Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis.

Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.

Value of a molecular screening program to support clinical trial enrollment in Asian cancer patients: The Integrated Molecular Analysis of Cancer (IMAC) Study.

The value of precision oncology initiatives in Asian contexts remains unresolved. Here, we review the institutional implementation of prospective molecular screening to facilitate accrual of patients into biomarker-driven clinical trials, and to explore the mutational landscape of advanced tumors occurring in a prospective cohort of Asian patients (n = 396) with diverse cancer types. Next-generation sequencing (NGS) and routine clinicopathological assays, such as immunohistochemistry, copy number analysis and in situ hybridization tests, were performed on tumor samples. Actionable biomarker results were used to identify eligibility for early-phase, biomarker-driven clinical trials. Overall, NGS was successful in 365 of 396 patients (92%), achieving a mean depth of 1,943× and coverage uniformity of 96%. The median turnaround time from sample receipt to return of genomic results was 26.0 days (IQR, 19.0-39.0 days). Reportable mutations were found in 300 of 365 patients (82%). Ninety-one percent of patients at study enrollment indicated consent to receive incidental findings and willingness to undergo genetic counseling if required. The most commonly mutated oncogenes included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%); while the most frequently mutated tumor suppressor genes included TP53 (40%), SMARCB1 (12%), APC (8%), PTEN (6%) and SMAD4 (5%). Among 23 patients enrolled in genotype-matched trials, median progression-free survival was 2.9 months (IQR, 1.5-4.0 months). Nine of 20 evaluable patients (45%; 95% CI, 23.1-68.5%) derived clinical benefit, including 3 partial responses and 6 with stable disease lasting ≥ 8 weeks.

Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study.

Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild--alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate--any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-10× ULN, and/or total bilirubin ≤1-1.5× ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg/m(2) docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L/h/m(2) in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mg·h/L in Categories 1, 2, and 3, respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements. (ClinicalTrials.gov registration no. NCT00703378).

TARGET: A Phase II, Open-Label, Single-Arm Study of 5-Year Adjuvant Osimertinib in Completely Resected EGFR-Mutated Stage II to IIIB NSCLC Post Complete Surgical Resection.

INTRODUCTION: Osimertinib is a central nervous system (CNS)-active, third generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We present the rationale and design for TARGET (NCT05526755), which will evaluate the efficacy and safety of 5 years of adjuvant osimertinib in patients with completely resected EGFRm stage II to IIIB NSCLC. MATERIALS AND METHODS: TARGET is a phase II, multinational, open-label, single-arm study. Adults aged ≥18 years (Taiwan ≥20 years), with resected stage II to IIIB NSCLC are eligible; prior adjuvant chemotherapy is allowed. Eligible patients must have locally confirmed common (exon 19 deletion or L858R) or uncommon (G719X, L861Q, and/or S768I) EGFR-TKI sensitizing mutations, alone or in combination. Patients will receive osimertinib 80 mg once daily for 5 years or until disease recurrence, discontinuation or death. The primary endpoint is investigator-assessed disease-free survival (DFS) at 5 years (common EGFR mutations cohort). Secondary endpoints include: investigator-assessed DFS at 3 and 4 years; overall survival at 3, 4, and 5 years (common EGFR mutations cohort); DFS at 3, 4, and 5 years (uncommon EGFR mutations cohort); safety and tolerability, type of recurrence and CNS metastases (both cohorts). Exploratory endpoints include: tissue/plasma concordance; analysis of circulating molecules in plasma samples using different profiling approaches to detect minimal residual disease; incidence and change over time of incidental pulmonary nodules. RESULTS: TARGET is currently recruiting, and completion is expected in 2029.

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. METHODS: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups. ETHICS AND DISSEMINATION: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION: CRD42022330532.

Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis.

PURPOSE: The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021). PATIENTS AND METHODS: Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned. RESULTS: Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35-1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04-0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02-0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1-56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy. CONCLUSIONS: Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

Recommended testing algorithms for NTRK gene fusions in pediatric and selected adult cancers: Consensus of a Singapore Task Force.

The occurrence of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in a wide range of tumor types presents an attractive opportunity for using a tropomyosin receptor kinase (TRK) inhibitor as cancer therapy. Recent clinical studies have demonstrated highly efficacious outcomes associated with the use of TRK inhibitors, such as larotrectinib and entrectinib in NTRK fusion-bearing cancers, in both adult and pediatric populations. While NTRK gene fusions are commonly found in some uncommon adult and pediatric malignancies, they are also found, albeit rarely, in a wide range of more common malignancies. The potential value of testing for NTRK gene fusions in practically all advanced malignancies is underpinned by the remarkable therapeutic outcomes that TRK inhibitors offer. This requirement presents practical and financial challenges in real-world oncological practice. Furthermore, different testing platforms exist to detect NTRK gene fusions, each with its advantages and disadvantages. It is, therefore, imperative to develop strategies for NTRK gene fusion testing in an attempt to optimize the use of limited tissue specimen and financial resources, and to minimize the turnaround time. A multidisciplinary task force of Singapore medical experts in both public and private sectors was convened in late 2020 to propose testing algorithms for adult colorectal tumors, sarcomas, non-small cell lung cancer, and pediatric cancers, with particular adaptation to the Singapore oncological practice. The recommendations presented here highlight the heterogeneity of NTRK-fusion positive cancers, and emphasize the need to customize the testing methods to each tumor type to optimize the workflow.

Development, internal validation and calibration of a risk score to predict survival in patients with EGFR-mutant non-small cell lung cancer.

AIMS: EGFR tyrosine kinase inhibitors (TKIs) are first-line molecularly targeted therapies in patients with advanced non-small cell lung cancer (NSCLC) who carry sensitising EGFR mutations, due to its superior survival outcomes compared with conventional chemotherapy regimens. In this study, we sought to identify clinical, immune and biochemical variables with prognostic significance in this patient subgroup and incorporate them into a nomogram-based risk score. METHODS: A total of 199 patients with EGFR mutation-positive, advanced NSCLC (defined as stage IV at initial diagnosis or incurable disease recurrence) treated with first-line EGFR TKI therapy were retrospectively profiled. Univariable and multivariable survival analyses were conducted, with variables from the multivariable model with the highest Harrell's Concordance (C) Index selected for inclusion in the subsequent survival nomogram. Internal validation and internal calibration of our prognostic nomogram were also performed. RESULTS: Serum lactate dehydrogenase (LDH) and lung/pleural metastasis were independent predictors of unfavourable overall survival in all three multivariable models. A survival nomogram was generated based on the multivariable model with the highest Harrell's C Index, incorporating the following 11 variables: white cell count, haemoglobin, LDH, neutrophil/lymphocyte ratio, ethnicity (Chinese vs non-Chinese), Karnofsky-Performance Status (score of '90-100' or '70-80' vs '0-60'), Charlson Comorbidity Index (≥3, or 2, or 1 vs 0), neurological symptoms, brain, lung/pleural and adrenal metastases. CONCLUSION: We identified serum LDH as an independent predictor of unfavourable clinical outcomes in patients with advanced, EGFR mutation-positive NSCLC. We further developed a robust nomogram-based risk score that incorporates clinical, biochemical and immune variables that can provide more targeted prognostication and management in this patient subgroup.

Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy.

BACKGROUND: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status. METHODS: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes. RESULTS: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4-32.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients. CONCLUSIONS: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.

Statistical Process Control Charts for Monitoring Next-Generation Sequencing and Bioinformatics Turnaround in Precision Medicine Initiatives.

PURPOSE: Precision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes. PATIENTS AND METHODS: Trends in NGS and bioinformatics TAT were analyzed using simple regression models with TAT as the dependent variable and chronologically-ordered case number as the independent variable. The M-estimator "robust" regression and negative binomial regression were chosen to serve as sensitivity analyses to each other. Next, two popular statistical process control (SPC) approaches which are CUSUM and EWMA were utilized and the CUSUM log-likelihood ratio (LLR) charts were also generated. All statistical analyses were done in Stata version 16.0 (StataCorp), and nominal P < 0.05 was considered to be statistically significant. RESULTS: A total of 365 patients underwent successful molecular profiling. Both the robust linear model and negative binomial model showed statistically significant reductions in TAT with accumulating experience. The EWMA and CUSUM charts of overall TAT largely corresponded except that the EWMA chart consistently decreased while the CUSUM analyses indicated improvement only after a nadir at the 82nd case. CUSUM analysis found that the bioinformatics team took a lower number of cases (54 cases) to overcome the learning curve compared to the NGS team (85 cases). CONCLUSION: As NGS and bioinformatics lead precision oncology into the forefront of cancer management, characterizing the TAT of NGS and bioinformatics processes improves the timeliness of data output by potentially spotlighting problems early for rectification, thereby improving care delivery.

Upregulation of plasma C9 protein in gastric cancer patients.

Gastric cancer is one of the leading causes of cancer-related deaths worldwide. Current biomarkers used in the clinic do not have sufficient sensitivity for gastric cancer detection. To discover new and better biomarkers, protein profiling on plasma samples from 25 normal, 15 early-stage and 21 late-stage cancer was performed using an iTRAQ-LC-MS/MS approach. The level of C9 protein was found to be significantly higher in gastric cancer compared with normal subjects. Immunoblotting data revealed a congruent trend with iTRAQ results. The discriminatory power of C9 between normal and cancer states was not due to inter-patient variations and was independent from gastritis and Helicobacter pylori status of the patients. C9 overexpression could also be detected in a panel of gastric cancer cell lines and their conditioned media compared with normal cells, implying that higher C9 levels in plasma of cancer patients could be attributed to the presence of gastric tumor. A subsequent blind test study on a total of 119 plasma samples showed that the sensitivity of C9 could be as high as 90% at a specificity of 74%. Hence, C9 is a potentially useful biomarker for gastric cancer detection.

A meta-analysis on immune checkpoint inhibitor efficacy for advanced non-small cell lung cancer between East Asians versus non-East Asians.

BACKGROUND: We conducted a meta-analysis to assess the efficacy of immune checkpoint inhibitors (ICIs) (PD-1/L1 and CTLA-4 inhibitors) in first and subsequent lines in East Asians and non-East Asians. METHODS: We searched PubMed-MEDLINE, Embase and Scopus, from inception to 20 Sep 2019, and reviewed major conferences' abstracts, for randomised controlled trials of ICI in advanced-stage NSCLC (Stage IIIB or IV) without EGFR mutation that reported hazard ratios (HRs) stratified by geographical region including the region "Asia" or "East Asia". The primary outcome measures were overall survival (OS) and progression-free survival (PFS). The pooled HR and its 95% confidence interval (CI) for OS and PFS in East Asians and non-East Asians were calculated using a random effect model and the difference compared using an interaction test. RESULTS: A total of 5,465 patients from 7 randomised controlled trials involving CTLA-4 and/or PD-1/L1 inhibitors were included, with 1,740 (32%) East Asians and 3,725 (68%) non-East Asians. ICI was associated with an improvement in OS and PFS for both East Asian (OS HR, 0.74; 95% CI, 0.65-0.85; PFS HR, 0.56; 95% CI, 0.40-0.79) and non-East Asian patients (OS HR, 0.78; 95% CI, 0.72-0.85; PFS HR, 0.69; 95% CI, 0.56-0.85), with no significant difference between the two groups (Pinteraction=0.55 for OS; Pinteraction=0.33 for PFS). Subgroup analyses showed a statistically significant superior PFS (but not OS) for East Asians than non-East Asians in trials that used immune checkpoint inhibitor in the first-line treatment (Pinteraction=0.02). No significant regional difference was found in further subgroups of pure ICI and combination of ICI with chemotherapy. CONCLUSIONS: There is no significant difference in response to ICI between East Asians and non-East Asians with advanced stage NSCLC, and the statistically significant subgroup difference in PFS in the first line use of ICI may not be clinically significant.

Survival benefit and toxicity profile of adjuvant icotinib for patients with EGFR mutation-positive non-small cell lung carcinoma: a retrospective study.

BACKGROUND: Adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are increasing considered for the tailored management of resectable non-small cell lung cancer (NSCLC). This study aimed to analyze the survival and toxicity profile of patients with EGFR mutation-positive NSCLC treated with adjuvant icotinib. METHODS: This was a single-center retrospective study of patients with EGFR mutation-positive NSCLC who underwent R0 (microscopically margin-negative) resection and received adjuvant icotinib between November 2011 and December 2017. The outcomes included 2-year disease-free survival (DFS) rate, 3-year overall survival (OS) rates, DFS, OS, and adverse events (AEs). RESULTS: A total of 86 patients receiving adjuvant icotinib were included. Their mean age was 59.7±10.0 years, and 26 (30.2%) patients were male. The 2-year DFS rate was 86.7%, and the 3-year OS rate was 95.3% with adjuvant icotinib. DFS (P=0.044) and OS (P=0.003) are better in stage I/II disease than in stage III disease. There seems no differences in DFS and OS between patients with low or high preoperative CEA levels (cutoff of 5 ng/mL), patients with exon 19 or 21 EGFR mutation or patients with or without smoking history. The most common AEs with adjuvant icotinib were rash (83.7%) and diarrhea (19.8%). One (1.2%) patient-reported grade ≥3 AEs. No treatment-related death occurred. CONCLUSIONS: For patients with EGFR mutation-positive NSCLC, adjuvant icotinib might be associated with a promising survival benefit, with an acceptable toxicity profile.

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.

BACKGROUND: We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition. METHODS: In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov, NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28. FINDINGS: From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9-6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2-6·8; hazard ratio [HR] 0·67, 90% CI 0·35-1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1-37·3) versus 18·7 months in the chemotherapy group (15·9-20·7; HR 0·69, 0·34-1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1-16·6] vs 4·4 months [4·1-6·8]; HR 0·35, 0·17-0·74; median OS 37·3 months [90% CI 24·2-37·3] vs 17·9 months [12·0-20·7]; HR 0·33, 0·14-0·76) or MET amplification (n=19; median PFS 16·6 months [8·3-not estimable] vs 4·2 months [1·4-7·0]; HR 0·13, 0·04-0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25-not estimable]; HR 0·08, 0·01-0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. INTERPRETATION: Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration. FUNDING: Merck KGaA.

Integration of Antiangiogenic Therapy with Cisplatin and Gemcitabine Chemotherapy in Patients with Nasopharyngeal Carcinoma.

PURPOSE: Induction cisplatin and gemcitabine chemotherapy is a standard treatment for locally advanced nasopharyngeal carcinoma (NPC). Inhibition of VEGF axis has been shown to promote maturation of microvasculature and improve perfusion. We conducted a four-arm study to assess the effect of two doses of either sunitinib or bevacizumab with chemotherapy in NPC. PATIENTS AND METHODS: Patients with treatment-naïve locally advanced NPC were treated with three cycles of 3-weekly cisplatin and gemcitabine preceded by 1 week of anti-VEGF therapy for each cycle, followed by standard concurrent chemoradiation: arm A patients received 7 days of 12.5 mg/day sunitinib; arm B 7 days of 25 mg/day sunitinib; arm C bevacizumab 7.5 mg/kg infusion; arm D bevacizumab 2.5 mg/kg infusion. Patients with metastatic NPC were treated with up to six cycles of similar treatment without concurrent chemoradiation. RESULTS: Complete metabolic response (mCR) by whole body 18FDG PET was highest in arm C (significant difference in four groups Fisher exact test P = 0.001; type 1 error = 0.05), with 42% mCR (95% confidence interval, 18-67) and 3-year relapse-free survival of 88% in patients with locally advanced NPC. Significant increase in pericyte coverage signifying microvascular maturation and increased immune cell infiltration was observed in posttreatment tumor biopsies in Arm C. Myelosuppression was more profound in sunitinib containing arms, and tolerability was established in arm C where hypertension was the most significant toxicity. CONCLUSIONS: Bevacizumab 7.5 mg/kg with cisplatin and gemcitabine was well tolerated. Promising tumor response was observed and supported mechanistically by positive effects on tumor perfusion and immune cell trafficking into the tumor.

Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors.

Anaplastic lymphoma kinase (ALK) inhibitors are highly effective in patients with ALK fusion-positive lung cancer, but acquired resistance invariably emerges. Identification of secondary mutations has received considerable attention, but most cases cannot be explained by genetic causes alone, raising the possibility of epigenetic mechanisms in acquired drug resistance. Here, we investigated the dynamic changes in the transcriptome and enhancer landscape during development of acquired resistance to ALK inhibitors. Histone H3 lysine 27 acetylation (H3K27ac) was profoundly altered during acquisition of resistance, and enhancer remodeling induced expression changes in both miRNAs and mRNAs. Decreased H3K27ac levels and reduced miR-34a expression associated with the activation of target genes such as AXL. Panobinostat, a pan-histone deacetylase inhibitor, altered the H3K27ac profile and activated tumor-suppressor miRNAs such as miR-449, another member of the miR-34 family, and synergistically induced antiproliferative effects with ALK inhibitors on resistant cells, xenografts, and EML4-ALK transgenic mice. Paired analysis of patient samples before and after treatment with ALK inhibitors revealed that repression of miR-34a or miR-449a and activation of AXL were mutually exclusive of secondary mutations in ALK. Our findings indicate that enhancer remodeling and altered expression of miRNAs play key roles in cancer drug resistance and suggest that strategies targeting epigenetic pathways represent a potentially effective method for overcoming acquired resistance to cancer therapy.Significance: Epigenetic deregulation drives acquired resistance to ALK inhibitors in ALK-positive lung cancer. Cancer Res; 78(12); 3350-62. ©2018 AACR.

Does c-Met remain a rational target for therapy in patients with EGFR TKI-resistant non-small cell lung cancer?

Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and -independent c-Met activity, with a reduced risk of toxicity compared to non-selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered.

EGFR kinase inhibitors and gastric acid suppressants in EGFR-mutant NSCLC: a retrospective database analysis of potential drug interaction.

BACKGROUND: Erlotinib and gefitinib are weak base drugs whose absorption and clinical efficacy may be impaired by concomitant gastric acid suppressive (AS) therapy, yet proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2As) are widely indicated in non-small cell lung cancer (NSCLC) patients for the prevention and treatment of erlotinib-induced gastrointestinal injury and corticosteroid-associated gastric irritation. We assessed the clinical relevance of this potential drug-drug interaction (DDI) in a retrospective cohort of EGFR-mutant NSCLC patients. RESULTS: The AS usage rate was 35%. In the overall cohort, AS users did not experience poorer OS (HR: 1.47, 95% CI: 0.92 - 2.35, P = 0.10; median, 11.4 versus 17.5 months) or PFS (HR = 1.37, 95% CI: 0.89 - 2.12, P = 0.16; median, 7.6 versus 8.7 months) compared with non-users in multivariate Cox regression analysis. However, subgroup analyses indicated that AS usage was associated with significantly poorer OS and PFS in patients who had fewer or milder comorbidities (Charlson comorbidity index ≤ 2), those with Karnofsky performance status < 90, and never-smokers. MATERIALS AND METHODS: A retrospective database analysis of 157 patients given erlotinib or gefitinib for EGFR-mutant advanced NSCLC from two institutions was conducted. Patients were classified as AS-users if the periods of AS and anti-EGFR therapy overlapped by ≥ 30%. Overall survival (OS) and progression-free survival (PFS) were assessed according to AS usage. CONCLUSIONS: Concomitant AS therapy did not have an adverse impact on OS and/or PFS in the overall cohort. Our subgroup findings should be regarded exploratory and require replication in a large prospective cohort.

Evaluation of Scoring Systems and Prognostic Factors in Patients With Spinal Metastases From Lung Cancer.

STUDY DESIGN: A retrospective study of 180 patients with lung cancer spinal metastases, wherein prognostic score-predicted survival was compared with actual survival. OBJECTIVE: To evaluate and compare the accuracy of prognostic scoring systems in lung cancer spinal metastases. SUMMARY OF BACKGROUND DATA: The modified Tokuhashi, Tomita, modified Bauer, and Oswestry scores are currently used to guide decisions regarding operative treatment of patients with spinal metastases. The best system for predicting survival in patients with lung cancer spinal metastases remains undetermined. The high incidence of spinal metastases from lung cancer and improved survival of patients treated with systemic therapy warrants evaluation of these scoring systems in this particular context. METHODS: Patients with lung cancer spinal metastases treated at our institution between May 2001 and August 2012 were studied. Fifty-one patients were treated surgically. The primary outcome measure was survival from the time of diagnosis. Scoring-predicted survival was compared with actual survival. Potential prognostic factors were investigated using Cox regression analyses. Predictive values of each scoring system for 3- and 6-month survival were measured via receiver operating characteristic (ROC) curves. RESULTS: Histological subtype (P = 0.015), sex (P = 0.001), Karnofsky performance scale (P = 0.001), extent of neurological palsy (P = 0.002), and visceral metastases (P = 0.037) are significant predictors of survival. Besides the Oswestry spinal risk index, no significant differences were found between different prognostic subgroups within the individual scoring systems. Although the modified Bauer score was most accurate, all four scoring systems had areas under the ROC curve 0.5 or less. CONCLUSION: Although better prognostic scores correlated with longer survival, all four scoring systems are inaccurate in prognosticating patients with lung cancer spinal metastases. Specific lung cancer histology appears prognostic and should be considered, especially given the increased survival of patients receiving new targeted therapies appropriate to their disease. LEVEL OF EVIDENCE: 3.

Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.

The FDA-approved starting dosage of capecitabine is 1,250 mg/m(2), and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m(2). Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m(2) b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m(2) and 1,500 mg/m(2). At 1,500 mg/m(2), one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m(2) b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment.