EGFR Tyrosine Kinase Inhibitor (TKI) Combined With Concurrent or Sequential Chemotherapy for Patients With Advanced Lung Cancer and Gradual Progression After First-Line EGFR-TKI Therapy: A Randomized Controlled Study

IntroductionContinuing tyrosine kinase inhibitor (TKI) therapy may be beneficial when patients with non–small-cell lung cancer and EGFR mutations experience gradual disease progression after initial EGFR-TKI treatment. We aimed to compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients’ disease gradually progressed after first-line EGFR-TKI treatment.Patients and MethodsPatients with gradual progression who were EGFR-T790M mutation negative were randomly divided into two groups. In the concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI. In the sequential group, patients continued with EGFR-TKI until the disease progressed again, according to RECIST, then switched to chemotherapy. We evaluated the patients’ progression-free survival (PFS) and overall survival times.ResultsNinety-nine patients were enrolled: 49 in the concurrent group and 50 in the sequential group. The median PFS (mPFS) was 7.7 months (95% confidence interval [CI], 3.6-11.7) in the concurrent group and 5.7 months (95% CI, 3.5-7.9) in the sequential group (hazard ratio = 0.66; 95% CI, 0.44-1.00; P = .026), respectively. For the sequential group, the mPFS1 and mPFS2 were 1.8 months (95% CI, 1.4-2.3) and 3.8 months (95% CI, 3.1-4.5), respectively. The median overall survival of the concurrent group was longer than that of the sequential group (20.0 vs. 14.7 months; hazard ratio = 0.52; 95% CI, 0.32-0.85; P = .038).ConclusionFor patients with advanced non–small-cell lung cancer and gradual progression who are EGFR-T790M mutation negative after initial EGFR-TKI therapy, EGFR-TKI combined with chemotherapy confers longer PFS and overall survival than sequential EGFR-TKI and chemotherapy does.     

First-line Pembrolizumab Versus Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Non–small-cell Lung Cancer: A Systematic Review and Network Meta-analysis

BackgroundThis study aimed to comprehensively review the available evidence regarding the efficacy of first-line pembrolizumab for advanced/metastatic non–small-cell lung cancer (NSCLC), and to compare pembrolizumab monotherapy versus pembrolizumab plus chemotherapy versus chemotherapy alone.Materials and MethodsA search of the PubMed, EMBASE, and Cochrane Library databases was performed in July 2018, and abstracts from the American Society of Clinical Oncology meetings (2015-2018) were reviewed. Summaries of the results were pooled using a random-effect model to determine the pooled hazard ratio (HR) for progression-free survival (PFS), overall survival (OS), and their 95% confidence intervals (CIs). A network meta-analysis was used to indirectly compare pembrolizumab monotherapy with pembrolizumab plus chemotherapy.ResultsA total of 4 relevant phase III trials comprising 2754 patients were identified. Pembrolizumab (with or without chemotherapy) led to significant improvements in OS and PFS, irrespective of the programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS). In particular, for the subgroup with PD-L1 TPS ≥ 50%, the HR of PFS was 0.49 (95% CI, 0.32-0.76; P = .001), and that of OS was 0.57 (95% CI, 0.45-0.73; P < .001). In terms of PFS, pembrolizumab plus chemotherapy was superior to pembrolizumab monotherapy with an HR of PFS 0.52 (95% CI, 0.27-0.99; P = .048) for the subgroup with PD-L1 TPS ≥ 50%.ConclusionsFor patients with NSCLC with PD-L1 TPS ≥ 50%, pembrolizumab plus chemotherapy has a better PFS than pembrolizumab monotherapy in this meta-analysis. To confirm this finding, a prospective phase III trial that directly compares the treatments is warranted.     

Tumor Burden is Predictive of Survival in Patients With Non–Small-Cell Lung Cancer and With Activating Epidermal Growth Factor Receptor Mutations Who Receive Gefitinib

BackgroundAlthough activating epidermal growth factor receptor (EGFR) mutations are excellent predictors of gefitinib outcome in non–small-cell lung cancer (NSCLC), most patients become resistant to gefitinib. Despite our knowledge of the molecular basis of acquired resistance, clinical predictors have not been well elucidated. This study was undertaken to evaluate predictors of clinical outcome in patients with NSCLC and with EGFR mutations treated with gefitinib.Patients and MethodsA total of 170 patients with NSCLC and with EGFR mutations received gefitinib as a first-line (n = 50) and a second-line or more (n = 120) treatment at Seoul National University Hospital. Treatment outcomes were compared between groups based on clinicopathologic factors, such as treatment line, metastatic site, and mutation subtype.ResultsSurvival outcomes were similar between first-line and second-line or greater gefitinib treatment (overall response rate, 2P = .832; progression-free survival [PFS], 2P = .373; and overall survival [OS], 2P = .290). When the number of metastatic sites was at least 3, significantly reduced survival was observed (median PFS 8.5 vs. 14.0 months, 2P < .001; median OS 21.4 vs. 25.6 months, 2P = .002). In addition, the presence of at least 3 organs with metastases was an independent predictor of PFS (hazard ratio [HR] 1.97 [95% CI, 1.37-2.85]; 2P < .001) and OS (HR 2.00 [95% CI, 1.18-3.39]; 2P = .010). Patients who failed to respond to gefitinib within 6 months of treatment had more lymph node metastases and more sites of metastasis than those who responded later.ConclusionsTumor burden, expressed as the number of metastatic sites, is predictive of inferior survival in patients with NSCLC and with activating EGFR mutations who are treated with gefitinib.     

Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non–small-cell Lung Cancer

BackgroundImmune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non–small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune-related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC.MethodsIn this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).ResultsOverall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001).ConclusionsThis report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively.     

The Impact of Postoperative Conformal Radiotherapy after Radical Surgery on Survival and Recurrence in Pathologic T3N0M0 Esophageal Carcinoma: A Propensity Score-Matched Analysis

IntroductionThe role of conformal radiotherapy (cRT) in thoracic esophageal squamous cell carcinoma (TESCC) has not been addressed in adjuvant settings. The aim of this study was to investigate whether postoperative radiotherapy using cRT after an R0 resection improves outcomes in pT3N0M0 TESCC compared with resection alone.MethodsThis study included 678 patients with pT3N0M0 TESCC who were treated at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 2004 to December 2011. The patients were divided into two groups: a surgery plus cRT group (S+cRT group) comprising patients who underwent cRT after an R0 resection and a surgery group (S group), comprising a control group of patients who underwent an R0 resection alone. Propensity score matching was used to create patient groups that were balanced across several covariates (n = 83 in each group). Outcome measures included overall survival (OS), disease-free survival (DFS), and recurrence.ResultsIn the overall study cohort, 5-year OS (75.2% versus 58.5%, p = 0.004) and DFS (71.8% versus 49.2%, p = 0.001) rates were significantly higher in the S+cRT group than in the S group. These data were confirmed in the matched samples (5-year OS, 75.7% versus 58.8% [p = 0.017]; DFS, 71.7% versus 50.3% [p = 0.009]). The overall (p = 0.001) and locoregional (p = 0.004) recurrence rates in the S+cRT group were significantly lower than in the S group. Multivariate Cox analyses in the matched samples revealed that surgery and postoperative cRT were independently associated with longer OS (hazard ratio = 0.505, 95% confidence interval: 0.291–0.876, p = 0.015) and longer DFS (hazard ratio = 0.513, 95% confidence interval: 0.309–0.854, p = 0.010) than resection alone.ConclusionsPostoperative radiotherapy using cRT is strongly associated with improved OS and DFS in patients with pT3N0M0 TESCC. A multicenter, randomized phase III clinical trial is warranted to confirm these findings.     

Real-World Efficacy of First-Line Pembrolizumab in Patients With Advanced or Recurrent Non–Small-Cell Lung Cancer and High PD-L1 Tumor Expression

BackgroundIn clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent.Patients and MethodsNinety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics.ResultsThe objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P < .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease.ConclusionThe outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.     

Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study

BackgroundBrigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial.Patients and MethodsThis was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases.ResultsOf the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients.ConclusionEfficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.     

Phase II Study of Topotecan and Bevacizumab in Advanced,Refractory Non–Small-Cell Lung Cancer

BackgroundThis clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non–small-cell lung cancer in a second-line setting.Patient and MethodsPatients aged 18 years old and older received topotecan (4.0 mg/m²) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan.ResultsForty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression.ConclusionBevacizumab in combination with topotecan as a salvage therapy for metastatic non–small-cell lung cancer is well tolerated and is worthy of further investigation.     

Nomograms for Predicting Overall and Recurrence-free Survival From Pathologic Stage IA and IB Lung Cancer After Lobectomy

BackgroundStage I non–small-cell lung cancer (NSCLC) is potentially curable with surgical resection. Significant proportions of patients may still experience recurrence and death despite undergoing curative surgery. This study describes predictive nomograms for recurrence-free (RFS) and overall survival (OS) after lobectomy.Patients and MethodsA total of 301 patients with the American Joint Committee on Cancer pathologic stage IA and IB NSCLC who underwent open, thoracoscopic, or robotic lobectomy from January 2011 to April 2017 were analyzed. Multivariate Cox proportional hazards regression models were used to create nomograms for OS and RFS. Kaplan-Meier survival curves were calculated for OS and RFS comparing high-risk and low-risk cohorts based on nomogram scores.ResultsHistology (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.10-0.56; P = .002), lymphovascular invasion (HR, 0.46; 95% CI, 0.29-0.74; P = .001), smoking status (HR, 3.46; 95% CI, 1.25-9.55: P = .02), and total lymph nodes removed (HR, 1.05; 95% CI, 1.01-1.10; P = .021) were significant predictors for OS in a multivariate model. Lymphovascular invasion (HR, 0.55; 95% CI, 0.36-0.83; P = .0040), smoking status (HR, 2.56; 95% CI, 1.16-5.62; P = .02), total lymph nodes removed (HR, 1.04; 95% CI, 1.00-1.08; P = .029), and tumor size (HR, 1.30; 95% CI, 1.30-1.68; P = .047) were significant predictors of RFS in a multivariate model.ConclusionNomograms can predict OS and RFS for pathologic stage IA and IB NSCLC after lobectomy regardless of operative approach. The risk for death and recurrence after stratification by the nomogram scores may provide guidance regarding adjuvant therapy and surveillance.     

Impact of Radiotherapy on the Efficacy and Toxicity of anti-PD-1 Inhibitors in Metastatic NSCLC

BackgroundThe impact of radiotherapy (RT) on the efficacy and toxicity of immune checkpoint inhibitors (ICIs) in patients with metastatic non–small-cell lung cancer (NSCLC) is unclear.Materials and MethodsWe identified patients with metastatic NSCLC treated with the anti-programmed death 1 antibodies nivolumab or pembrolizumab between January 2016 and May 2019 at 3 tertiary centers, who were also treated with palliative RT either during or within 3 months of starting anti-programmed death 1 treatment. Patient demographics, tumor characteristics, and treatment history were collected. Response rates, progression-free survival (PFS), and overall survival (OS) were analyzed and correlated with RT use.ResultsA total of 269 patients were identified, with a median follow-up of 19.4 months. The median age was 70 years (range, 35-90 years), and they were 63% male, 60% smokers, and 65% had adenocarcinoma histology. At the commencement of ICI treatment, the majority (86%) had ≥ 1 line of prior therapy and 34% had brain metastases. A total of 102 (38%) patients received RT within 3 months of starting ICI or subsequently during ICI treatment. Of patients that received RT, 86 (84%) received conventional hypofractionated RT, and, in the majority, 81 (79%) the intent of RT was symptom control. The use of RT did not increase grade 3/4 immune-related adverse events. The overall median PFS was 2.0 months (95% confidence interval, 1.3-2.6 months) and the median OS was 9.0 months (95% confidence interval, 6.4-9.5 months). There were no significant differences in median PFS (3.0 vs. 2.0 months; P = .515) and median OS (9.0 vs. 9.0 months; P = .917) in the patients who received RT versus those that did not.ConclusionsIn patients with metastatic NSCLC, the addition of RT to ICI was not associated with increased toxicity or improved survival.     

Comparison of Chemotherapy Plus Pembrolizumab vs. Chemotherapy Alone in EGFR-Mutant Non–small-Cell Lung Cancer Patients

IntroductionPlatinum doublet chemotherapy is the standard of care in patients with non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation who had disease progression after tyrosine kinase inhibitor (TKI). We aimed to assess immune checkpoint inhibitors efficacy in EGFR-mutant advanced NSCLC.Materials and MethodsWe retrospectively reviewed the data of sensitive EGFR-mutant NSCLC patients who progressed after EGFR-TKIs and received platinum doublet chemotherapy plus immunotherapy between 2015 and 2021. Efficacy outcomes, including overall response rate, progression-free survival, and overall survival, were assessed and compared with those of patients who had received platinum-based doublet chemotherapy.ResultsOf the total 869 patients, 82 treated with pembrolizumab and chemotherapy and 82 with only chemotherapy were selected. The median progression-free survival in patients administered pembrolizumab was significantly longer than those not administered pembrolizumab (6.7 months; 95% confidence interval [CI] 5.0-8.5 vs. 4.2 months; 95% CI 3.3-5.0, hazard ratio [HR] 0.64, 95% CI 0.46-0.89, P = .0076). Improved median overall survival was also observed in patients receiving pembrolizumab plus chemotherapy (26.7 [95% CI 22.6-30.8] vs. 13.4 months [95% CI 10.4-16.4], HR, 0.49 [95% CI 0.31-0.75], P = .0052). In addition, the overall response rate was higher in patients treated with than patients treated without pembrolizumab (34.1% and 20.7%, respectively).ConclusionThe combination of pembrolizumab with chemotherapy is associated with improved efficacy and survival in patients with EGFR-mutant NSCLC after TKI resistance, but these findings need to be confirmed in further prospective studies.     

Real-world Efficacy and Safety of Nivolumab for Advanced Non–Small-cell Lung Cancer: A Retrospective Multicenter Analysis

Background

Nivolumab, an immune checkpoint inhibitor, is now a standard treatment for previously treated advanced non–small-cell lung cancer based on the results from phase III clinical trials. We evaluated the real-world efficacy and safety of nivolumab in a nonselected population and identified the clinical characteristics that influence efficacy.

Angiogenic and Antiangiogenic VEGFA Splice Variants in Colorectal Cancer: Prospective Retrospective Cohort Study in Patients Treated With Irinotecan-Based Chemotherapy and Bevacizumab

BackgroundAlternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms.Patients and MethodsFormalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR.ResultsAt a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR = 2.62; 95% CI, 1.35-5.12; P = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor was associated with inferior PFS (HR = 1.28; 95% CI, 1.00-1.64), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR = 1.71; 95% CI, 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left-sided but unfavorable in patients with right-sided primary tumors (P_interaction < .001).ConclusionThe antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.     

Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer

BackgroundThe REAL-2 and ML17032 trials demonstrated that the oral fluoropyrimidine, capecitabine, is noninferior to 5-fluorouracil (5-FU) for overall survival (OS) and progression-free survival (PFS), respectively, in advanced oesophago-gastric cancer.MethodsIndividual patient data were collected on all patients randomised within the trials (n = 1318). Kaplan–Meier survival curves were generated and the log-rank test was used to compare OS and PFS between patients receiving 5-FU combinations and capecitabine combinations. Stepwise multivariate Cox regression analysis was used to calculate corrected hazard ratios (HRs) and 95% confidence intervals (CIs) for OS and PFS. Logistic regression was used for objective response rate. Forest plots with tests of heterogeneity were generated.ResultsOS was superior in the 654 patients treated with capecitabine combinations compared with the 664 patients treated with 5-FU combinations; HR 0.87 (95% CI 0.77–0.98, P = 0.02). Poor performance status, age <60 and metastatic disease were independent predictors of poor survival. There was no significant difference in PFS between treatment groups on multivariate analysis. Assessable patients treated with capecitabine combinations were significantly more likely to have an objective response to treatment than those treated with 5-FU combinations; odds ratio 1.38 (95% CI 1.10–1.73, P = 0.006).ConclusionOS is superior in patients treated with capecitabine combinations compared with 5-FU combinations in advanced oesophago-gastric cancer.     

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone to Prophylactic Cranial Irradiation and Consolidative Extracranial Irradiation for Extensive-Disease Small Cell Lung Cancer (ED SCLC): NRG Oncology RTOG 0937

IntroductionNRG Oncology RTOG 0937 is a randomized phase II trial evaluating 1-year overall survival (OS) with prophylactic cranial irradiation (PCI) or PCI plus consolidative radiation therapy (PCI+cRT) to intrathoracic disease and extracranial metastases for extensive-disease SCLC.MethodsPatients with one to four extracranial metastases were eligible after a complete response or partial response to chemotherapy. Randomization was to PCI or PCI+cRT to the thorax and metastases. Original stratification included partial response versus complete response after chemotherapy and one versus two to four metastases; age younger than 65 years versus 65 years or older was added after an observed imbalance. PCI consisted of 25 Gy in 10 fractions. cRT consisted of 45 Gy in 15 fractions. To detect an improvement in OS from 30% to 45% with a 34% hazard reduction (hazard ratio = 0.66) under a 0.1 type 1 error (one sided) and 80% power, 154 patients were required.ResultsA total of 97 patients were randomized between March 2010 and February 2015. Eleven patients were ineligible (nine in the PCI group and two in the PCI+cRT group), leaving 42 randomized to receive PCI and 44 to receive PCI+cRT. At planned interim analysis, the study crossed the futility boundary for OS and was closed before meeting the accrual target. Median follow-up was 9 months. The 1-year OS was not different between the groups: 60.1% (95% confidence interval [CI]: 41.2–74.7) for PCI and 50.8% (95% CI: 34.0–65.3) for PCI+cRT (p = 0.21). The 3- and 12-month rates of progression were 53.3% and 79.6% for PCI and 14.5% and 75% for PCI+cRT, respectively. Time to progression favored PCI+cRT (hazard ratio = 0.53, 95% CI: 0.32–0.87, p = 0.01). One patient in each arm had grade 4 therapy-related toxicity and one had grade 5 therapy-related pneumonitis with PCI+cRT.ConclusionsOS exceeded predictions for both arms. cRT delayed progression but did not improve 1-year OS.     

Role of Antiangiogenic Agents Combined With EGFR Tyrosine Kinase Inhibitors in Treatment-naive Lung Cancer: A Meta-Analysis

BackgroundAntiangiogenic agents combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered potentially effective biologically synergistic drug combinations for EGFR-mutant advanced non–small-cell lung cancer (NSCLC), although some controversy remains. The European Commission has approved the use of bevacizumab plus erlotinib as first-line treatment of EGFR-mutated NSCLC; however, it has not yet been approved by the U.S. Food and Drug Administration. Recently, several phase III, randomized controlled trials of combinations of antiangiogenic agents and EGFR-TKIs have been reported. These studies have not yet been included in any previous meta-analysis.Materials and MethodsWe performed a meta-analysis to compare antiangiogenic agents plus EGFR-TKIs versus EGFR-TKIs alone for treatment of EGFR-mutant NSCLC. The main outcomes were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), and adverse events (AEs).ResultsWe identified 9 previous reports of 6 randomized controlled trials and 1 prospective cohort study, involving 1295 patients. Compared with EGFR-TKIs alone, antiangiogenic agents plus EGFR-TKIs resulted in a higher PFS (hazard ratio, 0.58; 95% confidence interval [CI], 0.50-0.67; P < .001). However, no significant differences in OS (hazard ratio, 0.79; 95% CI, 0.53-1.18; P = .26) and ORR (risk ratio, 1.03; 95% CI, 0.97-1.10; P = .30) were found between the 2 groups. An increased risk of serious AEs (risk ratio, 1.41; 95% CI, 1.11-1.79; P = .005) was found in the combination drug therapy group.ConclusionsAntiangiogenic agents plus EGFR-TKIs enhanced PFS for patients with EGFR-mutant NSCLC but with a greater risk of serious AEs. No significant benefits for OS and ORR were found between the 2 groups.     

The Effects of Time to Treatment Initiation for Patients With Non–small-cell Lung Cancer in the United States

BackgroundThe purpose of this study was to determine the effects of time from diagnosis to treatment (TTI) on survival in patients with nonmetastatic non–small-cell lung cancer (NSCLC).Materials and MethodsThe National Cancer Database was queried for patients with stages 1 to 3 NSCLC between 2004 and 2013. Patients with missing survival status/time, unknown TTI, or receipt of palliative therapy were excluded. Multivariable Cox proportional hazards modeling, logistic regression, and recursive partitioning analysis were performed to determine associated variables and survival outcomes.ResultsAltogether, 1,393,232 patients met inclusion criteria. The median follow-up was 36 months. The median TTI increased between 2004 and 2013 from 35 to 39 days (P < .001). On multivariable Cox proportional hazards modeling, TTI groups 31 to 60 days, 61 to 90 days, and > 90 days were independently related to poorer overall survival (OS) compared with TTI 1 to 30 days (hazard ratio, 1.04, 1.10, and 1.14; 95% confidence interval [CI], 1.02-1.06, 1.07-1.12, and 1.11-1.17, respectively; P < .001 for all). Recursive partitioning analysis revealed that TTI of ≤ 45 days was the most optimal threshold for survival (P < .001); patients with TTI ≤ 45 days had a median OS of 70.2 months (95% CI, 69.3-71.1 months) versus 61.5 months (95% CI, 60.5-62.4) (P < .001). There were significant disparities by age, race, ethnicity, and income for delayed (> 45 days) TTI (P < .001 for all). Subgroup analysis revealed that stage 1 and 2 patients with TTI > 45 days had a higher risk of mortality compared with TTI ≤ 45 days (hazard ratio, 1.15 and 1.05; 95% CI, 1.12-1.17 and 1.01-1.09, respectively) (P < .001).ConclusionsIncreased TTI is independently associated with poorer survival in non-metastatic NSCLC. TTI ≤ 45 days is a clinically targetable time frame associated with improved outcomes and ought to be considered for patients with lung cancer undergoing definitive therapy.     

Prognostic Factors in the Radical Nonsurgical Treatment of Stage IIIB Non–Small-Cell Lung Cancer

BackgroundMany patients diagnosed with stage IIIB (AJCC sixth edition; T4, N3, or both; no pleural effusion) non–small-cell lung cancer (NSCLC) are treated with curative intent, despite a low cure rate. Guidelines are required to help select patients for radical therapy so that the patients with little chance of cure may be spared the toxicities of aggressive treatment. A retrospective analysis was performed to investigate factors influencing outcomes in these patients.Materials and MethodsFrom 2002 to 2009, all cases of stage IIIB NSCLC from the authors' institution were identified. Patients treated with radical radiotherapy (minimum dose, 50 Gy), with or without chemotherapy, were included. Charts were reviewed for patient demographic data, baseline blood work, tumor factors, treatment factors, and hospitalizations. The primary outcome was overall survival (OS), measured from time of diagnosis.ResultsOf 238 patients identified, 184 eligible cases were reviewed. The median follow-up for all patients was 17.2 months (range, 1.7-237.1). The median progression-free survival was 10.8 months (95% CI, 9.6-12.4). Median survival was 17.9 months, and OS was 68%, 42%, and 28% at 1, 2, and 3 years, respectively. In multivariate analysis, female gender (hazard ratio [HR], 0.58; 95% CI, 0.37-0.88; P = .0013), ≤ 5% weight loss (HR, 0.64; 95% CI, 0.43-0.93; P = .01), and absence of N3 disease (HR, 0.64; 95% CI, 0.42-0.96; P = .03) were associated with significantly longer survival.ConclusionOS was significantly longer in women, in patients with ≤ 5% weight loss, and in those without N3 disease. Good patient selection remains important in the radical treatment of stage IIIB NSCLC.     

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors

BackgroundRapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non–small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Materials and MethodsArchival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).ResultsFifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005).ConclusionsA low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.     

Carboplatin and Paclitaxel Plus ASA404 as First-Line Chemotherapy for Extensive-Stage Small-Cell Lung Cancer: A Multicenter Single Arm Phase II Trial (SAKK 15/08)

IntroductionSmall-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC.MethodsPatients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m²) plus ASA404 (1800 mg/m²) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks.ResultsMedian age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non–small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued.ConclusionsThis is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.