients to treatment intensification with HT-RT or palliative HT in polymetastatic disease.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528443PMC
February 2019

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

J Clin Oncol 2019 04 24;37(11):876-884. Epub 2019 Jan 24.

1 National Cancer Centre Singapore, Singapore.

Purpose: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC.

Patients And Methods: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.

Results: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154).

Conclusion: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.
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http://dx.doi.org/10.1200/JCO.18.00177DOI Listing
April 2019

Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases.

BMC Cancer 2018 Dec 3;18(1):1198. Epub 2018 Dec 3.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.

Background: Afatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control.

Methods: We performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models.

Results: Out of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3-19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15-0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34-1.80).

Conclusion: In patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.
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http://dx.doi.org/10.1186/s12885-018-5110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276185PMC
December 2018

Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates.

Nature 2018 05 16;557(7706):575-579. Epub 2018 May 16.

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.

Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types. Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients. Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control, in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8 TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein-Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8 TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8 TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39 CD8 TILs. Furthermore, frequencies of CD39 expression among CD8 TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.
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http://dx.doi.org/10.1038/s41586-018-0130-2DOI Listing
May 2018

Assessment of psychological distress among Asian adolescents and young adults (AYA) cancer patients using the distress thermometer: a prospective, longitudinal study.

Support Care Cancer 2018 Sep 11;26(9):3257-3266. Epub 2018 Apr 11.

Division of Medical Oncology, 11 Hospital Drive, National Cancer Centre Singapore, Singapore, 169610, Singapore.

Purpose: Since few studies have investigated whether the Distress Thermometer (DT) in Asian adolescent and young adult (AYA) cancer patients (between 15 and 39 years), we investigated the appropriateness of the DT as a screening tool for psychological symptom burden in these AYA patients and to evaluate AYA patients' distress across a trajectory of three time points longitudinally over a 6-month period.

Methods: This was a prospective, longitudinal study. Recruited Asian AYA patients were diagnosed with lymphomas, sarcomas, primary brain malignancies, or germ cell tumors. Patients completed the DT, PedsQL Generic Core Scales, and the Rotterdam Symptom Checklist. Data were analyzed using STATA version 15.

Results: Approximately half of the patients experienced clinically significant DT distress (distress score ≥ 4) early in their cancer journey with 43.1% patients presenting with distress at time of diagnosis and 47.7% patients 1 month after diagnosis. Among AYA patients > 24 years old, worry (68.3%), insurance/financial issues (61%), treatment decisions (43.9%), work/school issues (41.5%), nervousness (41.5%), and sadness (41.5%) were the top five identified problems. On the other hand, the top five identified problems among AYA ≤ 24 years were worry (54.2%), nervousness (41.7%), bathing/dressing problems (37.5%), work/school issues (33.3%), and fatigue (33.3%). DT scores were significantly associated with certain psychological symptom burden items such as worry (p < 0.001), depressed mood (p = 0.020), and nervousness (p = 0.015).

Conclusion: The DT is a useful screening tool for psychological distress in AYA cancer patients with clinically significant distress being identified in the early phases of the cancer journey.
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http://dx.doi.org/10.1007/s00520-018-4189-yDOI Listing
September 2018

A Decade of Never-smokers Among Lung Cancer Patients-Increasing Trend and Improved Survival.

Clin Lung Cancer 2018 09 17;19(5):e539-e550. Epub 2018 Mar 17.

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: It is not known whether clinicopathologic characteristics, treatment, and survival of never-smokers among lung cancer incident cases have changed over time. We assessed the trend and overall survival (OS) of these patients within our institution during a 10-year period.

Patients And Methods: We reviewed 2 cohorts of non-small-cell lung cancer patients with a diagnosis from 1999 to 2002 and from 2008 to 2011. The patient characteristics and OS were compared by smoking status within each cohort and between the 2 cohorts over time.

Results: Of the 992 patients in the 1999-2002 cohort and the 1318 patients in the 2008-2011 cohort, 902 and 1272 had a known smoking status, respectively. The proportion of never-smokers increased from 31% in 1999-2002 to 48% in 2008-2011 (P < .001). Within both cohorts, the differences in characteristics among never-, former-, and current-smokers have remained largely constant over time. A greater proportion of never-smokers had Eastern Cooperative Oncology Group performance status 0 to 1 and adenocarcinoma. The median OS increased from 15.5 months in 1999-2002 to 24.9 months in 2008-2011 (P = .001) for never-smokers, 12.3 to 15.9 months (P = .150) for former-smokers, and 10.5 to 13.9 months (P = .011) for current-smokers. The larger survival improvement among never-smokers was likely accounted for by the larger increase in never-smokers who were treated with tyrosine kinase inhibitors and pemetrexed over time.

Conclusion: We found an increasing trend of never-smokers among incident lung cancer cases and improved survival for these patients during a 10-year period. The documentation of smoking status in any national cancer registry is vital to estimate the true incidence of lung cancer among never-smokers over time.
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http://dx.doi.org/10.1016/j.cllc.2018.03.013DOI Listing
September 2018

Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.

Nat Commun 2018 01 15;9(1):216. Epub 2018 Jan 15.

Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, 138672, Singapore.

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
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http://dx.doi.org/10.1038/s41467-017-02584-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768770PMC
January 2018

Improved Survival of Advanced Lung Cancer in Singapore Over the Past Decade.

Ann Acad Med Singap 2017 Sep;46(9):333-338

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Introduction: We reviewed changes in clinical characteristics, treatment and survival of lung cancer patients in Singapore over the past decade.

Materials And Methods: We reviewed all primary lung cancer cases from January 2004 to December 2013. Basic demographic, clinical and treatment data were extracted from the database. Overall survival (OS) was calculated using Kaplan-Meier method; survival curves were compared using log-rank test. Linear regression trend lines were estimated using least squares approach, and Cox regression analyses were performed to identify prognostic factors.

Results: Among 6006 lung cancer patients, the median age was 68 years old, 65% were males, 88% were Chinese, 92% had non-small-cell lung cancer and 76% had advanced stage IIIB/IV. There were proportionally more adenocarcinomas diagnosed over the years, while that of squamous cell carcinoma (SCC) and small-cell-lung cancer (SCLC) have remained stable. The median OS of all patients increased from 9.2 months in 2004 to 11.5 months in 2013. This survival improvement was statistically significant among patients with stage IIIB/IV (6.7 to 8.7 months; = 0.005) and adenocarcinoma (12.7 to 15.4 months; = 0.041). There was no improvement in median OS for SCC or SCLC. The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) (hazard ratio [HR] 0.68; 95% CI, 0.63 to 0.73) and pemetrexed (HR, 0.69; 95% CI, 0.63 to 0.76) were significantly associated with improved OS.

Conclusion: Survival of patients with advanced stage IIIB/IV lung adenocarcinoma has improved over the past decade, and is potentially associated with the use of EGFR TKI and pemetrexed.
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September 2017

The Issue of Tissue in Molecular Stratification.

Oncologist 2017 12 11;22(12):1560. Epub 2017 Sep 11.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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http://dx.doi.org/10.1634/theoncologist.2017-0165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728023PMC
December 2017

Comparison of health state values derived from patients and individuals from the general population.

Qual Life Res 2017 12 14;26(12):3353-3363. Epub 2017 Aug 14.

Saw Swee Hock School of Public Health, National University of Singapore, Tahir Foundation Building (MD1), 12 Science Drive 2, Singapore, Singapore.

Purpose: Utility values are critical for cost-utility analyses that guide healthcare decisions. We aimed to compare the utility values of the 5-level EuroQoL-5Dimension (EQ-5D-5L) health states elicited from members of the general public and patients with heart disease or cancer.

Methods: In face-to-face interviews with 157 heart disease patients, 169 cancer patients, and 169 members from the general population, participants valued 10 EQ-5D-5L health states using a composite Time Trade-Off method.

Results: Pooling utility values for all health states, heart disease patients and cancer patients had mean utility values lower by 0.11 points (P value = 0.014) and 0.06 points (P value = 0.148), respectively, compared to the general population. Adjusting for sociodemographic characteristics, differences in health state utility values between the patient and the general populations were rendered non-significant, except that heart disease patients gave higher utility values (mean difference = 0.08; P value = 0.007) to mild health states than the general population. Difference in utility values, defined as utility value of a better health state minus that of a poorer health state, was higher among heart disease patients compared to the general population, before and after adjusting for sociodemographic characteristics.

Conclusions: Patients may differ from members of the general population in the strength of their preferences for hypothetical health states. Using utility values derived from the general population may under-estimate the comparative effectiveness of healthcare interventions for certain diseases, such as heart diseases.
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http://dx.doi.org/10.1007/s11136-017-1683-5DOI Listing
December 2017

Continued Response to One Dose of Nivolumab Complicated by Myasthenic Crisis and Myositis.

J Thorac Oncol 2017 07;12(7):e90-e91

Department of Anatomic Pathology, Singapore General Hospital, Singapore.

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http://dx.doi.org/10.1016/j.jtho.2017.02.024DOI Listing
July 2017

Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH).

J Clin Oncol 2017 Aug 13;35(24):2781-2789. Epub 2017 Jun 13.

Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne; Martin Früh, Kantonsspital St Gallen, St Gallen, Switzerland; Scott Gettinger, Yale Cancer Center, New Haven, CT; Melissa L. Johnson, Sarah Cannon Research Institute, Nashville, TN; Pasi A. Jänne, Dana-Farber Cancer Institute, Boston, MA; Marina C. Garassino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Daniel Christoph, Universitätsklinikum Essen, and the Ruhrlandklinik, Universität Duisburg-Essen, Essen; Martin Reck, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; Chee Keong Toh, National Cancer Centre, Singapore, Singapore; Naiyer A. Rizvi and Jamie E. Chaft, Memorial Sloan Kettering Cancer Center; Jamie E. Chaft, Weill Cornell Medical College, New York, NY; Enric Carcereny Costa, Catalan Institute of Oncology Badalona, Badalona; Luis Paz-Ares, Hospital Universitario Doce de Octubre & IIS i+12, CNIO, Ciberonc and Universidad Complutense, Madrid; Enriqueta Felip, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain; Jyoti D. Patel, University of Chicago, Chicago, IL; Laura Q.M. Chow, University of Washington, Seattle, WA; Marianna Koczywas, City of Hope, Duarte; Zhengrong Li, Jiaheng Qiu, Marcin Kowanetz, Simonetta Mocci, Geetha Shankar, and Alan Sandler, Genentech, South San Francisco, CA; Cheryl Ho, Vancouver Centre, BC Cancer Agency, Vancouver, British Columbia; Jeffrey Rothenstein, R.S. McLaughlin Durham Regional Cancer Centre, Oshawa; Frances A. Shepherd, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Ontario, Canada; Michel van den Heuvel, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; and Takayasu Kurata, Kansai Medical University Hirakata Hospital, Osaka, Japan.

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.
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http://dx.doi.org/10.1200/JCO.2016.71.9476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562171PMC
August 2017

Outcomes of Dose-Attenuated Docetaxel in Asian Patients with Castrate-Resistant Prostate Cancer.

Ann Acad Med Singap 2017 May;46(5):195-201

Department of Medical Oncology, National Cancer Centre Singapore, Singapore.

Introduction: High levels of toxicities have been observed when docetaxel is administered at the standard dose of 75 mg/m every 3 weeks (Q3W) in the real-world treatment of Asian patients with metastatic castrate-resistant prostate cancer (CRPC). This study aimed to evaluate the efficacy and tolerability of 2 attenuated regimens more widely used in an Asian setting to minimise toxicity - 60 mg/m Q3W and weekly docetaxel (20 mg/m to 35 mg/m).

Materials And Methods: Medical records of 89 CRPC patients between December 2003 and April 2013 were reviewed. Pairwise statistical analysis was performed, comparing efficacy and safety outcomes of 75 mg/m Q3W and weekly docetaxel with 60 mg/m Q3W. Treatment endpoints used were prostate-specific antigen (PSA) response (decrease of ≥50% from baseline), pain improvement after cycle 2, overall survival, time to disease progression and radiological response.

Results: Patients who received docetaxel at 75 mg/m Q3W were younger than those who received 60 mg/m Q3W (62 years and 66 years, respectively; = 0.0489). Both groups had similar response rates. Compared with patients on 60 mg/m Q3W, more patients on weekly regimens were symptomatic at baseline (63.2% and 87.5%, respectively; = 0.0173). Longer overall survival was observed in the 60 mg/m Q3W arm than the weekly docetaxel arm (16.9 months and 10.6 months, respectively; = 0.0131), though other measures of response did not differ significantly.

Conclusion: Our data supports the use of 60 mg/m Q3W docetaxel which has similar efficacy and an acceptable toxicity profile compared to the standard 75 mg/m Q3W regimen. Weekly docetaxel has significant palliative benefits among symptomatic patients despite lower overall survival.
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May 2017

Influence of the KDM4A rs586339 polymorphism on overall survival in Asian non-small-cell lung cancer patients.

Pharmacogenet Genomics 2017 03;27(3):120-123

aLaboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research bNational Cancer Centre, Division of Medical Oncology cClinical Pharmacology, SingHealth dDepartment of Clinical Sciences, Duke-NUS Medical School, Singapore.

The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1.68, P=0.042). In the current study, we investigated the association between the same polymorphism with OS in our Asian NSCLC-adenocarcinoma patients comprising Chinese (N=572), Malays (N=50), and Indians (N=22). KDM4A SNP-A482 genotype status was determined by Sanger sequencing. OS was calculated from the date of diagnosis to date of death or censored at the date of last follow-up. Kaplan-Meier analysis, log-rank test, and Cox regression methods were utilized to evaluate OS outcomes. KDM4A SNP-A482 had a minor allele (C) frequency of 18.8% and a major allele (A) frequency of 81.2% in our Asian NSCLC (adenocarcinoma) patients. However, the OS in our Asian NSCLC patients homozygous for KDM4A SNP-A482 was not significantly different from those who were wild type or heterozygous at this locus [CC vs. AA/AC: median OS (95% confidence interval): 40.2 (18.7-61.6) vs. 29.6 (26.9-32.3) months; P=0.858]. The results remained statistically nonsignificant even after adjustment for epidermal growth factor receptor mutational status, suggesting that KDM4A SNP-A482 does not significantly influence OS in Asian NSCLC patients.
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http://dx.doi.org/10.1097/FPC.0000000000000266DOI Listing
March 2017

Metronomic chemotherapy: A relook at its basis and rationale.

Cancer Lett 2017 03 18;388:328-333. Epub 2016 Dec 18.

Division of Medical Oncology, National Cancer Centre, Singapore. Electronic address:

Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema.
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http://dx.doi.org/10.1016/j.canlet.2016.12.013DOI Listing
March 2017

EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients.

J Thorac Oncol 2017 03 28;12(3):529-538. Epub 2016 Nov 28.

Clinical Pharmacology, SingHealth, Singapore; Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; Office of Clinical Sciences, Duke-National University of Singapore Medical School, Singapore. Electronic address:

Introduction: Activating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy.

Methods: Patients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS.

Results: Significant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15-nucleotide deletion "non-ELREA" group having the shortest OS of 11.3 months (overall p = 0.025).

Conclusions: EGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment.
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http://dx.doi.org/10.1016/j.jtho.2016.11.2225DOI Listing
March 2017

Dual modulation of MCL-1 and mTOR determines the response to sunitinib.

J Clin Invest 2017 01 28;127(1):153-168. Epub 2016 Nov 28.

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
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http://dx.doi.org/10.1172/JCI84386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199697PMC
January 2017

Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules.

PLoS One 2016 2;11(5):e0154316. Epub 2016 May 2.

Division of Medical Oncology, National Cancer Center, Singapore, Singapore.

Purpose: This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC).

Methods: This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily.

Results: The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group.

Conclusions: Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups.

Trial Registration: ClinicalTrials.gov NCT00702182.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154316PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852941PMC
July 2017

Differential radiologic characteristics of renal tumours on multiphasic computed tomography.

Singapore Med J 2017 May 19;58(5):262-266. Epub 2016 Apr 19.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Introduction: This study analysed the tumour attenuation characteristics of different subtypes of renal cell carcinomas (RCCs), including clear cell RCC (ccRCC), papillary RCC (pRCC), mixed RCC, chromophobe RCC (chRCC) and oncocytoma.

Methods: We randomly selected 100 RCC cases that underwent nephrectomy between 2004 and 2012 from a collaborative database. Of these cases, 36 were excluded due to the absence of available imaging. The remaining 64 cases comprised 35 ccRCCs, 11 pRCCs, eight chRCCs, seven mixed RCCs and three oncocytomas. The cases were classified as computed tomography (CT) kidney, CT urogram (with plain, nephrographic and pyelographic phases) or CT abdomen (with portovenous and delayed phases). A circular region of interest (ROI) ≥ 1 cm was drawn and the same standard ROI size was used for each phase at the same site; three different circular ROIs were drawn per lesion per phase. Analysis of variance and t-test were used to examine differences in the radiological characteristics.

Results: There was no statistical difference in the attenuation and degree of enhancement between mixed RCCs and ccRCCs. The attenuation and degree of enhancement of the oncocytomas were significantly higher than those of the other RCC subtypes.

Conclusion: While mixed RCCs did not have attenuation characteristics that differed significantly from those of ccRCCs, oncocytomas can be distinguished from ccRCCs, pRCCs, chRCCs and mixed RCCs by their high radiological density and enhancement. The ability to differentiate oncocytomas from these tumours potentially allows the preoperative selection of patients with small renal masses for conservative management.
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http://dx.doi.org/10.11622/smedj.2016081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435845PMC
May 2017