Platinum-based Doublet Chemotherapy Research Articles

Nivolumab versus Docetaxel in a Predominantly Chinese Patient Population with Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 078 Randomised Phase 3 Clinical Trial

BACKGROUND: Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated non-small-cell lung cancer (NSCLC). METHODS: CheckMate 078 was a randomised, open-label, phase 3 clinical trial enrolling patients from China, Russia, and Singapore with NSCLC whose disease progressed during/after platinum-based doublet chemotherapy. Patients (N=504) were included regardless of tumour histology and programmed death ligand 1 (PD-L1) expression; those with EGFR/ALK alterations were excluded. Patients were randomised 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), stratified by performance status, histology, and tumour PD-L1 expression. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate (ORR) and progression-free survival. FINDINGS: OS was significantly improved with nivolumab (n=338) versus docetaxel (n=166); median OS (95% CI), 12·0 (10·4-14·0) versus 9·6 (7·6- 11·2) months, respectively; hazard ratio (97·7% CI), 0·68 (0·52-0·90); p=0·0006. ORR was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5·3 months. Minimum follow-up was 8·8 months. The frequency of grade ≥3 treatment-related adverse events was 10% with nivolumab and 48% with docetaxel. INTERPRETATION: This is the first phase 3 study in a predominantly Chinese population reporting results with a PD-1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies. CLINICAL TRIAL NUMBER: CheckMate 078 is registered on ClinicalTrials.gov, number NCT02613507. FUNDING STATEMENT: The study was funded by Bristol-Myers Squibb. Bristol-Myers Squibb was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. DECLARATION OF INTERESTS: Y-LW has received grants from Roche; has received personal fees from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi; and has received non-financial support from AstraZeneca. JW has received non-financial support from AstraZeneca. TM has received grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eisai, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, SFJ Pharmaceuticals, Taiho, Takeda, and XCovery and has received personal fees from ACEA Biosciences, AstraZeneca, Boehringer Ingelheim, BristolMyers Squibb, Celgene, ChiMed, Clovis Oncology, Eli Lilly, Fishawack Facilitate Ltd, Ignyta Inc, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, OncoGenex, Pfizer, Roche/Genentech, SFJ Pharmaceuticals, Taiho, Takeda, and Vertex. CB and J Cai are employees of Bristol-Myers Squibb. All other authors report no competing interests. ETHICS APPROVAL STATEMENT: The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guidelines on good clinical practice. The study protocol was approved by an institutional review board or independent ethics committee at each site. An independent data monitoring committee monitored the activity and safety of nivolumab versus docetaxel throughout the study

Expression of p63 as predictive and prognostic factor in advanced non-small-cell lung cancer

Background/Aim. Serbia belongs to the group of countries with a high lung cancer incidence and mortality rate. p63 gene plays an important role in development of lung cancer and immunohistochemical expression of p63 is considered to be a reliable marker for squamous histology. The results of some in vitro studies show a significant association of p63 expression and cisplatin chemoresistance. The aim of this study was to estimate the significance of p63 expression as predictive and prognostic factor in advanced non-small-cell lung cancer (NSCLC). Methods. Expression of p63 in 85 NSCLC (stages III, and IV) was investigated by the use of immunohistochemistry. Four weeks after the completion of 2 cycles of platinum-based doublet chemotherapy all the patients were evaluated based on the treatment response. Kaplan-Meier analysis with log-rank tests were used for overall survival (OS) and progression free survival (PFS) calcultations. Results. The expression of p63 was present in 49.4% of the patients out of whom 38.8% were with positive expression (p63+) and 10.6% of the patients were with weak expression (p63+-). Positive expression of p63 was seen in 93.9% of squamous cell carcinomas (SQCC), 5% of adenocarcinomas (AC), and in no patient with not otherwise specified (NOS) NSCLC. Weak expression of p63 was found in 12.5% of AC, 25% of NOS and only in 3% of SQCC. Analysis of the impact of the presence of p63 expression on the initial response to chemotherapy showed no statistical significance. The patients with weak p63 expression had a significantly shorter OS than the patients with no p63 expression (p = 0.049), and the tendency of shorter OS than the patients with p63 expression (p = 0.068). Conclusion. This study shows that p63 expression has no predictive significance for tumor response to initial chemotherapy regimen gemcitabine/ cisplatin or paclitaxel/cisplatin observed in advanced NSCLC. Weak expression of p63 have a negative prognostic effect in stage III and IV NSCLC.

Hepatotoxicity in Advanced Lung Adenocarcinoma: A Retrospective Study of 2108 Cases.

The study aimed to identify the risk factors and frequency of hepatotoxicity in patients with advanced lung adenocarcinoma. Liver function tests were documented in 2108 patients with advanced (IIIB/IV) lung adenocarcinoma at a single institution who received first line platinum-based doublet chemotherapy. Hepatotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Risk factors for hepatotoxicity were assessed using logistic regression analysis. Differences in hepatotoxicity between pemetrexed and non-pemetrexed regimens were evaluated after propensity score matching. After accounting for hepatic dysfunction during the first-line treatment, 892 patients receiving beyond first-line treatment were included in the subsequent analyses. Hepatotoxicity in beyond first-line treatment was compared between patients having epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy alone. In the first-line analysis, 316 (15.0%) patients developed liver dysfunction. Younger age (Odds Ratio [OR] 2.398, 95% Confidence Interval [95% CI] 1.755-3.275), pretreatment liver impairment (OR 2.285, 95% CI 1.622-3.220), and pemetrexed-contained chemotherapy (OR 1.835, 95% CI 1.408-2.393) were risk factors of hepatotoxicity (all P<0.001). Significant differences were observed for patients with all grades of hepatotoxicity while no differences were found concerning grade ¾ hepatotoxicity between 844 pemetrexed and 844 non-pemetrexed regimen matched cases (P<0.0001 and P=0.4220, respectively). After first-line treatment, the presence of hepatitis virus (OR 2.905, 95% CI 1.487-5.675; P=0.002) and TKI therapy (OR 2.621, 95% CI 1.809-3.798; P<0.001) were additionally associated with increased hepatotoxicity. Patients with advanced lung adenocarcinoma with younger age, pretreatment liver injury, and presence of hepatitis virus were at high risk for hepatotoxicity following chemotherapy. Pemetrexed-contained chemotherapy and TKIs should be used cautiously in patients who are susceptible to liver damage.

Bevacizumab in combination with different platinum-based doublets in the first-line treatment for advanced nonsquamous non-small-cell lung cancer: A network meta-analysis.

Platinum-based doublet chemotherapy with or without bevacizumab is the standard treatment for untreated advanced nonsquamous non-small-cell lung cancer (NS-NSCLC). However, adding bevacizumab to chemotherapies other than paclitaxel-carboplatin is, though widely applied clinically, largely unjustified due to the lack of head-to-head data. We performed a Bayesian network meta-analysis (NMA) to address this important issue. Data of 8,548 patients from 18 randomized controlled trials (RCTs) receiving six treatments, including taxane-platinum (Taxane-Pt), gemcitabine-platinum (Gem-Pt), pemetrexed-platinum (Pem-Pt), taxane-platinum + bevacizumab (Taxane-Pt + B), gemcitabine-platinum + bevacizumab (Gem-Pt + B) and pemetrexed-platinum + bevacizumab (Pem-Pt + B), were incorporated into the analyses. Direct and indirect evidence of overall survival (OS) and progression-free survival (PFS) were synthesized at the hazard ratio (HR) scale and evidence of objective response rate (ORR) and serious adverse events (SAE) were synthesized at the odds ratio (OR) scale. Taxane-Pt + B showed significant advantages in OS (HR = 0.79, p < 0.001), PFS (HR = 0.54, p < 0.001) and ORR (OR = 2.7, p < 0.001) over Taxane-Pt with comparable tolerability (OR = 3.1, p = 0.08). Gem-Pt + B showed no OS benefit compared to any other treatment. No significant differences were detected between Pem-Pt + B and Pem-Pt in four outcomes. In terms of the benefit-risk ratio, Pem-Pt and Taxane-Pt + B were ranked the first and second, respectively. In conclusion, in the first-line treatment for advanced NS-NSCLC, Taxane-Pt and Gem-Pt are the most and least preferable regimens to be used with bevacizumab, respectively. Adding bevacizumab to Pem-Pt remains unjustified because it fails to improve efficacy or tolerability. In terms of the benefit-risk ratio, Pem-Pt and Taxane-Pt + B are the best and second-best treatment for this population.

Radiation Dose to the Thoracic Vertebral Bodies Is Associated With Acute Hematologic Toxicities in Patients Receiving Concurrent Chemoradiation for Lung Cancer: Results of a Single-Center Retrospective Analysis

Totest the hypothesis that increasing radiation therapy (RT) dose to the thoracic vertebral bodies (TVBs) contributes to the development of hematologic toxicities (HTs) in patients with lung cancer. Cases of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with definitive chemoradiation with concurrent platinum-based doublet chemotherapy at our institution from 2007 to 2016 were identified. Mean TVB dose and the volume of TVBs receiving at least 5 to 60Gy(V5-V60) were retrospectively recorded. Logistic regression was used to test associations between grade ≥3 HT (HT3+) and dosimetric/clinical parameters. Normal tissue complication probability was evaluated using the Lyman-Kutcher-Burman (LKB) model for HT3+, and receiver operating characteristics analysis was used to determine dosimetric cut-points. We identified 201 patients, the majority having NSCLC (n=162, 81%) and stage III to IV disease (n=179, 89%). All patients received either cisplatin/etoposide (n=107, 53%) or carboplatin/paclitaxel (n=94, 47%). Median RT dose was 60Gy (range, 60-70Gy). The rate of HT3+ was 49% (n=99). Increasing mean TVB dose(per Gy) was associated with higher odds of developing HT3+ (odds ratio 1.041, 95% confidence interval 1.004-1.080, P=.032), as were increasing TVB V5 to V20. Thesedosimetric correlates to HT3+ persisted on multivariate analysis. Constrained optimization of the LKB model for HT3+ yielded the parameters: n=1, m=1.79, and TD50=21.4Gy. Optimal cut-points identified were V5=65%, V10=60%, V20=50%, and mean dose=23.5Gy. Patients with values above these cut-points had an approximately 2-fold increased risk of HT3+. We found that mean TVB dose and low-dose parameters (V5-V20) were associated with HT3+ in chemoradiation for lung cancer. Per the LKB model, bone marrow behaves like a parallel organ (n=1), implying that mean TVB dose is a useful predictor for toxicity. These data suggest that efforts to spare dose to the TVBs may reduce rates of severe HT.

452P - Pemetrexed versus best supportive care following platinum-based doublet chemotherapy for patients with advanced nonsmall cell nonsquamous lung cancer

Background: From very beginning optimal treatment strategy for advanced disease ca lung (Stage IIIB or IV) was, four to six cycles platinum based combined (doublet) regimen then observation and subsequently administration of second line chemotherapy with the progression of disease. Maintenance therapy in ca lung is a latest growing idea, improving quality of life. The advantage of using switch maintenance therapy over continuation therapy that a valuable number of tumor cells responds to different active agent when resistant to the first-line treatment. On the basis of this, we conducted a reterospectivev study compare pemetrexed versus best supportive care (BSC) as switch maintenance therapy. Methods: Between July 2012 and January 2014, newly diagnosed patients with Stage IIIB/IV NSCLC (nonsquamous) received six cycles of carboplatin AUC 6 or 7 (day1) and paclitaxel (175 mg/m2 day 1) every 3 weeks, nonprogressores and patients with stable disease were randomized 1:1 to receive maintenance pemetrexed 500 mg/m2 IV infusion over 10 minutes on day 1 of each 21-day cycle or BSC alone untill progression of disease. Vitamin B12, Folic acid and dexamethasone added to pemetrexed according to standard protocol. The primary endpoint was a comparison of overall survival (OS) between pemetrexed and BSC group, and the secondary endpoint was progression-free survival (PFS). Results: Initially total of 128 patients were enrolled in this study. Patients characteristics were as follows (stage IV disease 54%, ECOG performance status 0-1: 71.2s%, median age 54 years, male 81%,). These all patients received 6 cycles of initial therap. Further 71.09% (91 patients) nonprogessors randomly distributed for Pemetrexed (n = 46) and BSC group (n = 45). The median OS for Pemetrexed group was 13.2 months and 10.6 months for BSC, with a hazard ratio (HR) 0.77 (95% CI: 0.61–0.93, P = 0.003). The median PFS was 6.4 months for pemetrexed versus 4.8 months for BSC, with a HR 0.66 (95% CI: 0.48–0.84, P = 0.007). Hematological toxicities were the main toxicities specially grade 3/4 neutropenia and anemia Conclusions: Switch maintenance therapy with Pemetrexed, after doublet chemotherapy specially platinum based in advanced nonsquamous NSCLC has produced appreciable longer OS and PFS compared to BSC alone at the cost of higher grade 3/4 hematological toxicities. Legal entity responsible for the study: sp medical college radiotherapy department bikaner rajasthan Funding: None Disclosure: All authors have declared no conflicts of interest.

Cost-effectiveness of osimertinib in the UK for advanced EGFR-T790M non-small cell lung cancer

Aim: This study presents the cost-utility analysis that was developed to inform the NICE health technology assessment of osimertinib vs platinum-based doublet chemotherapy (PDC) in patients with EGFR-T790M mutation-positive non-small cell lung cancer (NSCLC) who have progressed on epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy.Methods and materials: A partitioned survival model with three health states (progression-free, progressed disease, and death) from a UK payer perspective and over lifetime (15 years) was developed. Direct costs included disease management, treatment-related (acquisition, administration, monitoring, adverse events), and T790M testing costs. Efficacy and safety data were taken from clinical trials AURA extension and AURA2 for osimertinib and IMPRESS for PDC. An adjusted indirect treatment comparison was applied to reduce the potential bias in the non-randomized comparison. Parametric functions were utilized to extrapolate survival beyond the observed period. Health state utility values were calculated from EQ-5D data collected in the trials and valued using UK tariffs. Resource use and costs were based on published sources.Results: Osimertinib was associated with a gain of 1.541 quality-adjusted life-years (QALYs) at an incremental cost of £64,283 vs PDC (incremental cost-effectiveness ratio [ICER]: £41,705/QALY gained). Scenario analyses showed that none of the plausible scenarios produced an ICER above £44,000 per QALY gained, and probabilistic sensitivity analyses demonstrated a 63.4% probability that osimertinib will be cost-effective at a willingness-to-pay threshold of £50,000.Limitations: The analysis is subject to some level of uncertainty inherent to phase 2 single-arm data and the immaturity of the currently available survival data for osimertinib.Conclusions: Osimertinib may be considered a cost-effective treatment option compared with PDC in the second-line setting in patients with EGFR-T790M mutation-positive NSCLC from a UK payer perspective. Further data from the ongoing AURA clinical trial program will reduce the inherent uncertainty in the analysis.

Radiotherapy for Oligometastatic Lung Cancer.

Non-small cell lung cancer (NSCLC) typically presents at an advanced stage, which is often felt to be incurable, and such patients are usually treated with a palliative approach. Accumulating retrospective and prospective clinical evidence, including a recently completed randomized trial, support the existence of an oligometastatic disease state wherein select individuals with advanced NSCLC may experience historically unprecedented prolonged survival with aggressive local treatments, consisting of radiotherapy and/or surgery, to limited sites of metastatic disease. This is reflected in the most recent AJCC staging subcategorizing metastatic disease into intra-thoracic (M1a), a single extra thoracic site (M1b), and more diffuse metastases (M1c). In the field of radiation oncology, recent technological advances have allowed for the delivery of very high, potentially ablative, doses of radiotherapy to both intra- and extra-cranial disease sites, referred to as stereotactic radiosurgery and stereotactic body radiotherapy (or SABR), in much shorter time periods compared to conventional radiation and with minimal associated toxicity. At the same time, significant improvements in systemic therapy, including platinum-based doublet chemotherapy, molecular agents targeting oncogene-addicted NSCLC, and immunotherapy in the form of checkpoint inhibitors, have led to improved control of micro-metastatic disease and extended survival sparking newfound interest in combining these agents with ablative local therapies to provide additive, and in the case of radiation and immunotherapy, potentially synergistic, effects in order to further improve progression-free and overall survival. Currently, despite the tantalizing potential associated with aggressive local therapy in the setting of oligometastatic NSCLC, well-designed prospective randomized controlled trials sufficiently powered to detect and measure the possible added benefit afforded by this approach are desperately needed.

Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy.

The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I–III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients.

Abstract CT126: Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients (pts) with advanced, refractory squamous (SQ) NSCLC treated with nivolumab (NIVO): CheckMate 063

Abstract Introduction: NIVO is a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor providing long-term survival with a favorable safety profile and QoL benefit, approved for previously treated advanced/metastatic NSCLC. Although the likelihood of benefit from NIVO appears correlated with PD-L1 expression in non-SQ NSCLC, pts without PD-L1 may also benefit; this trend is not seen in SQ NSCLC. As sHLA-G/E are immunosuppressive molecules, we hypothesized that baseline peripheral sHLA-G/E may be associated with NIVO outcomes. Methods: CheckMate 063 is a phase 2, single-arm study of NIVO in SQ NSCLC pts who progressed on/after prior platinum-based doublet chemotherapy (PT-DC). Of 117 pts treated, 50 had evaluable baseline serum and archived tumor samples. sHLA-G and -E serum levels (‘low’ defined as &amp;lt;median; ‘high’ as ≥median) were measured by ELISA. Percent CD3+ and CD8+ T cells in tumor samples were evaluated by IHC. Results: Pts achieving PR or SD had lower baseline sHLA-G and -E (Table). Pts with longer OS had low sHLA-G and -E. Median OS was 8.6 vs 6.0 mo (HR 0.58 [0.31, 1.09]) in pts with low vs high sHLA-G, respectively; median OS was 13.6 vs 4.6 mo (HR 0.52 [95% CI 0.27, 0.97]) in pts with low vs high sHLA-E. Longest OS occurred in pts with both low sHLA-G and -E (n=14; median OS 15.1 mo [4.57, not reached]). No correlation was seen between baseline sHLA-G and -E levels (Spearman’s r=0.18; P=0.22). High peripheral sHLA-G and -E were negatively correlated with CD3/CD8+ T-cell tumor microenvironment infiltration (CD3+ r=-0.39 and -0.26; CD8+ r=-0.40 and -0.24, respectively). sHLA-G and -E were not associated with smoking and ECOG performance status. Table.Baseline sHLA-G and -E levels stratified by RECIST v1.1PR n=7SD n=3PD n=33bNE n=4PMedian sHLA-Ga4.687.5410.2921.140.41Median sHLA-Ea15.2511.3019.7330.830.39ang/mL; bn=32 for sHLA-ENE=non-evaluable; PD=progressive disease; PR=partial response; SD=stable disease Conclusion: Lower baseline sHLA-G and -E levels in NIVO pts with advanced, refractory SQ NSCLC were associated with improved OS. Further studies are warranted to determine if sHLA-G/E are prognostic or predictive biomarkers in SQ and non-SQ NSCLC. Citation Format: Vera Rebmann*, Wilfried E. Eberhardt*, Naiyer Rizvi, Scott J. Antonia, David Planchard, Federico Cappuzzo, Julien Mazières, Gérard Zalcman, Hervé Lena, Jürgen Wolf, Leora Horn, Thomas Stinchcombe, Grace Dy, Anne Blackwood-Chirchir, Chelsea Jin, William J. Geese, Suresh S. Ramalingam, *Authors contributed equally to the current work. Soluble HLA-G and -E (sHLA-G/E) as potential biomarkers of clinical outcomes in patients (pts) with advanced, refractory squamous (SQ) NSCLC treated with nivolumab (NIVO): CheckMate 063 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT126. doi:10.1158/1538-7445.AM2017-CT126

Ceritinib versus chemotherapy in patients with ALK-rearranged non-small-cell lung cancer previously given chemotherapy and crizotinib (ASCEND-5): a randomised, controlled, open-label, phase 3 trial

Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Novartis Pharmaceuticals Corporation.

Efficacy and safety of endostar in the treatment of advanced lung squamous cell carcinoma.

e20574 Background: From the early 2000s, many advances in non-small cell lung cancer (NSCLC) have been made with the emergence of targeted therapies. However, because of safety concerns and a lower prevalence of relevant therapeutic targets, patients with squamous NSCLC have been excluded from many of these breakthroughs. Endostar is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. This study is to explore the clinical efficacy and safety of endostar in advanced squamous NSCLC patients. Methods: We performed a retrospective analysis of 259 newly diagnosed advanced squamous NSCLC patients who had received platinum-based doublet chemotherapy (PBDC) between September 2009 and March 2016. Of these patients, 116 received Endostar combined with PBDC, and 143 received PBDC only. Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and analyzed. Results: After a median follow-up of 13.5 months, a improvement in PFS was observed in the Endostar group, the median PFS was7.7 months compared with 5.4 months in the control group (HR, 0.745; P= 0.034). The median OS was 19.0 months in the Endostar group versus 14.3 months in the control group, but the difference was not significant (HR, 0.780; P= 0.094). Multivariate analysis demonstrated that in patients with advanced squamous NSCLC, anti-angiogenesis therapy with Endostar, radiotherapy of primary tumor and Ⅲb stage were significant and independent predictors of improved PFS ( P&lt; 0.05). For both arms, hematologic and gastrointestinal toxicities were the most common adverse events. Patients treated with Endostar had slightly higher rates of cardiac disorder and thromboembolic event, as compared with the control patients, but there were no statistically significant differences in toxicities overall between the 2 treatment groups. Conclusions: The current study indicates that Endostar as an anti-angiogenesis therapy combined with PBDC is able to provide further survival benefits with satisfactory toxicity in previously untreated squamous NSCLC patients, which merits further evaluation in randomized trials.

CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: Data from a randomized phase III trial (AURA3).

9005 Background: CNS metastases (mets) are common in pts with advanced NSCLC. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from a pooled analysis of 2 Phase II trials (AURA extension: NCT01802632, AURA2: NCT02094261) showed activity in the CNS. We report the first evidence of osimertinib efficacy in CNS mets from a randomized Phase III study (AURA3; NCT02151981) in pts with T790M-positive advanced NSCLC who have progressed on or after prior EGFR-TKI therapy. Methods: Pts were randomized 2:1 to osimertinib 80 mg once daily or platinum-based doublet chemotherapy every 3 wks for up to 6 cycles; maintenance pemetrexed was allowed. Pts with stable, asymptomatic CNS mets were eligible for enrolment. A prespecified subgroup analysis was conducted in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR), to define CNS objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by RECIST v1.1. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS mets present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS mets. Results: As of 15 April 2016, 116/419 (28%) pts were included in the cFAS. In the cEFR (n = 46), CNS ORR was 70% (21/30; 95% CI 51, 85) with osimertinib and 31% (5/16; 95% CI 11, 59) with chemotherapy (OR, 5.13; 95% CI 1.44, 20.64; p = 0.015). In the cFAS, CNS ORR was 40% (30/75; 95% CI 29, 52) with osimertinib and 17% (7/41; 95% CI 7, 32) with chemotherapy (OR, 3.24; 95% CI 1.33, 8.81; p = 0.014). In the cEFR and cFAS, median CNS DoR was 8.9 months (m) (95% CI 4.3, NC and 4.3, NC) for osimertinib and 5.7 m (95% CI NC, NC and 4.4, 5.7; respectively) for chemotherapy. Median CNS PFS in the cFAS was significantly longer with osimertinib than with chemotherapy (11.7 vs 5.6 m; HR 0.32; 95% CI 0.15, 0.69; p = 0.004). Conclusions: Consistent with the overall response to osimertinib reported in pts with T790M-positive advanced NSCLC, osimertinib was superior to chemotherapy in the treatment of pts with CNS mets; CNS response rate was higher, responses were more durable and CNS PFS was longer. Clinical trial information: NCT02151981.

Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.

Nutritional and functional status impairments to predict early death in elderly patients with advanced non-small-cell lung cancer (NSCLC).

e20600 Background: Early death for some patients can be explained by direct effect of tumor or can be secondary to cancer treatment.As for many patients it is not fully predictable, the factors influencing and determining early death in older individuals receiving chemotherapy for advanced NSCLC were analyzed. Methods: Advanced NSCLC patients, &gt; 70 years, ECOG performance status 0-1, treatment naïve, stage IIIB and IV, EGFR and ALK negative, were eligible. Geriatric assessment was performed at baseline and included: Performance status, ADLs, IADLs, CIRSG score and index, Mini Nutritional Assessment (MNA), Mini Mental State Evaluation (MMSE), educational and social status assessment, Geriatric Depression Scale (GDS).All patients, according to their classification in frail, vulnerable or fit, received best supportive care, monotherapy or doublet chemotherapy.For all patients data on number of cycles, response, discontinuation of treatment, dose reductions, grade 3/4 hematological and non-hematological toxicity were recorded. Patients who died within 90 days of diagnosis were considered.A descriptive statistic was calculated and a logistic regression analysis with the assessment of factors and covariates influencing early death events was performed. Results: From June 2010 to March 2016, 204 patients were assigned to platinum-based doublet (n = 73) or single-agent chemotherapy (n = 131).Median age was 75, 72% were males, 52% had non-squamous histology. Median number of cycles was 4, and was 3 for comorbidities. IADLs were impaired in 42%, ADLs in 6%,MNA in 15% and MMSE 10% of patients.Sixty-eight percent of patients were dead at the time of the analysis; 24% (49/204) had partial response, 25% (51/204) had stable disease and 51% (104/204) had progressive disease.At multivariate logistic model IADLs (p 0.001, OR 1.4 95%CI 0.4-1.6),MNA (p 0.001, OR 1.35 CI 0.1-1.35) and polypharmacy (p 0.008, OR 1.2 CI 1-1.4) were significantly associated with the occurrence of early death. Conclusions: The identification and management of patients with nutritional and functional impairments could help oncologists to reduce the risk of early death during chemotherapy for advanced NSCLC.

Strategies targeting angiogenesis in advanced non-small cell lung cancer.

Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy. Numerous oral multitargeting angiogenic small molecule tyrosine kinase inhibitors (TKIs) have been widely evaluated in advanced NSCLC, but only nintedanib in combination with platinum-based doublet chemotherapy has demonstrated a survival benefit in the second-line setting. Additionally, small-molecule TKIs remain the standard of care for patients with mutated EGFR, ALK or ROS1. Moreover, immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) are changing the current strategy in the treatment of advanced NSCLC without driver gene mutations. The potential synergistic activity of antiangiogenic agents and TKIs or immunotherapy is an interesting topic of research. This review will summarize the novel antiangiogenic agents, antiangiogenic monotherapy, as well as potential combination therapeutic strategies for the clinical management of advanced NSCLC.

Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial

Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here. The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851. Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1]). The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients. National Cancer Institute and Genentech.

Vitamin D deficiency is associated with a poor prognosis in advanced non-small cell lung cancer patients treated with platinum-based first-line chemotherapy.

This study aimed to examine the prognostic role of the plasma 25-hydroxyvitamin D (25(OH)D) level in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based doublet first-line chemotherapy. A total of 195 advanced NSCLC patients were consecutively and prospectively hospitalized to receive platinum-based first-line chemotherapy. The baseline 25(OH)D level was measured at the time of diagnosis. Main outcome measures included overall survival (OS) and progression-free survival (PFS). With 10 ng/mL as the cutoff value for the baseline plasma 25(OH)D level, patients with 25(OH)D < 10 ng/mL (n = 54) and those with 25(OH)D ≥ 10 ng/mL (n = 141) were found to have similar characteristics in terms of age, sex, smoking status, pathological type, Eastern Cooperative Oncology Group (ECOG) performance status, and clinical staging (all P-values > 0.05). The median OS values of patients with 25(OH)D < 10 ng/mL and ≥ 10 ng/mL were 17.9 months (95% confidence interval [CI], 14.4-21.4 months) and 20.8 months (95%CI, 17.9-23.8 months), respectively; the median PFS values were 9.4 months (95%CI, 8.2-10.5 months) and 9.4 months (95%CI, 8.3-10.5 months), respectively. Both univariate and multivariate analyses showed that having a plasma 25(OH)D level < 10 ng/mL was associated with a significantly shorter OS (P = 0.003; P = 0.009), while the baseline plasma 25(OH)D level was not significantly associated with PFS. Deficiency of 25(OH)D is an independent prognostic factor for a poor OS in advanced NSCLC patients treated with platinum-based first-line chemotherapy.

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial

Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5-13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2-16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96-1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group. In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. The Ministry of Health, Labour and Welfare of Japan.

Polymorphism in XRCC1 gene modulates survival and clinical outcomes of advanced North Indian lung cancer patients treated with platinum-based doublet chemotherapy.

Survival in lung cancer patients is genetically determined. Single nucleotide polymorphisms (SNPs) in DNA repair genes are observed to play a critical role in survival as DNA repair itself can behave as double-edged sword. We aim to explore the association of DNA repair gene XRCC1 in survival and clinical outcomes for North Indian population. Blood sample from patients diagnosed with lung cancer was taken. DNA isolation and genotyping were performed for the SNPs of XRCC1 gene. Further, patients were followed up through telephonic conversation after every 2months for 3years. Statistical analysis was carried out using Kaplan-Meier to determine the median survival time (MST) and Cox proportional regression model to determine the hazards ratio. Further, logistic regression was used to calculate to calculate the objective response. The mutant genotype for XRCC1 399 is observed to have a better survival (MST=9.6). Histological stratification did not reveal any association for any SNP except for SCLC subtype in XRCC1 632 with an increased death rate (HR 3.08, p=0.02). On stratification according to chemotherapy regimen administered; cisplatin/carboplatin+docetaxel was observed to increase survival for XRCC1 399 mutant genotype (AA) (HR 0.26, p=0.05). Cisplatin/carboplatin+irinotecan increased survival in both heterozygotes (GA) and combined variants (GA+AA) (HR 0.22, p=0.014; HR 0.23, p=0.012). The polymorphic variants within the XRCC1 gene have found to play an important role in overall survival of lung cancer patients undergoing specific chemotherapy regimen.