Platinum-based Doublet Chemotherapy Research Articles

P1.17-02 Low Prognostic Nutritional Index Predicts Poor Survival in Stage IIIB Non-Small Cell Lung Cancer Patients Treated with Chemoradiotherapy

The prognostic role of prognostic nutritional index (PNI) has been widely investigated and showed in many types of cancer. However, to our best knowledge, the significance of PNI has never been investigated in locally advanced non-small cell lung cancer (NSCLC) who were treated with concurrent chemoradiotherapy ( CCRT). Therefore in this current study, we aimed to investigate the prognostic impact of PNI on survival outcomes of locally advanced NSCLC undergoing CCRT. The data of 358 patients with stage IIIB NSCLC treated with CCRT were analyzed retrospectively. All patients received 60 to 66 Gy (2 Gy per fraction) thoracic radiotherapy and at least one course of platinum-based doublet chemotherapy concomitantly. For each patient PNI was calculated by the known formula in blood samples those were available prior to CCRT: [PNI=10×serum albumin (g/dl) + 0.005×total lymphocyte count (mm3)]. The primary endpoint was the association between PNI and overall survival (OS). Secondary endpoints were locoregional progression-free survival (LPFS) and progression-free survival (PFS). The survival curves were calculated by Kaplan-Meier method and log-rank test. The cutoff value of the PNI was analyzed by receiver operating curve (ROC). At a median follow-up of 22.5 months (2.4-123.5 months) 108 patients (30.2%) were still alive. For the whole study cohort median OS was 25.2 months (95 % CI: 22.7-27.7). The median LPFS and PFS were 15.4 months (95% CI: 14.4-16.4) and 10.7 months (95% CI: 9.7-11.7) respectively. In ROC analysis, calculated cutoff value of PNI was 40.1 (AUC: 67.8% (62.0-73.6); sensitivity: 73.1; specificity: 68.4, p<0.001). According to this, patients were grouped as follows, group 1: PNI>40 and group 2: PNI<40. Accordingly, for the patients in group 1, OS (36.7 vs. 16.8 months, p<0.001), LPFS (19.5 vs. 11.5 months, p<0.001) and PFS (13.6 vs. 8.6 months, p<0.001) times were significantly better as compared to patients in group 2. Results of the multivariate analysis demonstrated that the prognostic worth of PNI was independent of the other covariates (p<0.001, for each survival endpoints). Being the first of its kind study the result of this current investigation revealed that the PNI which is easy to calculate, easily achievable with no additional cost has a strong prognostic value in prognostic stratification of the stage IIIB NSCLC patients undergoing to CCRT.

Salvage Concurrent Chemo-radiation Therapy for Loco-regional Recurrence Following Curative Surgery of Non-small Cell Lung Cancer.

PurposeThis study is to report clinical outcomes of salvage concurrent chemo-radiation therapy (CCRT) in treating patients with loco-regional recurrence (LRR) following initial complete resection of non-small cell lung cancer.Materials and MethodsBetween February 2004 and December 2016, 127 patients underwent salvage CCRT for LRR. The median radiation therapy (RT) dose was 66 Gy and clinical target volume was to cover recurrent lesion with margin without elective inclusion of regional lymphatics. Majority of patients (94.5%) received weekly platinum-based doublet chemotherapy during RT course.ResultsThe median follow-up time from the start of CCRT was 25 months. The median survival duration was 49 months, and overall survival (OS) rates at 2 and 5 years were 72.9% and 43.9%. The 2- and 5-year rates of in-field failure-free survival, distant metastasis free survival, and progression free survival were 82.4% and 73.8%, 50.4% and 39.9%, and 34.6% and 22.3%, respectively. Grade ≥ 3 radiation-related esophagitis and pneumonitis occurred in 14 (11.0%) and six patients (4.7%), respectively. On both univariate and multivariate analysis, higher biologically equivalent dose (BED10) (≥ 79.2 Gy10 vs. < 79.2 Gy10; hazard ratio [HR], 0.431), smaller CTV (≤ 80 cm3 vs. > 80 cm3; HR, 0.403), and longer disease-free interval (> 1 year vs. ≤ 1 year; HR, 0.489) were significantly favorable factors for OS.ConclusionThe current study has demonstrated that high dose salvage CCRT focused to the involved lesion only was highly effective and safe. In particular, higher BED10, smaller CTV, and longer disease-free interval were favorable factors for improved survival.

Therapeutic efficacy and safety of Kang-ai injection combined with platinum-based doublet chemotherapy in advanced NSCLC: A meta-analysis

AimsKang-ai injection (KA) is a famous Chinese patent medicine authorized by China Food and Drug Administration, which is widely used to treat advanced non-small cell lung cancer (NSCLC) in China. This meta-analysis is aimed to evaluate the therapeutic efficacy and safety of KA on advanced NSCLC. MethodsSeven databases were examined for related studies until January 15, 2018. Odds ratio (OR) was used to evaluate tumor response, Karnofsky Performance Scale (KPS) improvement and adverse reactions, and mean difference (MD) was used to estimate immune functions. Key findingsThirty randomized controlled trials involving 1956 patients with advanced NSCLC were included. The results showed that compared with the platinum-based doublet chemotherapy (PBDC) alone, KA combined with PBDC could significantly enhance tumor response (OR = 1.69, 95% CI [1.40, 2.04], P < 0.00001), KPS improvement (OR = 3.01, 95% CI [2.36, 3.84], P < 0.00001) and immune functions including the percentages of CD3+ (MD = 8.90, 95% CI [3.06, 14.73], P = 0.003), CD4+ (MD = 9.43, 95% CI [6.32, 12.53], P < 0.00001) and NK (MD = 4.81, 95% CI [1.95, 7.68], P = 0.001) and the ratio of CD4+/CD8+ (MD = 0.29, 95% CI [0.04, 0.53], P = 0.02). Moreover, KA combined with PBDC markedly decreased the incidences of adverse reactions including gastrointestinal reaction (OR = 0.38, 95% CI [0.30, 0.47], P < 0.00001), myelosuppression (OR = 0.32, 95% CI [0.23, 0.45], P < 0.00001) and hair loss (OR = 0.53, 95% CI [0.36, 0.76], P < 0.00001). However, there was no significant difference between the combination treatment group and the control group in the percentage of CD8+ (MD = −2.93, 95% CI [−6.68, 0.82], P = 0.13). SignificanceDespite the small sample size and study limitations, the results of this meta-analysis indicated that the combination therapy of KA and PBDC (especially NP regimen) might be a beneficial therapeutic method for advanced NSCLC patients.

Long-term survival follow-up of atezolizumab in combination with platinum-based doublet chemotherapy in patients with advanced non–small-cell lung cancer

BackgroundBefore the availability of immunotherapy, chemotherapy was standard first-line therapy for non–small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 (NCT01633970) assessed atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naïve NSCLC. MethodsPatients received atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four–six cycles, then atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). ResultsSeventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2–8.3), 8.4 months (95% CI: 4.7–11) and 5.7 months (95% CI: 4.4–14.8), respectively. Median OS was 12.9 months (95% CI: 8.8–21.3), 18.9 months (95% CI: 9.9–27.4) and 17.0 months (95% CI: 12.7–not evaluable), respectively. ConclusionAtezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. ClinicalTrials.gov identifierNCT01633970.

Metastatic Gastric cancer: Real world scenario from a developing country.

Aim:Data on epidemiology and outcome in metastatic stomach carcinoma patients from India are scarce. We aimed to evaluate clinical features and treatment outcome in patients treated at our center.Materials and Methods:This is a single institutional review of metastatic gastric carcinoma patients treated between May 2011 and October 2016. Patients who received at least one cycle of chemotherapy were included for modified intent-to-treat survival analysis.Results:total of 143 patients were diagnosed with metastatic stomach carcinoma with a median age of 56 years (range: 29–86). The most common symptoms were abdominal pain in 112 (78%) patients. The most common site was body in 81 (57%) patients. Common site of metastasis was peritoneum in 86 (60%) and liver in (62%). Seventy-one (50%) patients were eligible for survival analysis. Common chemotherapy regimens were capecitabine-cisplatin in 27 (38%) and EOX in 22 (31%) patients. Survival status could not be assessed in 29 (41%) patients who lost to follow-up. After a median follow-up 9.7 months (range: 0.5–37.7), median progression-free survival (PFS) was 7.9 months (range: 0.5–23.9) and median overall survival (OS) was 12.2 months (range: 0.5–37.7). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 and the presence of linitis plastica showed a trend toward inferior PFS (P = 0.052 and 0.053, respectively) only in univariate analysis. Female sex and ECOG PS ≥2 predicted inferior OS in both univariate and multivariate analysis (P = 0.012, 0.02 and 0.03 and 0.05, respectively).Conclusions:Platinum-based doublet chemotherapy was used in the majority of patients. The overall outcome was comparable to that of the available literature. Female sex and ECOG PS ≥2 predicted the inferior outcome.

Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer

BackgroundBavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β2 glycoprotein 1 (β2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methodsKey eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). ResultsA total of 597 patients were enrolled. Median OS was 10.5months in the docetaxel+bavituximab arm and was 10.9months in the docetaxel+placebo arm (HR 1.06; 95% CI 0.88–1.29; P=0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82–1.22; P=0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels≥200µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63–1.06; P=0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26–0.81; P=0.006). ConclusionsThe combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial numberNCT01999673.

Erratum to factors associated with the prognosis and long-term survival of patients with metastatic lung adenocarcinoma: a retrospective analysis.

[This corrects the article DOI: 10.21037/jtd.2018.03.143.].

Abstract 2604: PD-L1 rs2282055 is associated with opposite treatment effect between platinum-based chemotherapy and nivolumab treatment

Abstract Treatment of lung cancer is improved recently, especially immune-check point inhibitors prolong progression-free survival (PFS) and overall survival (OS), however, Lung cancer is still leading cause of death worldwide. This is because of response rates in the treatment of non-small cell lung cancer (NSCLC) with combination platinum-based chemotherapy vary from 20% to 40%, and response rates of the treatment of NSCLC with nivolumab is around 20%, whereas with leaving a large number of patients with either stable or progressive disease. It is currently difficult to predict treatment response to chemotherapy and nivolumab since there are no precise biomarkers for it. Recently, we have reported that PD-L1 single nucleotide polymorphisms (SNPs) are associated with response to nivolumab treatment. This study was intended to determine the efficacy of platinum-based combination chemotherapy either in a doublet or triplet, and nivolumab treatment respect to PD-L1 SNPs among patients with NSCLC. A total of 139 patients with NSCLC were treated with platinum-based doublet or triplet chemotherapy, 73 patients treated with nivolumab and were also evaluated for PD-L1 SNPs from plasma DNA. We investigated the association among PD-L1 SNPs, objective response rate (ORR) and PFS. PD-L1 rs2282055 was associated with ORR and PFS in the patients treated with pulatinum-based chemotherapy and nivolumab. In the patients treated with nivolumab, the ORR was 24%, 12%, and 0% for the G/G, G/T and T/T genotypes of PD-L1 rs2282055, respectively. The G allele of PD-L1 rs2282055 was significantly associated with better clinical response compared with the T allele (P = 0.0056 [Cochran-Armitage trend test]). The median PFS time was 2.1 months (95% confidence interval [CI], 1.8 months to 3.9 months) for the G/G and G/T genotypes and 2.2 months (95% confidence interval [CI], 0.9 months to 2.6 months) for the T/T genotype (P = 0.0210). On the other hand, The T allele of PD-L1 rs2282055 was significantly associated with better clinical response compared with the G allele in the patients treated with platinum-based combination chemotherapy either in a doublet or triplet (P = 0.0080 [Cochran-Armitage trend test]). The median PFS time was 11.0 months (95% confidence interval [CI], 6.2 months to 16.3 months) for the T/T genotypes and 7.3 months (95% confidence interval [CI], 6.0 months to 8.2 months) for the G/T and G/G genotype (P = 0.0284). In conclusion, these results suggest that the T/T genotype of PD-L1 SNP rs2282055 associated with the better treatment effect of platinum-based combination chemotherapy, on the contrary, the T/T of rs2282055 negatively associated with response to nivolumab treatment. It might be used as a biomaker for selection of the regimen of NSCLC treatment. Citation Format: Takashi Nomizo, Hiroaki Ozasa, Takahiro Tsuji, Tomoko Funazo, Yuto Yasuda, Hironori Yoshida, Yuichi Sakamori, Toyohiro Hirai, Yong Hak Kim. PD-L1 rs2282055 is associated with opposite treatment effect between platinum-based chemotherapy and nivolumab treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2604.

New PDL1 inhibitors for non-small cell lung cancer: focus on pembrolizumab.

The advent of immune-checkpoint inhibitors during the past decade represents a major advancement in the treatment of non-small cell lung cancer (NSCLC) with personalized treatment. Platinum-based chemotherapy has reached its efficacy threshold, with its use remaining limited by its toxicity. For NSCLC, inhibitors of the PD1 protein and its ligand PDL1 show promising clinical activity and induce durable responses in patients with advanced disease. The US Food and Drug Administration has approved pembrolizumab for treatment-naïve metastatic NSCLC with ≥50% of tumor cells expressing PDL1 and for metastatic NSCLC with ≥1% PDL1 expression after progression following first-line platinum-based doublet chemotherapy. In 2017, it also authorized the first-line combination of pembrolizumab and carboplatin–pemetrexed chemotherapy without selection based on PDL1 expression, but European health authorities are still waiting for the results of a Phase III trial. In this review, the clinical results of published and ongoing studies evaluating pembrolizumab for advanced NSCLC are analyzed and the potential role of PDL1 as a factor predictive of overall responses addressed.

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study

BackgroundThis is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methodsALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). ResultsAltogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9–12.2] with alectinib and 1.4 months (95% CI: 1.3–1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08–0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17–0.59); median PFS was 7.1 months (95% CI: 6.3–10.8) with alectinib and 1.6 months (95% CI: 1.3–4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks). ConclusionAlectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registrationClinicalTrials.gov NCT02604342; Roche study MO29750

Do older patients with non-small cell lung cancer also benefit from first-line platinum-based doublet chemotherapy? Observations from a pooled analysis of 730 prospectively-treated patients (Alliance Study A151622).

This study sought to define the role of first-line platinum-based doublet chemotherapy in older patients with non-small cell lung cancer (NSCLC). We analyzed three first-line NSCLC trials: CALGB 9730, CALGB 30203, and CALGB 30801, which tested carboplatin and paclitaxel; carboplatin and gemcitabine; and carboplatin with either pemetrexed or gemcitabine, respectively. Overall survival was the primary endpoint. Age-based comparisons with a cutpoint of 65 years were performed with Cox proportional hazards models with adjustments for sex, tumor histology, cancer stage, chemotherapy, and smoking history and after stratifying by performance score. Secondary endpoints were grade 3-5 adverse events, chemotherapy cycles completed, and whether toxicity prompted chemotherapy discontinuation. 730 patients were included; 337 (46%) were 65+ years of age. No statistically significant difference in survival was observed for older (≥65) versus younger patients (HR = 1.096; 95% CI = (0.94, 1.28); p = 0.25). A trend emerged with increased odds of a grade 3-5 adverse event for patients ≥65 years versus <65 years (OR = 1.52; 95% CI = (0.99, 2.31); p = 0.05). The proportion of completed chemotherapy cycles was marginally lower in older patients (difference = -5%; 95% CI = (-9, 0.2); p = 0.06) for those ≥65 years versus <65 years, but no statistically significant difference occurred in the rate of chemotherapy discontinuation for toxicity (OR = 1.4; 95% CI = (0.85, 2.19); p = 0.21) for patients ≥65 years versus <65 years. A cutpoint of 70 years yielded similar results. These findings support carboplatin doublet-based chemotherapy in select older patients with advanced NSCLC.

Role of Poly Adenosine Diphosphate Ribose Polymerase Inhibitors in Advanced Stage Ovarian Cancer

Ovarian cancer is one of the leading causes of death from gynecologic cancers. In this present era of cancer treatment, therapeutic options for patients with advanced or recurrent ovarian cancer are limited. The present standard of care treatment for advanced ovarian cancer is a platinum-based doublet chemotherapy (paclitaxel and carboplatin with or without bevacizumab) after a maximum attempt of surgical cytoreduction. However, there are no promising options for the management of patients with ovarian cancer refractory to the platinum-based chemotherapy. Therefore, newer, safe, and more effective treatment modalities are required for patients with advanced or recurrent ovarian cancer. Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors have shown an impressive safety profile and anti-tumor efficacy in patients with breast cancer 1 and 2 (BRCA1 and BRCA2) gene-mutated ovarian cancer who were previously treated with the standard of care chemotherapy. We have done a detailed review of the literature to emphasize the role of PARP inhibitors in the treatment of advanced or relapsed ovarian cancer.

Comparative effectiveness study of first-line pemetrexed-platinum doublet chemotherapy with or without bevacizumab for Chinese patients with advanced non-squamous non-small-cell lung cancer.

e21053Background: Bevacizumab plus platinum-based doublet chemotherapy is recommended by NCCN as a category 1 regimen and is widely used for advanced NS-NSCLC. In China, one of the most common firs...

Incidence and Impact of Pretreatment Tumor Cavitation on Survival Outcomes of Stage III Squamous Cell Lung Cancer Patients Treated With Radical Concurrent Chemoradiation Therapy

To investigate the incidence and influence of tumor cavitation (TC) on survival outcomes of locally advanced squamous cell lung cancer (LA-SqCLC) patients treated with concurrent chemoradiation therapy (C-CRT). Records of 789 stages IIIA/B squamous cell lung cancer (SqCLC) patients treated with C-CRT who received 1 to 3 cycles of platinum-based doublet chemotherapy during 60 to 66Gy radiation therapy (RT) were analyzed retrospectively. Primary endpoint was the association between overall survival (OS) and pretreatment TC status. Secondary endpoints included locoregional progression-free survival (LRPFS), progression-free survival (PFS), and incidence of TC and correlated factors. Pretreatment TC occurred in 95 patients (12%), being significantly more common in those patients with ever-smoking history (12.6% vs 3.9%; P<.001), weight loss >5% (20.9% vs 7.1%; P<.001), and hemoptysis (27.1% vs 6.4%; P<.001). Rates of acute and late toxicities were similar in patients who presented with and without TC (P>.05 for each). For the whole cohort, at a median follow-up of 22.9months (range: 2.4-71.1), the respective median OS, LRPFS, and PFS estimates were 23.7, 14.7, and 10.7months. In multivariate analysis, stage IIIB disease (P<.001; hazard ratio [HR]: 1.33; 95% CI: 1.21-1.45), weight loss >5% (P<.001; HR: 2.10; 95% CI: 1.85-2.35), anemia (P<.001; HR: 1.82; 95% CI: 1.67-1.97), and presence of TC (P<.001; HR: 1.54; 95% CI: 1.37-1.71) appeared to be independently associated with poorer OS durations, likewise the LRPFS (P<.001 for each of these covariates), and PFS (P<.001 for each of these covariates), respectively. Present results showed that the TC occurred in 12% of LA-SqCLC patients, which was strongly associated with poorer PFS, LRPFS, and OS outcomes after definitive C-CRT.

Chemoradiotherapy-induced hemoglobin nadir values and survival in patients with stage III non-small cell lung cancer

PurposeWe investigated the influence of change in hemoglobin (Hgb) levels during concurrent chemoradiotherapy (C-CRT) on outcomes of non-anemic patients with stage IIIA/B non-small cell lung cancer (NSCLC). MethodsWe identified 722 patients with stage IIIA/B NSCLC without anemia at baseline [hemoglobin (Hgb) <12 g/dL for women or <13 g/dL for men], either nonsmokers or ex-smokers, who received C-CRT between 2007 and 2012. All patients had received 1−3 cycles of platinum-based doublet chemotherapy during radiotherapy to 60−66 Gy and had documented Hgb measurements before treatment and at weekly intervals for 6 weeks during the C-CRT. Potential associations were assessed between baseline, nadir, extent of change in Hgb level, and anemia and overall survival (OS), locoregional progression-free survival (LRPFS), and PFS. ResultsThe median baseline Hgb level was 13.9 g/dL (range 12.0–16.8) and declined to a median 12.4 g/dL (range 7.9–16.1) during treatment. Anemia appeared in 237 patients (32.8%) and was more common among women (44.8% vs. 26.5%, P < 0.001). Neither baseline Hgb level nor change during treatment nor anemia emergence influenced any survival endpoint. Receiver operating curve analysis revealed an Hgb nadir of 11.1 g/dL to be associated with outcomes, in that a nadir Hgb <11.1 g/dL (in 156 patients) was linked with shorter median OS time (P < 0.001), LRPFS time (P < 0.001), and PFS time (P < 0.001); retained significance for all three endpoints in multivariate analyses; and was more strongly associated with OS in squamous cell carcinoma (P < 0.001) than in adenocarcinoma (P = 0.009). ConclusionNadir Hgb <11.1 g/dL levels during C-CRT were associated with significantly poorer survival times in initially non-anemic patients presenting with locally advanced NSCLC.

Factors associated with the prognosis and long-term survival of patients with metastatic lung adenocarcinoma: a retrospective analysis.

Outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based doublet chemotherapy is usually poor, with overall survival ranges from 8-13 months. However, the overall survival is improved to 21-28 months in the era of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This study aimed to explore the prognostic factors to predict long-term survival in the era of EGFR TKI. A total 1,030 patients were studied who had been diagnosed with metastatic adenocarcinoma of lung from January 2005 to December 2009 at Linkou Chang Gung Memorial Hospital. Long-term survivors (LTS) were defined as patients who survived five years or more after the initial diagnosis of stage IV disease. Data on patient age, gender, smoking status, performance status at diagnosis, TNM stage, metastatic pattern, number of metastases, and organs with tumor involvement, EGFR gene mutation status, types of treatment received, EGFR TKI treatment and longest EGFR TKI duration were retrospectively obtained from medical charts. We calculated the odds ratio (OR) of long-term survival from collected clinical parameters to predict long-term survival. In this large retrospective study, we reported a five-year survival of 5.0% among patients with metastatic adenocarcinoma of lung. A total 52 LTS and 978 non-LTS were identified. Patients had more contralateral or pleural/pericardial metastases in the LTS group than in the non-LTS group (51.9% vs. 19.0%, P<0.001), while less extrathoracic spread than in the non-LTS group (42.3% vs. 79.6%, P<0.001). The mutation of the EGFR gene was more frequent in the LTS group than in the non-LTS group (19.2% vs. 7.1%, P=0.006). In conclusion, our results suggest that an age younger than 60 years, absence of extrathoracic spread and EGFR TKI treatment duration of more than one year play an important role in the long-term for survivors who survive for more than 5 years.

Feasibility Study of Sequentially Alternating EGFR-TKIs and Chemotherapy for Patients with Non-small Cell Lung Cancer

The purpose of this trial was to evaluate the feasibility and efficacy of alternating platinum-based doublet chemotherapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Chemotherapy-naive patients with advanced NSCLC harboring an EGFR mutation were enrolled. All patients underwent induction chemotherapy by sequentially alternating pemetrexed/cisplatin/bevacizumab and EGFR-TKIs followed by maintenance therapy with pemetrexed/bevacizumab and EGFR-TKIs. The primary outcome was the completion rate of the induction therapy. Eighteen eligible patients were enrolled between May 2011 and March 2016. The completion rate of induction therapy was 72.2% (13/18). Unfortunately, one patient developed grade 4 acute renal injury, but no other serious complications concerning this protocol were observed. Furthermore, diarrhea, rashes, and hematological adverse effects were mild. The completion rate of induction therapy was promising. Alternating chemotherapy and EGFR-TKIs should be further investigated regarding feasibility and efficacy.

Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations

BackgroundThe North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events.Patients and methodsProgression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80).ResultsAt the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report.ConclusionsThis updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice.Trial registration numberUMIN C000002789, Post-results.

PACIFIC trial: new perspectives for immunotherapy in lung cancer

Lung cancer still represents the most frequent cause of cancer-related mortality worldwide and 85% of all lung neoplastic disease are classified as non-small-cell lung cancer (NSCLC) (1); approximately one third of NSCLC are locally advanced disease at diagnosis (2). Actually, the standard-of-care for unresectable or inoperable stage IIIA and IIIB disease for patients with good performance status consists of platinum-based doublet chemotherapy (CT) concurrent with 60 Gy of radiotherapy (RT) administered daily over 6 weeks followed by possible further two cycles of consolidative CT (2). The supportive evidence for the use of concomitant chemoradiotherapy (CT/RT) is rooted in many clinical trials, with evidence of better results of concurrent CT/RT compared to either modality of administration of CT and RT, alone or sequential (3). The 5-year overall survival (OS) rate is 15–35% for stage IIIA and 5–10% for stage IIIB (4). Although survival outcomes are poor, notable is that a subset of the patients are potentially curable.

CheckMate 648: A randomized phase 3 study of nivolumab plus ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus cisplatin in patients with unresectable advanced, recurrent, or metastatic previously untreated esophageal squamous cell carcinoma.

TPS193 Background: Esophageal cancer (EC) is the sixth most common cause of cancer-related death worldwide, with a 5-y survival rate of 5%–8% in pts with metastatic disease. First–line platinum-based doublet chemotherapy (CTX) provides a modest survival benefit in pts with metastatic squamous cell EC (mESCC), with a median OS of 7.6 months. Over 40% of pts with EC have PD-L1+ tumors, which are associated with worse OS outcomes. Nivolumab (NIVO), an anti–PD-1 mAb, demonstrated efficacy and a manageable safety profile in pts with ESCC. In the phase 2 ATTRACTION-1 trial, NIVO 3 mg/kg produced an ORR of 17% and median OS of 10.8 months in heavily pretreated pts with ESCC (Kudo T et al Lancet Oncol 2017). NIVO + ipilimumab (IPI) yielded enhanced responses with a manageable safety profile in multiple tumor types. Similarly, NIVO + platinum-based CTX resulted in encouraging clinical activity and an acceptable safety profile in pts with metastatic gastric cancer and SCC NSCLC. This randomized phase 3 study will evaluate the efficacy and safety of NIVO + IPI or NIVO + fluorouracil (5-FU)/cisplatin (Cis) vs 5-FU/Cis as first-line treatment (Tx) in pts with advanced (adv) or mESCC (CheckMate 648; NCT03143153). Methods: 939 pts aged ≥ 18 y with histologically confirmed unresectable advanced, recurrent or mESCC, not amenable to curative approaches, and no prior systemic therapy for advanced/metastatic disease, with adequate organ function and ECOG PS 0 or 1 will be randomized 1:1:1 to NIVO + IPI, NIVO + 5-FU/Cis or 5-FU/Cis. Pts with autoimmune diseases, serious or uncontrolled medical disorders; active infections or positive for HIV, AIDS, or hepatitis B/C, indicating acute or chronic infection and/or detectable virus; and previous Tx with other therapy targeting T-cell co-stimulation or immune checkpoint pathways are excluded. Primary endpoints are OS and PFS by central assessment in pts with a PD-L1+ tumor (defined as PD-L1 expression on ≥ 1% of tumor cells). Secondary endpoints include ORR, PFS, and OS in all pts, as well as ORR in pts with PD-L1+ tumors. Clinical trial information: NCT03143153.